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Handa T, Saha A, Narayanan A, Ronzier E, Kumar P, Singla J, Tomar S. Structural Virology: The Key Determinants in Development of Antiviral Therapeutics. Viruses 2025; 17:417. [PMID: 40143346 PMCID: PMC11945554 DOI: 10.3390/v17030417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
Structural virology has emerged as the foundation for the development of effective antiviral therapeutics. It is pivotal in providing crucial insights into the three-dimensional frame of viruses and viral proteins at atomic-level or near-atomic-level resolution. Structure-based assessment of viral components, including capsids, envelope proteins, replication machinery, and host interaction interfaces, is instrumental in unraveling the multiplex mechanisms of viral infection, replication, and pathogenesis. The structural elucidation of viral enzymes, including proteases, polymerases, and integrases, has been essential in combating viruses like HIV-1 and HIV-2, SARS-CoV-2, and influenza. Techniques including X-ray crystallography, Nuclear Magnetic Resonance spectroscopy, Cryo-electron Microscopy, and Cryo-electron Tomography have revolutionized the field of virology and significantly aided in the discovery of antiviral therapeutics. The ubiquity of chronic viral infections, along with the emergence and reemergence of new viral threats necessitate the development of novel antiviral strategies and agents, while the extensive structural diversity of viruses and their high mutation rates further underscore the critical need for structural analysis of viral proteins to aid antiviral development. This review highlights the significance of structure-based investigations for bridging the gap between structure and function, thus facilitating the development of effective antiviral therapeutics, vaccines, and antibodies for tackling emerging viral threats.
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Affiliation(s)
- Tanuj Handa
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247667, India; (T.H.); (A.S.); (P.K.); (J.S.)
| | - Ankita Saha
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247667, India; (T.H.); (A.S.); (P.K.); (J.S.)
| | - Aarthi Narayanan
- Department of Biology, College of Science, George Mason University, Fairfax, VA 22030, USA;
| | - Elsa Ronzier
- Biomedical Research Laboratory, Institute for Biohealth Innovation, George Mason University, Fairfax, VA 22030, USA;
| | - Pravindra Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247667, India; (T.H.); (A.S.); (P.K.); (J.S.)
| | - Jitin Singla
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247667, India; (T.H.); (A.S.); (P.K.); (J.S.)
| | - Shailly Tomar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee 247667, India; (T.H.); (A.S.); (P.K.); (J.S.)
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Frick DN, Bavisotto RV, Hopper NC, Tysoe WT. Analogs of NIH Molecular Probe ML283 Are Potent SARS-CoV-2 Helicase Inhibitors. ACS Chem Biol 2025; 20:281-296. [PMID: 39910979 DOI: 10.1021/acschembio.4c00458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
The National Institutes of Health molecular probe ML283 was synthesized as a potent, selective inhibitor of the helicase encoded by the hepatitis C virus. Because modeling with AutoDock Vina predicted that ML283 might bind the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nonstructural protein 13 (nsp13) helicase, the effects of a collection of ML283 analogs and other hepatitis C virus (HCV) helicase inhibitors on the SARS-CoV-2 helicase were analyzed. Only modest impacts on nsp13-catalyzed ATP hydrolyses were observed with some compounds, most of which were analogs of the drug ebselen, not ML283. In contrast, a new molecular-beacon-based helicase assay revealed that ML283 and many ML283 analogs are potent SARS-CoV-2 helicase inhibitors. Analog potencies correlate with the binding energies predicted by modeling, which suggests that a pocket surrounded by the carboxy-terminal nsp13 RecA-like helicase motor domain might be exploitable for antiviral drug development.
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Affiliation(s)
- David N Frick
- Department of Chemistry & Biochemistry, The University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53217, United States
| | - Robert V Bavisotto
- Department of Chemistry & Biochemistry, The University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53217, United States
| | - Nicholas C Hopper
- Department of Chemistry & Biochemistry, The University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53217, United States
| | - Wilfred T Tysoe
- Department of Chemistry & Biochemistry, The University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53217, United States
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Vargas-Ruiz A, Araiza-Hernández DM, González-Díaz FR, Marín-Flamand E, Sánchez Betancourt JI, Sánchez-Mendoza AE, García-Camacho LA. Phylogenetic analysis and molecular structure of NS1 proteins of porcine parvovirus 5 isolates from Mexico. Arch Virol 2025; 170:40. [PMID: 39856382 PMCID: PMC11761469 DOI: 10.1007/s00705-024-06182-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 10/03/2024] [Indexed: 01/27/2025]
Abstract
Porcine parvovirus 5 (PPV5) is an unclassified member of the family Parvoviridae with no reported pathogenicity, although it is associated with multisystemic, reproductive, and respiratory diseases. Its open reading frame 1 (ORF1) encodes non-structural protein 1 (NS1), which is predicted to have helicase activity that is essential for viral replication. This protein contains a C-motif with an invariant asparagine residue that forms the core of the enzyme's active site, in conjunction with the Walker A and B motifs. The aim of this study was the phylogenetic and molecular characterization of the NS1 of PPV5 through nested PCR and sequencing of three Mexican PPV5-positive samples. Subsequently, a phylogenetic tree, identity matrices of nucleotide and amino acid sequences, and a three-dimensional model of NS1 were constructed. The amplified sequences, which represented 96.9% of the PPV5 ORF1, occupied the same branch in the phylogenetic tree and exhibited the most nucleotide sequence similarity to the corresponding region of PPV4 and the most amino acid sequence similarity to the NS1 proteins of PPV4 and PPV6. A three-dimensional model of NS1 displayed a C-motif characteristic of superfamily 3 (SF3) helicases. The phylogenetic proximity of PPV5 to PPV4 and PPV6 suggests that it may belong to the genus Copiparvovirus. Further studies on helicases from viruses infecting domestic animals may be useful in developing antiviral drugs for both human and veterinary medicine.
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Affiliation(s)
- Alejandro Vargas-Ruiz
- Facultad de Estudios Superiores Cuautitlán, Departamento de Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Carretera Cuautitlán-Teoloyucan Km 2.5, Cuautitlán Izcalli, 54714, Estado de México, México
| | - Diana Michele Araiza-Hernández
- Facultad de Estudios Superiores Cuautitlán, Departamento de Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Carretera Cuautitlán-Teoloyucan Km 2.5, Cuautitlán Izcalli, 54714, Estado de México, México
| | - Francisco Rodolfo González-Díaz
- Facultad de Estudios Superiores Cuautitlán, Unidad de Investigación Multidisciplinaria, Universidad Nacional Autónoma de México (UNAM), Estado de México, México
| | - Ernesto Marín-Flamand
- Facultad de Estudios Superiores Cuautitlán, Departamento de Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Carretera Cuautitlán-Teoloyucan Km 2.5, Cuautitlán Izcalli, 54714, Estado de México, México
| | - José Ivan Sánchez Betancourt
- Grupo de Investigación del Departamento de Medicina y Zootecnia de Cerdos, Facultad de Medicina y Zootecnia, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Ana Elvia Sánchez-Mendoza
- Facultad de Estudios Superiores Cuautitlán, Departamento de Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Carretera Cuautitlán-Teoloyucan Km 2.5, Cuautitlán Izcalli, 54714, Estado de México, México
| | - Lucia Angélica García-Camacho
- Facultad de Estudios Superiores Cuautitlán, Departamento de Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Carretera Cuautitlán-Teoloyucan Km 2.5, Cuautitlán Izcalli, 54714, Estado de México, México.
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Kelly B, Boudreau JE, Beyea S, Brewer K. Molecular imaging of viral pathogenesis and opportunities for the future. NPJ IMAGING 2025; 3:3. [PMID: 39872292 PMCID: PMC11761071 DOI: 10.1038/s44303-024-00056-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 10/24/2024] [Indexed: 01/30/2025]
Abstract
Molecular imaging is used in clinical and research settings. Since tools to study viral pathogenesis longitudinally and systemically are limited, molecular imaging is an attractive and largely unexplored tool. This review discusses molecular imaging probes and techniques for studying viruses, particularly those currently used in oncology that are applicable to virology. Expanding the repertoire of probes to better detect viral disease may make imaging even more valuable in (pre-)clinical settings.
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Affiliation(s)
- Brianna Kelly
- Biomedical MRI Research Laboratory (BMRL), IWK Health Centre, Halifax, NS Canada
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS Canada
| | - Jeanette E. Boudreau
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS Canada
- Department of Pathology, Dalhousie University, Halifax, NS Canada
- Beatrice Hunter Cancer Research Institute (BHCRI), Halifax, NS Canada
| | - Steven Beyea
- IWK Health Centre, Halifax, NS Canada
- Department of Diagnostic Radiology, Dalhousie University, Halifax, NS Canada
- School of Biomedical Engineering, Dalhousie University, Halifax, NS Canada
- Department of Physics & Atmospheric Science, Dalhousie University, Halifax, NS Canada
| | - Kimberly Brewer
- Biomedical MRI Research Laboratory (BMRL), IWK Health Centre, Halifax, NS Canada
- Department of Microbiology & Immunology, Dalhousie University, Halifax, NS Canada
- IWK Health Centre, Halifax, NS Canada
- Department of Diagnostic Radiology, Dalhousie University, Halifax, NS Canada
- School of Biomedical Engineering, Dalhousie University, Halifax, NS Canada
- Department of Physics & Atmospheric Science, Dalhousie University, Halifax, NS Canada
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Murithi A, Panangipalli G, Wen Z, Olsen MS, Lübberstedt T, Dhugga KS, Jung M. Global Transcriptomic Analysis of Inbred Lines Reveal Candidate Genes for Response to Maize Lethal Necrosis. PLANTS (BASEL, SWITZERLAND) 2025; 14:295. [PMID: 39861649 PMCID: PMC11768128 DOI: 10.3390/plants14020295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/10/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025]
Abstract
Maize lethal necrosis (MLN) is a significant threat to food security in Sub-Saharan Africa (SSA), with limited commercial inbred lines displaying tolerance. This study analyzed the transcriptomes of four commercially used maize inbred lines and a non-adapted inbred line, all with varying response levels to MLN. RNA-Seq revealed differentially expressed genes in response to infection by maize chlorotic mottle virus (MCMV) and sugarcane mosaic virus (SCMV), the causative agents of MLN. Key findings included the identification of components of the plant innate immune system, such as differentially regulated R genes (mainly LRRs), and activation/deactivation of virus resistance pathways, including RNA interference (RNAi) via Argonaute (AGO), Dicer-like proteins, and the ubiquitin-proteasome system (UPS) via RING/U-box and ubiquitin ligases. Genes associated with redox signaling, WRKY transcription factors, and cell modification were also differentially expressed. Additionally, the expression of translation initiation and elongation factors, eIF4E and eIF4G, correlated with the presence of MLN viruses. These findings provide valuable insights into the molecular mechanisms of MLN resistance and highlight potential gene candidates for engineering or selecting MLN-resistant maize germplasm for SSA.
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Affiliation(s)
- Ann Murithi
- Corteva Agriscience, 7000 NW 62nd Ave, Johnston, IA 50131, USA; (G.P.); (M.J.)
- International Maize and Wheat Improvement Center (CIMMYT), Carretera México-Veracruz, Km. 45, Texcoco 56237, Mexico; (Z.W.); (K.S.D.)
- Genetics and Genomics Graduate Program, Iowa State University, 2014 Molecular Building, 2437 Pammel Dr., Ames, IA 5001, USA
| | | | - Zhengyu Wen
- International Maize and Wheat Improvement Center (CIMMYT), Carretera México-Veracruz, Km. 45, Texcoco 56237, Mexico; (Z.W.); (K.S.D.)
- Keygene, Inc., 9600 Gudelsky Dr., Rockville, MD 20850, USA
| | - Michael S. Olsen
- Bayer, Crop Science Division, 800 N. Lindbergh Blvd., St. Louis, MO 63167, USA;
| | - Thomas Lübberstedt
- Department of Agronomy, Iowa State University, 716 Farm House Lane, Ames, IA 50011, USA;
| | - Kanwarpal S. Dhugga
- International Maize and Wheat Improvement Center (CIMMYT), Carretera México-Veracruz, Km. 45, Texcoco 56237, Mexico; (Z.W.); (K.S.D.)
| | - Mark Jung
- Corteva Agriscience, 7000 NW 62nd Ave, Johnston, IA 50131, USA; (G.P.); (M.J.)
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Becchimanzi A, De Leva G, Mattossovich R, Camerini S, Casella M, Jesu G, Di Lelio I, Di Giorgi S, de Miranda JR, Valenti A, Gigliotti S, Pennacchio F. Deformed wing virus coopts the host arginine kinase to enhance its fitness in honey bees (Apis mellifera). BMC Biol 2025; 23:12. [PMID: 39800727 PMCID: PMC11727705 DOI: 10.1186/s12915-025-02117-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Deformed wing virus (DWV) is a major honey bee pathogen that is actively transmitted by the parasitic mite Varroa destructor and plays a primary role in Apis mellifera winter colony losses. Despite intense investigation on this pollinator, which has a unique environmental and economic importance, the mechanisms underlying the molecular interactions between DWV and honey bees are still poorly understood. Here, we report on a group of honey bee proteins, identified by mass spectrometry, that specifically co-immunoprecipitate with DWV virus particles. RESULTS Most of the proteins identified are involved in fundamental metabolic pathways. Among the co-immunoprecipitated proteins, one of the most interesting was arginine kinase (ArgK), a conserved protein playing multiple roles both in physiological and pathological processes and stress response in general. Here, we investigated in more detail the relationship between DWV and this protein. We found that argK RNA level positively correlates with DWV load in field-collected honey bee larvae and adults and significantly increases in adults upon DWV injection in controlled laboratory conditions, indicating that the argK gene was upregulated by DWV infection. Silencing argK gene expression in vitro, using RNAi, resulted in reduced DWV viral load, thus confirming that argK upregulation facilitates DWV infection, likely through interfering with the delicate balance between metabolism and immunity. CONCLUSIONS In summary, these data indicate that DWV modulates the host ArgK through transcriptional regulation and cooptation to enhance its fitness in honey bees. Our findings open novel perspectives on possible new therapies for DWV control by targeting specific host proteins.
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Affiliation(s)
- Andrea Becchimanzi
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
- BAT Center-Interuniversity Center for Studies On Bioinspired Agro-Environmental Technology, University of Naples Federico II, Naples, Italy
| | - Giovanna De Leva
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
| | - Rosanna Mattossovich
- Institute of Biosciences and BioResources, National Council of Research of Italy, Naples, Italy
| | - Serena Camerini
- Core Facilities, Istituto Superiore di Sanità (ISS), Rome, Italy
| | | | - Giovanni Jesu
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
| | - Ilaria Di Lelio
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
- BAT Center-Interuniversity Center for Studies On Bioinspired Agro-Environmental Technology, University of Naples Federico II, Naples, Italy
| | | | - Joachim R de Miranda
- Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Anna Valenti
- Institute of Biosciences and BioResources, National Council of Research of Italy, Naples, Italy.
| | - Silvia Gigliotti
- Institute of Biosciences and BioResources, National Council of Research of Italy, Naples, Italy.
| | - Francesco Pennacchio
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy.
- BAT Center-Interuniversity Center for Studies On Bioinspired Agro-Environmental Technology, University of Naples Federico II, Naples, Italy.
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Zhou S, Liu N, Tian Y, Pan H, Han Y, Li Z, Zhang J, Guan S, Chen H, Song Y. Enzymatic characterization and dominant sites of foot-and-mouth disease virus 2C protein. Heliyon 2024; 10:e35449. [PMID: 39170175 PMCID: PMC11336754 DOI: 10.1016/j.heliyon.2024.e35449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 07/21/2024] [Accepted: 07/29/2024] [Indexed: 08/23/2024] Open
Abstract
Foot-and-mouth disease virus (FMDV) 2C protein is a conserved non-structural protein and crucial for replication of the virus. In this study, FMDV 2C protein was prepared and the enzymatic activities were investigated in detail. The protein could digest ssDNA or ssRNA into a small fragment at about 10 nt, indicating that the protein has nuclease activity. But it did not show digestion to blunt-end dsDNA or dsRNA. The nuclease activity of 2C protein could be inhibited in 2 mM Zn2+ or Ca2+ while enhanced by Mg2+ or Mn2+. FMDV 2C protein exhibited unwinding activity to all the three kinds of dsDNA and dsRNA (5' protruded, 3' protruded, and blunt-end). The unwinding velocity to 5' protruded dsRNA was higher than to the blunt-end dsRNA. 2C protein only showed unwinding activity in high concentration of Mg2+, but no unwinding activity in physiological concentrations of Mg2+ and Ca2+, as well as in cell lysate. The 2C protein could catalyze two structured ssRNA to form double strand, thus it was proved to have RNA chaperone activity. The Mg2+ and ATP in different concentrations did not show promotion to the RNA chaperone activity. Finally, six mutant proteins (K116A, D160A, D170A, N207A, R226A, and F316A) were constructed and the enzymatic activities were analyzed. All the six mutations reduced the ATPase activity, D170A and F361A could inactivate the nuclease activity, while the N207A and F316A could inactivate the helicase activity. Our study provides a comprehensive understanding of the enzymatic activities of FMDV 2C protein.
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Affiliation(s)
- Saisai Zhou
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Nankun Liu
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yang Tian
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Hong Pan
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yang Han
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Zhen Li
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Jinhua Zhang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Shuaiyin Guan
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Huanchun Chen
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yunfeng Song
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
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Grimes SL, Denison MR. The Coronavirus helicase in replication. Virus Res 2024; 346:199401. [PMID: 38796132 PMCID: PMC11177069 DOI: 10.1016/j.virusres.2024.199401] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 04/16/2024] [Accepted: 05/17/2024] [Indexed: 05/28/2024]
Abstract
The coronavirus nonstructural protein (nsp) 13 encodes an RNA helicase (nsp13-HEL) with multiple enzymatic functions, including unwinding and nucleoside phosphatase (NTPase) activities. Attempts for enzymatic inactivation have defined the nsp13-HEL as a critical enzyme for viral replication and a high-priority target for antiviral development. Helicases have been shown to play numerous roles beyond their canonical ATPase and unwinding activities, though these functions are just beginning to be explored in coronavirus biology. Recent genetic and biochemical studies, as well as work in structurally-related helicases, have provided evidence that supports new hypotheses for the helicase's potential role in coronavirus replication. Here, we review several aspects of the coronavirus nsp13-HEL, including its reported and proposed functions in viral replication and highlight fundamental areas of research that may aid the development of helicase inhibitors.
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Affiliation(s)
- Samantha L Grimes
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Mark R Denison
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Shiryaev V, Klimochkin Y. Computer-aided Design of Wide-spectrum Coronavirus Helicase NSP13 Cage Inhibitors: A Molecular Modelling Approach. Curr Comput Aided Drug Des 2024; 20:1027-1041. [PMID: 37921184 DOI: 10.2174/0115734099247900231016055626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 08/01/2023] [Accepted: 08/17/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND The coronavirus helicase NSP13 plays a critical role in its life cycle. The found NSP13 inhibitors have been tested only in vitro but they definitely have the potential to become antiviral drugs. Thus, the search for NSP13 inhibitors is of great importance. OBJECTIVES The goal of the present work was to develop a general approach to the design of ligands of coronaviral NSP13 helicase and to propose on its basis potential inhibitors. METHODS The structure of the NSP13 protein was refined by molecular dynamics and the cavity, responsible for RNA binding, was chosen as the inhibitor binding site. The potential inhibitor structures were identified by molecular docking and their binding was verified by molecular dynamics simulation. RESULTS A number of potential NSP13 inhibitors were identified and the binding modes and probable mechanism of action of potential inhibitors was clarified. CONCLUSION Using the molecular dynamics and molecular docking techniques, we have refined the structure of the coronavirus NSP13 helicase, a number of potential inhibitors, containing cage fragment were proposed and their probable mechanism of action was clarified. The proposed approach is also suitable for the design of ligands interacting with other viral helicases.
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Affiliation(s)
- Vadim Shiryaev
- Department of Organic Chemistry, Faculty of Chemical Technology, Samara State Technical University, 443100, Samara, Russia
| | - Yuri Klimochkin
- Department of Organic Chemistry, Faculty of Chemical Technology, Samara State Technical University, 443100, Samara, Russia
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10
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Mia ME, Howlader M, Akter F, Hossain MM. Preclinical and Clinical Investigations of Potential Drugs and Vaccines for COVID-19 Therapy: A Comprehensive Review With Recent Update. CLINICAL PATHOLOGY (THOUSAND OAKS, VENTURA COUNTY, CALIF.) 2024; 17:2632010X241263054. [PMID: 39070952 PMCID: PMC11282570 DOI: 10.1177/2632010x241263054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 06/03/2024] [Indexed: 07/30/2024]
Abstract
The COVID-19 pandemic-led worldwide healthcare crisis necessitates prompt societal, ecological, and medical efforts to stop or reduce the rising number of fatalities. Numerous mRNA based vaccines and vaccines for viral vectors have been licensed for use in emergencies which showed 90% to 95% efficacy in preventing SARS-CoV-2 infection. However, safety issues, vaccine reluctance, and skepticism remain major concerns for making mass vaccination a successful approach to treat COVID-19. Hence, alternative therapeutics is needed for eradicating the global burden of COVID-19 from developed and low-resource countries. Repurposing current medications and drug candidates could be a more viable option for treating SARS-CoV-2 as these therapies have previously passed a number of significant checkpoints for drug development and patient care. Besides vaccines, this review focused on the potential usage of alternative therapeutic agents including antiviral, antiparasitic, and antibacterial drugs, protease inhibitors, neuraminidase inhibitors, and monoclonal antibodies that are currently undergoing preclinical and clinical investigations to assess their effectiveness and safety in the treatment of COVID-19. Among the repurposed drugs, remdesivir is considered as the most promising agent, while favipiravir, molnupiravir, paxlovid, and lopinavir/ritonavir exhibited improved therapeutic effects in terms of elimination of viruses. However, the outcomes of treatment with oseltamivir, umifenovir, disulfiram, teicoplanin, and ivermectin were not significant. It is noteworthy that combining multiple drugs as therapy showcases impressive effectiveness in managing individuals with COVID-19. Tocilizumab is presently employed for the treatment of patients who exhibit COVID-19-related pneumonia. Numerous antiviral drugs such as galidesivir, griffithsin, and thapsigargin are under clinical trials which could be promising for treating COVID-19 individuals with severe symptoms. Supportive treatment for patients of COVID-19 may involve the use of corticosteroids, convalescent plasma, stem cells, pooled antibodies, vitamins, and natural substances. This study provides an updated progress in SARS-CoV-2 medications and a crucial guide for inventing novel interventions against COVID-19.
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Affiliation(s)
- Md. Easin Mia
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Mithu Howlader
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Farzana Akter
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md. Murad Hossain
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
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11
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Jiang L, Xiao M, Liao QQ, Zheng L, Li C, Liu Y, Yang B, Ren A, Jiang C, Feng XH. High-sensitivity profiling of SARS-CoV-2 noncoding region-host protein interactome reveals the potential regulatory role of negative-sense viral RNA. mSystems 2023; 8:e0013523. [PMID: 37314180 PMCID: PMC10469612 DOI: 10.1128/msystems.00135-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/11/2023] [Indexed: 06/15/2023] Open
Abstract
A deep understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions is crucial to developing effective therapeutics and addressing the threat of emerging coronaviruses. The role of noncoding regions of viral RNA (ncrRNAs) has yet to be systematically scrutinized. We developed a method using MS2 affinity purification coupled with liquid chromatography-mass spectrometry and designed a diverse set of bait ncrRNAs to systematically map the interactome of SARS-CoV-2 ncrRNA in Calu-3, Huh7, and HEK293T cells. Integration of the results defined the core ncrRNA-host protein interactomes among cell lines. The 5' UTR interactome is enriched with proteins in the small nuclear ribonucleoproteins family and is a target for the regulation of viral replication and transcription. The 3' UTR interactome is enriched with proteins involved in the stress granules and heterogeneous nuclear ribonucleoproteins family. Intriguingly, compared with the positive-sense ncrRNAs, the negative-sense ncrRNAs, especially the negative-sense of 3' UTR, interacted with a large array of host proteins across all cell lines. These proteins are involved in the regulation of the viral production process, host cell apoptosis, and immune response. Taken together, our study depicts the comprehensive landscape of the SARS-CoV-2 ncrRNA-host protein interactome and unveils the potential regulatory role of the negative-sense ncrRNAs, providing a new perspective on virus-host interactions and the design of future therapeutics. Given the highly conserved nature of UTRs in positive-strand viruses, the regulatory role of negative-sense ncrRNAs should not be exclusive to SARS-CoV-2. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic affecting millions of lives. During replication and transcription, noncoding regions of the viral RNA (ncrRNAs) may play an important role in the virus-host interactions. Understanding which and how these ncrRNAs interact with host proteins is crucial for understanding the mechanism of SARS-CoV-2 pathogenesis. We developed the MS2 affinity purification coupled with liquid chromatography-mass spectrometry method and designed a diverse set of ncrRNAs to identify the SARS-CoV-2 ncrRNA interactome comprehensively in different cell lines and found that the 5' UTR binds to proteins involved in U1 small nuclear ribonucleoprotein, while the 3' UTR interacts with proteins involved in stress granules and the heterogeneous nuclear ribonucleoprotein family. Interestingly, negative-sense ncrRNAs showed interactions with a large number of diverse host proteins, indicating a crucial role in infection. The results demonstrate that ncrRNAs could serve diverse regulatory functions.
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Affiliation(s)
- Liuyiqi Jiang
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Mu Xiao
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qing-Qing Liao
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Luqian Zheng
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chunyan Li
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yuemei Liu
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bing Yang
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Aiming Ren
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chao Jiang
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xin-Hua Feng
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
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12
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Yeager C, Carter G, Gohara DW, Yennawar NH, Enemark E, Arnold J, Cameron CE. Enteroviral 2C protein is an RNA-stimulated ATPase and uses a two-step mechanism for binding to RNA and ATP. Nucleic Acids Res 2022; 50:11775-11798. [PMID: 36399514 PMCID: PMC9723501 DOI: 10.1093/nar/gkac1054] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 10/16/2022] [Accepted: 10/26/2022] [Indexed: 11/19/2022] Open
Abstract
The enteroviral 2C protein is a therapeutic target, but the absence of a mechanistic framework for this enzyme limits our understanding of inhibitor mechanisms. Here, we use poliovirus 2C and a derivative thereof to elucidate the first biochemical mechanism for this enzyme and confirm the applicability of this mechanism to other members of the enterovirus genus. Our biochemical data are consistent with a dimer forming in solution, binding to RNA, which stimulates ATPase activity by increasing the rate of hydrolysis without impacting affinity for ATP substantially. Both RNA and DNA bind to the same or overlapping site on 2C, driven by the phosphodiester backbone, but only RNA stimulates ATP hydrolysis. We propose that RNA binds to 2C driven by the backbone, with reorientation of the ribose hydroxyls occurring in a second step to form the catalytically competent state. 2C also uses a two-step mechanism for binding to ATP. Initial binding is driven by the α and β phosphates of ATP. In the second step, the adenine base and other substituents of ATP are used to organize the active site for catalysis. These studies provide the first biochemical description of determinants driving specificity and catalytic efficiency of a picornaviral 2C ATPase.
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Affiliation(s)
- Calvin Yeager
- Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Griffin Carter
- Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - David W Gohara
- Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO 63104, USA
| | - Neela H Yennawar
- The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Eric J Enemark
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Jamie J Arnold
- Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Craig E Cameron
- To whom correspondence should be addressed. Tel: +1 919 966 9699; Fax: +1 919 962 8103;
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13
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Dey R, Samadder A, Nandi S. Exploring the Targets of Novel Corona Virus and Docking-based Screening of Potential Natural Inhibitors to Combat COVID-19. Curr Top Med Chem 2022; 22:2410-2434. [PMID: 36281864 DOI: 10.2174/1568026623666221020163831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 09/07/2022] [Accepted: 09/21/2022] [Indexed: 01/20/2023]
Abstract
There is a need to explore natural compounds against COVID-19 due to their multitargeted actions against various targets of nCoV. They act on multiple sites rather than single targets against several diseases. Thus, there is a possibility that natural resources can be repurposed to combat COVID-19. However, the biochemical mechanisms of these inhibitors were not known. To reveal the mode of anti-nCoV action, structure-based docking plays a major role. The present study is an attempt to explore various potential targets of SARS-CoV-2 and the structure-based screening of various potential natural inhibitors to combat the novel coronavirus.
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Affiliation(s)
- Rishita Dey
- Department of Zoology, Cytogenetics and Molecular Biology Lab., University of Kalyani, Kalyani, Nadia, 741235, India.,Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
| | - Asmita Samadder
- Department of Zoology, Cytogenetics and Molecular Biology Lab., University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sisir Nandi
- Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
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14
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Elbehery AHA, Deng L. Insights into the global freshwater virome. Front Microbiol 2022; 13:953500. [PMID: 36246212 PMCID: PMC9554406 DOI: 10.3389/fmicb.2022.953500] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/11/2022] [Indexed: 11/29/2022] Open
Abstract
Viruses are by far the most abundant life forms on this planet. Yet, the full viral diversity remains mostly unknown, especially in environments like freshwater. Therefore, we aimed to study freshwater viruses in a global context. To this end, we downloaded 380 publicly available viral metagenomes (>1 TB). More than 60% of these metagenomes were discarded based on their levels of cellular contamination assessed by ribosomal DNA content. For the remaining metagenomes, assembled contigs were decontaminated using two consecutive steps, eventually yielding 273,365 viral contigs longer than 1,000 bp. Long enough contigs (≥ 10 kb) were clustered to identify novel genomes/genome fragments. We could recover 549 complete circular and high-quality draft genomes, out of which 10 were recognized as being novel. Functional annotation of these genomes showed that most of the annotated coding sequences are DNA metabolic genes or phage structural genes. On the other hand, taxonomic analysis of viral contigs showed that most of the assigned contigs belonged to the order Caudovirales, particularly the families of Siphoviridae, Myoviridae, and Podoviridae. The recovered viral contigs contained several auxiliary metabolic genes belonging to several metabolic pathways, especially carbohydrate and amino acid metabolism in addition to photosynthesis as well as hydrocarbon degradation and antibiotic resistance. Overall, we present here a set of prudently chosen viral contigs, which should not only help better understanding of freshwater viruses but also be a valuable resource for future virome studies.
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Affiliation(s)
- Ali H. A. Elbehery
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt
- *Correspondence: Ali H. A. Elbehery,
| | - Li Deng
- Helmholtz Centre Munich – German Research Centre for Environmental Health, Institute of Virology, Neuherberg, Germany
- Chair of Microbial Disease Prevention, School of Life Sciences, Technical University of Munich, Freising, Germany
- Li Deng,
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15
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Keown RA, Dums JT, Brumm PJ, MacDonald J, Mead DA, Ferrell BD, Moore RM, Harrison AO, Polson SW, Wommack KE. Novel Viral DNA Polymerases From Metagenomes Suggest Genomic Sources of Strand-Displacing Biochemical Phenotypes. Front Microbiol 2022; 13:858366. [PMID: 35531281 PMCID: PMC9069017 DOI: 10.3389/fmicb.2022.858366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/08/2022] [Indexed: 01/21/2023] Open
Abstract
Viruses are the most abundant and diverse biological entities on the planet and constitute a significant proportion of Earth's genetic diversity. Most of this diversity is not represented by isolated viral-host systems and has only been observed through sequencing of viral metagenomes (viromes) from environmental samples. Viromes provide snapshots of viral genetic potential, and a wealth of information on viral community ecology. These data also provide opportunities for exploring the biochemistry of novel viral enzymes. The in vitro biochemical characteristics of novel viral DNA polymerases were explored, testing hypothesized differences in polymerase biochemistry according to protein sequence phylogeny. Forty-eight viral DNA Polymerase I (PolA) proteins from estuarine viromes, hot spring metagenomes, and reference viruses, encompassing a broad representation of currently known diversity, were synthesized, expressed, and purified. Novel functionality was shown in multiple PolAs. Intriguingly, some of the estuarine viral polymerases demonstrated moderate to strong innate DNA strand displacement activity at high enzyme concentration. Strand-displacing polymerases have important technological applications where isothermal reactions are desirable. Bioinformatic investigation of genes neighboring these strand displacing polymerases found associations with SNF2 helicase-associated proteins. The specific function of SNF2 family enzymes is unknown for prokaryotes and viruses. In eukaryotes, SNF2 enzymes have chromatin remodeling functions but do not separate nucleic acid strands. This suggests the strand separation function may be fulfilled by the DNA polymerase for viruses carrying SNF2 helicase-associated proteins. Biochemical data elucidated from this study expands understanding of the biology and ecological behavior of unknown viruses. Moreover, given the numerous biotechnological applications of viral DNA polymerases, novel viral polymerases discovered within viromes may be a rich source of biological material for further in vitro DNA amplification advancements.
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Affiliation(s)
- Rachel A. Keown
- Department of Biological Sciences, College of Arts and Sciences, University of Delaware, Newark, DE, United States
| | - Jacob T. Dums
- Biotechnology Program, North Carolina State University, Raleigh, NC, United States
| | | | | | - David A. Mead
- Varigen Biosciences Corporation, Middleton, WI, United States
| | - Barbra D. Ferrell
- Department of Plant and Soil Sciences, College of Agriculture and Natural Resources, University of Delaware, Newark, DE, United States
| | - Ryan M. Moore
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, United States
| | - Amelia O. Harrison
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, United States
| | - Shawn W. Polson
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, United States
- Department of Computer and Information Sciences, College of Arts and Sciences, University of Delaware, Newark, DE, United States
| | - K. Eric Wommack
- Department of Plant and Soil Sciences, College of Agriculture and Natural Resources, University of Delaware, Newark, DE, United States
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16
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Chavda VP, Kapadia C, Soni S, Prajapati R, Chauhan SC, Yallapu MM, Apostolopoulos V. A global picture: therapeutic perspectives for COVID-19. Immunotherapy 2022; 14:351-371. [PMID: 35187954 PMCID: PMC8884157 DOI: 10.2217/imt-2021-0168] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 01/19/2022] [Indexed: 02/06/2023] Open
Abstract
The COVID-19 pandemic is a lethal virus outbreak by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has severely affected human lives and the global economy. The most vital part of the research and development of therapeutic agents is to design drug products to manage COVID-19 efficiently. Numerous attempts have been in place to determine the optimal drug dose and combination of drugs to treat the disease on a global scale. This article documents the information available on SARS-CoV-2 and its life cycle, which will aid in the development of the potential treatment options. A consolidated summary of several natural and repurposed drugs to manage COVID-19 is depicted with summary of current vaccine development. People with high age, comorbity and concomitant illnesses such as overweight, metabolic disorders, pulmonary disease, coronary heart disease, renal failure, fatty liver and neoplastic disorders are more prone to create serious COVID-19 and its consequences. This article also presents an overview of post-COVID-19 complications in patients.
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Affiliation(s)
- Vivek P Chavda
- Department of Pharmaceutics & Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India
- Department of Pharmaceutics, K B Institute of Pharmaceutical Education & Research, Kadi Sarva Vishwavidhyalaya, Gandhinagar, Gujarat, 382023, India
| | - Carron Kapadia
- Department of Pharmaceutics & Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India
| | - Shailvi Soni
- Department of Pharmaceutics & Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India
| | - Riddhi Prajapati
- Department of Pharmaceutics & Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India
| | - Subhash C Chauhan
- Department of Immunology & Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA
| | - Murali M Yallapu
- Department of Immunology & Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA
| | - Vasso Apostolopoulos
- Institute for Health & Sport, Victoria University, Melbourne, VIC, 3030, Australia
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17
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Xiang R, Yu Z, Wang Y, Wang L, Huo S, Li Y, Liang R, Hao Q, Ying T, Gao Y, Yu F, Jiang S. Recent advances in developing small-molecule inhibitors against SARS-CoV-2. Acta Pharm Sin B 2022; 12:1591-1623. [PMID: 34249607 PMCID: PMC8260826 DOI: 10.1016/j.apsb.2021.06.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 06/13/2021] [Accepted: 06/23/2021] [Indexed: 02/07/2023] Open
Abstract
The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.
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Affiliation(s)
- Rong Xiang
- College of Life Sciences, Hebei Agricultural University, Baoding 071001, China
| | - Zhengsen Yu
- College of Life Sciences, Hebei Agricultural University, Baoding 071001, China
| | - Yang Wang
- College of Life Sciences, Hebei Agricultural University, Baoding 071001, China
| | - Lili Wang
- Research Center of Chinese Jujube, Hebei Agricultural University, Baoding 071001, China
| | - Shanshan Huo
- College of Life Sciences, Hebei Agricultural University, Baoding 071001, China
| | - Yanbai Li
- College of Life Sciences, Hebei Agricultural University, Baoding 071001, China
| | - Ruiying Liang
- College of Life Sciences, Hebei Agricultural University, Baoding 071001, China
| | - Qinghong Hao
- College of Life Sciences, Hebei Agricultural University, Baoding 071001, China
| | - Tianlei Ying
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai 200032, China
| | - Yaning Gao
- Beijing Pharma and Biotech Center, Beijing 100176, China,Corresponding authors. Tel.: +86 21 54237673, fax: +86 21 54237465 (Shibo Jiang); Tel.: +86 312 7528935, fax: +86 312 7521283 (Fei Yu); Tel.: +86 10 62896868; fax: +86 10 62899978, (Yanning Gao).
| | - Fei Yu
- College of Life Sciences, Hebei Agricultural University, Baoding 071001, China,Corresponding authors. Tel.: +86 21 54237673, fax: +86 21 54237465 (Shibo Jiang); Tel.: +86 312 7528935, fax: +86 312 7521283 (Fei Yu); Tel.: +86 10 62896868; fax: +86 10 62899978, (Yanning Gao).
| | - Shibo Jiang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai 200032, China,Corresponding authors. Tel.: +86 21 54237673, fax: +86 21 54237465 (Shibo Jiang); Tel.: +86 312 7528935, fax: +86 312 7521283 (Fei Yu); Tel.: +86 10 62896868; fax: +86 10 62899978, (Yanning Gao).
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18
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Chavda VP, Kapadia C, Soni S, Prajapati R, Chauhan SC, Yallapu MM, Apostolopoulos V. A global picture: therapeutic perspectives for COVID-19. Immunotherapy 2022. [PMID: 35187954 DOI: 10.2217/imt-2021-0168.10.2217/imt-2021-0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023] Open
Abstract
The COVID-19 pandemic is a lethal virus outbreak by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has severely affected human lives and the global economy. The most vital part of the research and development of therapeutic agents is to design drug products to manage COVID-19 efficiently. Numerous attempts have been in place to determine the optimal drug dose and combination of drugs to treat the disease on a global scale. This article documents the information available on SARS-CoV-2 and its life cycle, which will aid in the development of the potential treatment options. A consolidated summary of several natural and repurposed drugs to manage COVID-19 is depicted with summary of current vaccine development. People with high age, comorbity and concomitant illnesses such as overweight, metabolic disorders, pulmonary disease, coronary heart disease, renal failure, fatty liver and neoplastic disorders are more prone to create serious COVID-19 and its consequences. This article also presents an overview of post-COVID-19 complications in patients.
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Affiliation(s)
- Vivek P Chavda
- Department of Pharmaceutics & Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India
- Department of Pharmaceutics, K B Institute of Pharmaceutical Education & Research, Kadi Sarva Vishwavidhyalaya, Gandhinagar, Gujarat, 382023, India
| | - Carron Kapadia
- Department of Pharmaceutics & Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India
| | - Shailvi Soni
- Department of Pharmaceutics & Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India
| | - Riddhi Prajapati
- Department of Pharmaceutics & Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India
| | - Subhash C Chauhan
- Department of Immunology & Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA
| | - Murali M Yallapu
- Department of Immunology & Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA
| | - Vasso Apostolopoulos
- Institute for Health & Sport, Victoria University, Melbourne, VIC, 3030, Australia
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19
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Majewska A, Mlynarczyk-Bonikowska B. 40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs? Int J Mol Sci 2022; 23:ijms23073431. [PMID: 35408788 PMCID: PMC8998721 DOI: 10.3390/ijms23073431] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/10/2022] [Accepted: 03/18/2022] [Indexed: 01/17/2023] Open
Abstract
Herpes simplex virus types 1 and 2 HSV1 and 2, namely varicella-zoster VZV and cytomegalovirus CMV, are among the most common pathogens worldwide. They remain in the host body for life. The course of infection with these viruses is often asymptomatic or mild and self-limiting, but in immunocompromised patients, such as solid organ or bone marrow transplant recipients, the course can be very severe or even life-threatening. Unfortunately, in the latter group, the highest percentage of infections with strains resistant to routinely used drugs is observed. On the other hand, frequent recurrences of genital herpes can be a problem even in people with normal immunity. Genital herpes also increases the risk of acquiring sexually transmitted diseases, including HIV infection and, if present in pregnant women, poses a risk to the fetus and newborn. Even more frequently than herpes simplex, congenital infections can be caused by cytomegalovirus. We present the most important anti-herpesviral agents, the mechanisms of resistance to these drugs, and the associated mutations in the viral genome. Special emphasis was placed on newly introduced drugs such as maribavir and brincidofovir. We also briefly discuss the most promising substances in preclinical testing as well as immunotherapy options and vaccines currently in use and under investigation.
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Affiliation(s)
- Anna Majewska
- Department of Medical Microbiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland;
| | - Beata Mlynarczyk-Bonikowska
- Department of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
- Correspondence: ; Tel.: +48-225021313
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20
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Rahmah L, Abarikwu SO, Arero AG, Essouma M, Jibril AT, Fal A, Flisiak R, Makuku R, Marquez L, Mohamed K, Ndow L, Zarębska-Michaluk D, Rezaei N, Rzymski P. Oral antiviral treatments for COVID-19: opportunities and challenges. Pharmacol Rep 2022; 74:1255-1278. [PMID: 35871712 PMCID: PMC9309032 DOI: 10.1007/s43440-022-00388-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/24/2022] [Accepted: 07/06/2022] [Indexed: 01/18/2023]
Abstract
The use of antiviral COVID-19 medications can successfully inhibit SARS-CoV-2 replication and prevent disease progression to a more severe form. However, the timing of antiviral treatment plays a crucial role in this regard. Oral antiviral drugs provide an opportunity to manage SARS-CoV-2 infection without a need for hospital admission, easing the general burden that COVID-19 can have on the healthcare system. This review paper (i) presents the potential pharmaceutical antiviral targets, including various host-based targets and viral-based targets, (ii) characterizes the first-generation anti-SARS-CoV-2 oral drugs (nirmatrelvir/ritonavir and molnupiravir), (iii) summarizes the clinical progress of other oral antivirals for use in COVID-19, (iv) discusses ethical issues in such clinical trials and (v) presents challenges associated with the use of oral antivirals in clinical practice. Oral COVID-19 antivirals represent a part of the strategy to adapt to long-term co-existence with SARS-CoV-2 in a manner that prevents healthcare from being overwhelmed. It is pivotal to ensure equal and fair global access to the currently available oral antivirals and those authorized in the future.
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Affiliation(s)
- Laila Rahmah
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Jakarta, Indonesia
| | - Sunny O. Abarikwu
- Department of Biochemistry, University of Port Harcourt, Choba, Nigeria ,Universal Scientific Education and Research Network (USERN), Choba, Nigeria
| | - Amanuel Godana Arero
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Addis Ababa, Ethiopia
| | - Mickael Essouma
- Department of Internal Medicine and Specialties, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon ,Universal Scientific Education and Research Network, Yaoundé, Cameroon
| | - Aliyu Tijani Jibril
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran ,Nutritional and Health Team (NHT), Universal Scientific Education and Research Network (USERN), Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Accra, Ghana
| | - Andrzej Fal
- Department of Population Health, Division of Public Health, Wroclaw Medical University, Wroclaw, Poland ,Collegium Medicum, Warsaw Faculty of Medicine, Cardinal Stefan Wyszyński University, Warsaw, Poland ,Integrated Science Association (ISA), Universal Scientific Education and Research Network (USERN), Poznań, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Rangarirai Makuku
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Harare, Zimbabwe
| | - Leander Marquez
- College of Social Sciences and Philosophy, University of the Philippines Diliman, Quezon City, Philippines ,Education and Research Network (USERN), Universal Scientific, Quezon City, Philippines
| | - Kawthar Mohamed
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Manama, Bahrain
| | - Lamin Ndow
- National Health Laboratory Service, Kotu, Gambia ,Universal Scientific Education and Research Network (USERN), Banjul, Gambia
| | | | - Nima Rezaei
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran ,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Piotr Rzymski
- Integrated Science Association (ISA), Universal Scientific Education and Research Network (USERN), Poznań, Poland ,Department of Environmental Medicine, Poznan University of Medical Sciences, Poznań, Poland
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21
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Vardhan S, Sahoo SK. Exploring the therapeutic nature of limonoids and triterpenoids against SARS-CoV-2 by targeting nsp13, nsp14, and nsp15 through molecular docking and dynamic simulations. J Tradit Complement Med 2021; 12:44-54. [PMID: 34926189 PMCID: PMC8666293 DOI: 10.1016/j.jtcme.2021.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/28/2022] Open
Abstract
Background and aim The ongoing global pandemic due to SARS-CoV-2 caused a medical emergency. Since December 2019, the COVID-19 disease is spread across the globe through physical contact and respiratory droplets. Coronavirus caused a severe effect on the human immune system where some of the non-structural proteins (nsp) are involved in virus-mediated immune response and pathogenesis. To suppress the viral RNA replication mechanism and immune-mediated responses, we aimed to identify limonoids and triterpenoids as antagonists by targeting helicases (nsp13), exonuclease (nsp14), and endoribonuclease (nsp15) of SARS-CoV-2 as therapeutic proteins. Experimental procedure In silico molecular docking and drug-likeness of a library of 369 phytochemicals from limonoids and triterpenoids were performed to screen the potential hits that binds effectively at the active site of the proteins target. In addition, the molecular dynamics simulations of the proteins and their complexes with the potential hits were performed for 100 ns by using GROMACS. Results and conclusion The potential compounds 26-deoxyactein and 25-O-anhydrocimigenol 3-O-beta-d-xylopyranoside posing strong interactions with a minimum binding energy of -10.1 and -9.5 kcal/mol, respectively and sustained close contact with nsp13 for 100 ns. The nsp14 replication fork activity was hindered by the tomentosolic acid, timosaponin A-I, and shizukaol A with the binding affinity score of -9.2, -9.2, and -9.0 kcal/mol, respectively. The nsp15 endoribonuclease catalytic residues were inhibited potentially by limonin, 25-O-anhydrocimigenol 3-O-alpha-l-arabinopyranoside, and asperagenin posing strong binding affinity scores of -9.0, -8.8, and -8.7 kcal/mol, respectively. Computationally predicted potential phytochemicals for SARS-CoV-2 are known to possess various medicinal properties.
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Affiliation(s)
- Seshu Vardhan
- Department of Chemistry, Sardar Vallabhbhai National Institute of Technology (SVNIT), Surat, 395007, Gujarat, India
| | - Suban K Sahoo
- Department of Chemistry, Sardar Vallabhbhai National Institute of Technology (SVNIT), Surat, 395007, Gujarat, India
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22
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Potential Adjuvant Therapeutic Effect of Lactobacillus plantarum Probio-88 Postbiotics against SARS-COV-2. Vaccines (Basel) 2021; 9:vaccines9101067. [PMID: 34696175 PMCID: PMC8537773 DOI: 10.3390/vaccines9101067] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 12/11/2022] Open
Abstract
In response to the ongoing COVID-19 pandemic, the global effort to develop high efficacy countermeasures to control the infection are being conducted at full swing. While the efficacy of vaccines and coronavirus drugs are being tested, the microbiome approach represents an alternative pathophysiology-based approach to prevent the severity of the infection. In the current study, we evaluated the action of a novel probiotic Lactobacillus plantarum Probio-88 against SARS-COV-2 replication and immune regulation using an in vitro and in silico study. The results showed that extract from this strain (P88-CFS) significantly inhibited the replication of SARS-COV-2 and the production of reactive oxygen species (ROS) levels. Furthermore, compared with infected cells, P88-CFS treated cells showed a significant reduction in inflammatory markers such as IFN-α, IFN-β, and IL-6. Using an in silico molecular docking approach, it was postulated that the antiviral activity of L. plantarum Probio-88 was derived from plantaricin E (PlnE) and F (PlnF). The high binding affinity and formation of hydrogen bonding indicated that the association of PlnE and PlnF on SARS-COV-2 helicase might serve as a blocker by preventing the binding of ss-RNA during the replication of the virus. In conclusion, our study substantiated that P88-CFS could be used as an integrative therapeutic approach along with vaccine to contain the spread of the highly infectious pathogen and possibly its variants.
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23
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Ayele AG, Enyew EF, Kifle ZD. Roles of existing drug and drug targets for COVID-19 management. Metabol Open 2021; 11:100103. [PMID: 34222852 PMCID: PMC8239316 DOI: 10.1016/j.metop.2021.100103] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 06/27/2021] [Indexed: 02/07/2023] Open
Abstract
In December 2019, a highly transmissible, pneumonia epidemic caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), erupted in China and other countries, resulting in devastation and health crisis worldwide currently. The search and using existing drugs support to curb the current highly contagious viral infection is spirally increasing since the pandemic began. This is based on these drugs had against other related RNA-viruses such as MERS-Cov, and SARS-Cov. Moreover, researchers are scrambling to identify novel drug targets and discover novel therapeutic options to vanquish the current pandemic. Since there is no definitive treatment to control Covid-19 vaccines are remain to be a lifeline. Currently, many vaccine candidates are being developed with most of them are reported to have positive results. Therapeutic targets such as helicases, transmembrane serine protease 2, cathepsin L, cyclin G-associated kinase, adaptor-associated kinase 1, two-pore channel, viral virulence factors, 3-chymotrypsin-like protease, suppression of excessive inflammatory response, inhibition of viral membrane, nucleocapsid, envelope, and accessory proteins, and inhibition of endocytosis were identified as a potential target against COVID-19 infection. This review also summarizes plant-based medicines for the treatment of COVID-19 such as saposhnikoviae divaricata, lonicerae japonicae flos, scutellaria baicalensis, lonicera japonicae, and some others. Thus, this review aimed to focus on the most promising therapeutic targets being repurposed against COVID-19 and viral elements that are used in COVID-19 vaccine candidates.
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Key Words
- 3CLpro, 3-chymotrypsin-like protease
- AAK1, adaptor-associated kinase 1
- ACE-2, Angiotensin-Converting Enzyme-2
- CEF, Cepharanthine
- COVID-19
- COVID-19, coronavirus disease-2019
- Existing drug
- GAK, cyclin G-associated kinase
- MERS-CoV, Middle East respiratory syndrome coronavirus
- Management
- Nsp, non-structure protein
- ORF, open reading frame
- PLpro, papain-like protease
- RdRp, RNA-dependence RNA-polymerase
- SARS-COV-2, severe acute respiratory syndrome coronavirus-2
- TMPRSS2, transmembrane Serine Protease 2
- TPC2, two-pore channel 2
- Therapeutic target
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Affiliation(s)
- Akeberegn Gorems Ayele
- Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia
| | - Engidaw Fentahun Enyew
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Sciences, Gondar, Ethiopia
| | - Zemene Demelash Kifle
- Department of Pharmacology, School of Pharmacy, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
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24
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Junaid M, Akter Y, Siddika A, Nayeem SMA, Nahrin A, Afrose SS, Ezaj MMA, Alam MS. Nature-derived hit, lead, and drug-like small molecules: Current status and future aspects against key target proteins of Coronaviruses. Mini Rev Med Chem 2021; 22:498-549. [PMID: 34353257 DOI: 10.2174/1389557521666210805113231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND COVID-19 pandemic, the most unprecedented event of the year 2020, has brought millions of scientists worldwide in a single platform to fight against it. Though several drugs are now in the clinical trial, few vaccines available on the market already but the lack of an effect of those is making the situation worse. AIM OF THE STUDY In this review, we demonstrated comprehensive data of natural antiviral products showing activities against different proteins of Human Coronaviruses (HCoV) that are responsible for its pathogenesis. Furthermore, we categorized the compounds into the hit, lead, and drug based on the IC50/EC50 value, drug-likeness, and lead-likeness test to portray their potentiality to be a drug. We also demonstrated the present status of our screened antiviral compounds with respect to clinical trials and reported the lead compounds that can be promoted to clinical trial against COVID-19. METHODS A systematic search strategy was employed focusing on Natural Products (NPs) with proven activity (in vitro, in vivo, or in silico) against human coronaviruses, in general, and data were gathered from databases like PubMed, Web of Science, Google Scholar, SciVerse, and Scopus. Information regarding clinical trials retrieved from the Clinical Trial database. RESULTS Total "245" natural compounds were identified initially from the literature study. Among them, Glycyrrhizin, Caffeic acid, Curcumin is in phase 3, and Tetrandrine, Cyclosporine, Tacrolimus, Everolimus are in phase 4 clinical trial. Except for Glycyrrhizin, all compounds showed activity against COVID-19. CONCLUSIONS In summary, our demonstrated specific small molecules with lead and drug-like capabilities clarified their position in the drug discovery pipeline and proposed their future research against COVID-19.
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Affiliation(s)
- Md Junaid
- Natural Products Research Division, Advanced Bioinformatics, Computational Biology and Data Science Laboratory. Bangladesh
| | - Yeasmin Akter
- Natural Products Research Division, Advanced Bioinformatics, Computational Biology and Data Science Laboratory. Bangladesh
| | - Aysha Siddika
- Natural Products Research Division, Advanced Bioinformatics, Computational Biology and Data Science Laboratory. Bangladesh
| | - S M Abdul Nayeem
- Natural Products Research Division, Advanced Bioinformatics, Computational Biology and Data Science Laboratory. Bangladesh
| | - Afsana Nahrin
- Department of Pharmacy, University of Science and Technology Chittagong. Bangladesh
| | - Syeda Samira Afrose
- Natural Products Research Division, Advanced Bioinformatics, Computational Biology and Data Science Laboratory. Bangladesh
| | - Md Muzahid Ahmed Ezaj
- Natural Products Research Division, Advanced Bioinformatics, Computational Biology and Data Science Laboratory. Bangladesh
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25
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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase. Biochem J 2021; 478:2405-2423. [PMID: 34198322 PMCID: PMC8286831 DOI: 10.1042/bcj20210201] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here, we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterized pharmaceuticals for nsp13 inhibitors using a fluorescence resonance energy transfer-based high-throughput screening approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.
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26
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Srivastava V, Ahmad A. New perspective towards therapeutic regimen against SARS-CoV-2 infection. J Infect Public Health 2021; 14:852-862. [PMID: 34118735 PMCID: PMC8152204 DOI: 10.1016/j.jiph.2021.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 05/05/2021] [Accepted: 05/16/2021] [Indexed: 12/23/2022] Open
Abstract
The ongoing enormous loss of human life owing to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to a global crisis ranging from the collapse of health - care systems to socio-economic instability. As SARS-CoV-2 is a novel virus, very little information is available from researchers and therefore, a rigorous effort is required to decode its pathogenicity. There are no licenced treatment options available for treating SARS-CoV-2 infections and the development of a new antiviral drug targeting coronavirus cannot happen soon. Consequently, drug repurposing is a promising solution for combating the present pandemic. In this review, we have thoroughly discussed all the proteins encoded by the SARS-CoV-2 genome; their importance in pathogenicity and their potential role in drug discovery. Also, the budding threat of co-infections by other pathogenic microbes has been highlighted. Furthermore, the advances made in the medicinal field for the treatment and prevention of this viral infection is explained. Altogether, this review will provide some insightful discussions about this infectious disease and will meet certain of the knowledge gaps which exist by presenting an exhaustive and extensive scientific report on the ongoing mission for COVID-19 drug discovery.
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Affiliation(s)
- Vartika Srivastava
- Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa
| | - Aijaz Ahmad
- Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa; Infection Control, Charlotte Maxeke Johannesburg Academic Hospital, National Health Laboratory Service, Johannesburg, 2193, South Africa.
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27
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Vlachakis D. Genetic and structural analyses of ssRNA viruses pave the way for the discovery of novel antiviral pharmacological targets. Mol Omics 2021; 17:357-364. [PMID: 33725065 DOI: 10.1039/d0mo00173b] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In the era of big data and artificial intelligence, a lot of new discoveries have influenced the fields of antiviral drug design and pharmacophore identification. Viruses have always been a threat to society in terms of public health and economic stability. Viruses not only affect humans but also livestock and agriculture with a direct impact on food safety, economy and environmental imprint. Most recently, with the pandemic of COVID-19, it was made clear that a single virus can have a devastating impact on global well-being and economy. In this direction, there is an emerging need for the identification of promising pharmacological targets in viruses. Herein, an effort has been made to discuss the current knowledge, state-of-the-art applications and future implications for the main pharmacological targets of single-stranded RNA viruses.
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Affiliation(s)
- Dimitrios Vlachakis
- Laboratory of Genetics, Department of Biotechnology, School of Applied BIology and Biotechnology, Agricultural University of Athens, Athens, Greece.
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28
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Delli Ponti R, Mutwil M. Structural landscape of the complete genomes of dengue virus serotypes and other viral hemorrhagic fevers. BMC Genomics 2021; 22:352. [PMID: 34000991 PMCID: PMC8127238 DOI: 10.1186/s12864-021-07638-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 04/21/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND With more than 300 million potentially infected people every year, and with the expanded habitat of mosquitoes due to climate change, Dengue virus (DENV) cannot be considered anymore only a tropical disease. The RNA secondary structure is a functional characteristic of RNA viruses, and together with the accumulated high-throughput sequencing data could provide general insights towards understanding virus biology. Here, we profiled the RNA secondary structure of > 7000 complete viral genomes from 11 different species focusing on viral hemorrhagic fevers, including DENV serotypes, EBOV, and YFV. RESULTS In our work we demonstrated that the secondary structure and presence of protein-binding domains in the genomes can be used as intrinsic signature to further classify the viruses. With our predictive approach, we achieved high prediction scores of the secondary structure (AUC up to 0.85 with experimental data), and computed consensus secondary structure profiles using hundreds of in silico models. We observed that viruses show different structural patterns, where e.g., DENV-2 and Ebola virus tend to be less structured than the other viruses. Furthermore, we observed virus-specific correlations between secondary structure and the number of interaction sites with human proteins, reaching a correlation of 0.89 in the case of Zika virus. We also identified that helicases-encoding regions are more structured in several flaviviruses, while the regions encoding for the contact proteins exhibit virus-specific clusters in terms of RNA structure and potential protein-RNA interactions. We also used structural data to study the geographical distribution of DENV, finding a significant difference between DENV-3 from Asia and South-America, where the structure is also driving the clustering more than sequence identity, which could imply different evolutionary routes of this subtype. CONCLUSIONS Our massive computational analysis provided novel results regarding the secondary structure and the interaction with human proteins, not only for DENV serotypes, but also for other flaviviruses and viral hemorrhagic fevers-associated viruses. We showed how the RNA secondary structure can be used to categorise viruses, and even to further classify them based on the interaction with proteins. We envision that these approaches can be used to further classify and characterise these complex viruses.
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Affiliation(s)
- Riccardo Delli Ponti
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
| | - Marek Mutwil
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
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29
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Abidi SH, Almansour NM, Amerzhanov D, Allemailem KS, Rafaqat W, Ibrahim MAA, la Fleur P, Lukac M, Ali S. Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase. Sci Rep 2021; 11:10290. [PMID: 33986405 PMCID: PMC8119689 DOI: 10.1038/s41598-021-89724-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 04/13/2021] [Indexed: 01/08/2023] Open
Abstract
As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, - 54.8 and - 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.
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Affiliation(s)
- Syed Hani Abidi
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
| | - Nahlah Makki Almansour
- Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia
| | - Daulet Amerzhanov
- Nazarbayev University School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Khaled S Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | | | - Mahmoud A A Ibrahim
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt
| | - Philip la Fleur
- Nazarbayev University School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Martin Lukac
- Department of Computer Science, School of Engineering and Digital Sciences, Nazarbayev University, Astana, Kazakhstan
| | - Syed Ali
- Nazarbayev University School of Medicine, Nazarbayev University, Astana, Kazakhstan.
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30
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Rai PK, Mueed Z, Chowdhury A, Deval R, Kumar D, Kamal MA, Negi YS, Pareek S, Poddar NK. Current Overviews on COVID-19 Management Strategies. Curr Pharm Biotechnol 2021; 23:361-387. [PMID: 33966618 DOI: 10.2174/1389201022666210509022313] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/02/2021] [Accepted: 02/08/2021] [Indexed: 02/08/2023]
Abstract
The coronavirus pandemic has hit the world lately and caused acute respiratory syndrome in humans. The causative agent of the disease was soon brought to focus by scientists as SARS-CoV-2 and later called a novel coronavirus by the general public. Due to the severity and rapid spread of the disease, WHO classifies the COVID-19 pandemic as the 6th public health emergency even after taking efforts like worldwide quarantine and restrictions. Since only symptomatic treatment is available, the best way to control the spread of the virus is by taking preventive measures. Various types of antigen/antibody detection kits and diagnostic methods are available for the diagnosis of COVID-19 patients. In recent years, various phytochemicals and repurposing drugs are showing a broad range of anti-viral activities with different modes of action have been identified. Repurposing drugs such as arbidol, hydroxychloroquine, chloroquine, lopinavir, favipiravir, remdesivir, hexamethylene amiloride, and dexamethasone, tocilizumab, interferon-β, neutralizing antibodies exhibit in vitro anti-coronaviral properties by inhibiting multiple processes in the virus life cycle. Various research groups are involved in drug trials and vaccine development. Plant-based anti-viral compounds such as baicalin, calanolides, curcumin, oxymatrine, matrine, and resveratrol exhibit different modes of action against a wide range of positive/negative sense-RNA/DNA virus, and future researches need to be conducted to ascertain their role, use in managing SARS-CoV-2. Thus, this article is an attempt to review the current understanding of COVID-19 acute respiratory disease and summarize its clinical features with their prospective control and various aspects of the therapeutic approach.
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Affiliation(s)
- Pankaj Kumar Rai
- Department of Biotechnology, Invertis University, Bareilly, Uttar Pradesh, India
| | - Zeba Mueed
- Department of Biotechnology, Invertis University, Bareilly, Uttar Pradesh, India
| | - Abhiroop Chowdhury
- School of Environment & Sustainability, O.P. Jindal Global University, Sonipat, Haryana, India
| | - Ravi Deval
- Department of Biotechnology, Invertis University, Bareilly, Uttar Pradesh, India
| | - Dinesh Kumar
- Department of Biotechnology, Invertis University, Bareilly, Uttar Pradesh, India
| | - Mohammad A Kamal
- West China School of Nursing / Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan. China
| | - Yogeshwar Singh Negi
- Department of Biosciences, Manipal University Jaipur, DehmiKalan, Jaipur-Ajmer Expressway, Jaipur-303007, Rajasthan, India
| | - Shubhra Pareek
- Department of Chemistry, Manipal University Jaipur, DehmiKalan, Jaipur-Ajmer Expressway, Jaipur-303007, Rajasthan, India
| | - Nitesh Kumar Poddar
- Department of Biosciences, Manipal University Jaipur, DehmiKalan, Jaipur-Ajmer Expressway, Jaipur-303007, Rajasthan, India
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31
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The direct evidence and mechanism of traditional Chinese medicine treatment of COVID-19. Biomed Pharmacother 2021; 137:111267. [PMID: 33508618 PMCID: PMC7836975 DOI: 10.1016/j.biopha.2021.111267] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/06/2021] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus causing serious human disease to spread across the world in the past 20 years, after SARS and Middle East respiratory syndrome. As of mid-September 2020, more than 200 countries and territories have reported 30 million cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, including 950,000 deaths. Supportive treatment remains the mainstay of therapy for COVID-19. The World Health Organization reported that four candidate drugs, including remdesivir, are ineffective or have little effect on COVID-19. According to China News, 90 % of Chinese patients with COVID-19 use traditional Chinese medicine (TCM), with an effectiveness rate of 80 %, and no deterioration in patient condition. We have compiled the direct evidence of TCM treatment for COVID-19 as of December 31, 2020. We describe the advantages of TCM in the treatment of COVID-19 based on clinical evidence and the required methods for its clinical use. TCM can inhibit virus replication and transcription, prevent the combination of SARS-CoV-2 and the host, and attenuate the cytokine storm and immune deficiency caused by the virus infection. The cooperation of many countries is required to establish international guidelines regarding the use of TCM in patients with severe COVID-19 from other regions and of different ethnicities. Studies on the psychological abnormalities in patients with COVID-19, and medical staff, is lacking; it is necessary to provide a complete chain of evidence to determine the efficacy of TCM in the related prevention, treatment, and recovery. This study aims to provide a reference for the rational use of TCM in the treatment of COVID-19.
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32
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Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening: Identification of an allosteric small-molecule binding site on the Nsp13 helicase. PLoS One 2021; 16:e0246181. [PMID: 33596235 PMCID: PMC7888625 DOI: 10.1371/journal.pone.0246181] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/14/2021] [Indexed: 01/18/2023] Open
Abstract
The 2019 emergence of, SARS-CoV-2 has tragically taken an immense toll on human life and far reaching impacts on society. There is a need to identify effective antivirals with diverse mechanisms of action in order to accelerate preclinical development. This study focused on five of the most established drug target proteins for direct acting small molecule antivirals: Nsp5 Main Protease, Nsp12 RNA-dependent RNA polymerase, Nsp13 Helicase, Nsp16 2'-O methyltransferase and the S2 subunit of the Spike protein. A workflow of solvent mapping and free energy calculations was used to identify and characterize favorable small-molecule binding sites for an aromatic pharmacophore (benzene). After identifying the most favorable sites, calculated ligand efficiencies were compared utilizing computational fragment screening. The most favorable sites overall were located on Nsp12 and Nsp16, whereas the most favorable sites for Nsp13 and S2 Spike had comparatively lower ligand efficiencies relative to Nsp12 and Nsp16. Utilizing fragment screening on numerous possible sites on Nsp13 helicase, we identified a favorable allosteric site on the N-terminal zinc binding domain (ZBD) that may be amenable to virtual or biophysical fragment screening efforts. Recent structural studies of the Nsp12:Nsp13 replication-transcription complex experimentally corroborates ligand binding at this site, which is revealed to be a functional Nsp8:Nsp13 protein-protein interaction site in the complex. Detailed structural analysis of Nsp13 ZBD conformations show the role of induced-fit flexibility in this ligand binding site and identify which conformational states are associated with efficient ligand binding. We hope that this map of over 200 possible small-molecule binding sites for these drug targets may be of use for ongoing discovery, design, and drug repurposing efforts. This information may be used to prioritize screening efforts or aid in the process of deciphering how a screening hit may bind to a specific target protein.
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Zhang Y, Tang LV. Overview of Targets and Potential Drugs of SARS-CoV-2 According to the Viral Replication. J Proteome Res 2021; 20:49-59. [PMID: 33347311 PMCID: PMC7770889 DOI: 10.1021/acs.jproteome.0c00526] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Indexed: 01/18/2023]
Abstract
Since the novel coronavirus pandemic, people around the world have been touched in varying degrees, and this pandemic has raised a major global health concern. As there is no effective drug or vaccine, it is urgent to find therapeutic drugs that can serve to deal with the current epidemic situation in all countries and regions. We searched drugs and response measures for SARS-CoV-2 in the PubMed database, and then updated the potential targets and therapeutic drugs from the perspective of the viral replication cycle. The drug research studies of the viral replication cycle are predominantly focused on the process of the virus entering cells, proteases, and RdRp. The inhibitors of the virus entry to cells and RdRp, such as Arbidol, remdesivir, favipiravir, EIDD-2081, and ribavirin, are in clinical trials, while most of the protease inhibitors are mainly calculated by molecular docking technology, which needs in vivo and in vitro experiments to prove the effect for SARS-CoV-2. This review summarizes the drugs targeting the viral replication process and provides a basis and directions for future drug development and reuse on the protein level of COVID-19.
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Affiliation(s)
- Yi Zhang
- Institute
of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Liang V. Tang
- Institute
of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Silva LR, da Silva Santos-Júnior PF, de Andrade Brandão J, Anderson L, Bassi ÊJ, Xavier de Araújo-Júnior J, Cardoso SH, da Silva-Júnior EF. Druggable targets from coronaviruses for designing new antiviral drugs. Bioorg Med Chem 2020; 28:115745. [PMID: 33007557 PMCID: PMC7836322 DOI: 10.1016/j.bmc.2020.115745] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/26/2020] [Accepted: 08/29/2020] [Indexed: 01/18/2023]
Abstract
Severe respiratory infections were highlighted in the SARS-CoV outbreak in 2002, as well as MERS-CoV, in 2012. Recently, the novel CoV (COVID-19) has led to severe respiratory damage to humans and deaths in Asia, Europe, and Americas, which allowed the WHO to declare the pandemic state. Notwithstanding all impacts caused by Coronaviruses, it is evident that the development of new antiviral agents is an unmet need. In this review, we provide a complete compilation of all potential antiviral agents targeting macromolecular structures from these Coronaviruses (Coronaviridae), providing a medicinal chemistry viewpoint that could be useful for designing new therapeutic agents.
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Affiliation(s)
- Leandro Rocha Silva
- Chemistry and Biotechnology Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil; Laboratory of Organic and Medicinal Synthesis, Federal University of Alagoas, Campus Arapiraca, Manoel Severino Barbosa Avenue, Arapiraca 57309-005, Brazil
| | | | - Júlia de Andrade Brandão
- IMUNOREG - Immunoregulation Research Group, Laboratory of Research in Virology and Immunology, Institute of Biological Sciences and Health, Federal University of Alagoas, Campus AC. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil
| | - Letícia Anderson
- IMUNOREG - Immunoregulation Research Group, Laboratory of Research in Virology and Immunology, Institute of Biological Sciences and Health, Federal University of Alagoas, Campus AC. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil; CESMAC University Center, Cônego Machado Street, Maceió 57051-160, Brazil
| | - Ênio José Bassi
- IMUNOREG - Immunoregulation Research Group, Laboratory of Research in Virology and Immunology, Institute of Biological Sciences and Health, Federal University of Alagoas, Campus AC. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil
| | - João Xavier de Araújo-Júnior
- Chemistry and Biotechnology Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil; Laboratory of Medicinal Chemistry, Pharmaceutical Sciences Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil
| | - Sílvia Helena Cardoso
- Laboratory of Organic and Medicinal Synthesis, Federal University of Alagoas, Campus Arapiraca, Manoel Severino Barbosa Avenue, Arapiraca 57309-005, Brazil
| | - Edeildo Ferreira da Silva-Júnior
- Chemistry and Biotechnology Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil; Laboratory of Medicinal Chemistry, Pharmaceutical Sciences Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió 57072-970, Brazil.
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Ugurel OM, Mutlu O, Sariyer E, Kocer S, Ugurel E, Inci TG, Ata O, Turgut-Balik D. Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13). Int J Biol Macromol 2020; 163:1687-1696. [PMID: 32980406 PMCID: PMC7513821 DOI: 10.1016/j.ijbiomac.2020.09.138] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 09/15/2020] [Accepted: 09/19/2020] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2 has caused COVID-19 outbreak with nearly 2 M infected people and over 100K death worldwide, until middle of April 2020. There is no confirmed drug for the treatment of COVID-19 yet. As the disease spread fast and threaten human life, repositioning of FDA approved drugs may provide fast options for treatment. In this aspect, structure-based drug design could be applied as a powerful approach in distinguishing the viral drug target regions from the host. Evaluation of variations in SARS-CoV-2 genome may ease finding specific drug targets in the viral genome. In this study, 3458 SARS-CoV-2 genome sequences isolated from all around the world were analyzed. Incidence of C17747T and A17858G mutations were observed to be much higher than others and they were on Nsp13, a vital enzyme of SARS-CoV-2. Effect of these mutations was evaluated on protein-drug interactions using in silico methods. The most potent drugs were found to interact with the key and neighbor residues of the active site responsible from ATP hydrolysis. As result, cangrelor, fludarabine, folic acid and polydatin were determined to be the most potent drugs which have potency to inhibit both the wild type and mutant SARS-CoV-2 helicase. Clinical data supporting these findings would be important towards overcoming COVID-19.
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Affiliation(s)
- Osman Mutluhan Ugurel
- Yildiz Technical University, Faculty of Chemical and Metallurgical Engineering, Department of Bioengineering, Davutpasa Campus, 34210 Esenler, Istanbul, Turkey; Altinbas University, School of Engineering and Natural Science, Department of Basic Science, 34217 Bagcilar, Istanbul, Turkey
| | - Ozal Mutlu
- Marmara University, Faculty of Arts and Sciences, Department of Biology, Goztepe Campus, 34722 Kadikoy, Istanbul, Turkey
| | - Emrah Sariyer
- Artvin Coruh University, Vocational School of Health Services, Medical Laboratory Techniques, Artvin, Turkey
| | - Sinem Kocer
- Istanbul Yeni Yuzyil University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, 34010 Cevizlibag, Istanbul, Turkey
| | - Erennur Ugurel
- Yildiz Technical University, Faculty of Chemical and Metallurgical Engineering, Department of Bioengineering, Davutpasa Campus, 34210 Esenler, Istanbul, Turkey
| | - Tugba Gul Inci
- Yildiz Technical University, Faculty of Chemical and Metallurgical Engineering, Department of Bioengineering, Davutpasa Campus, 34210 Esenler, Istanbul, Turkey
| | - Oguz Ata
- Altinbas University, School of Engineering and Natural Science, Department of Software Engineering, 34217 Bagcilar, Istanbul, Turkey
| | - Dilek Turgut-Balik
- Yildiz Technical University, Faculty of Chemical and Metallurgical Engineering, Department of Bioengineering, Davutpasa Campus, 34210 Esenler, Istanbul, Turkey.
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Vallamkondu J, John A, Wani WY, Ramadevi SP, Jella KK, Reddy PH, Kandimalla R. SARS-CoV-2 pathophysiology and assessment of coronaviruses in CNS diseases with a focus on therapeutic targets. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165889. [PMID: 32603829 PMCID: PMC7320676 DOI: 10.1016/j.bbadis.2020.165889] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 02/06/2023]
Abstract
The novel Coronavirus disease of 2019 (nCOV-19) is a viral outbreak noted first in Wuhan, China. This disease is caused by Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2. In the past, other members of the coronavirus family, such as SARS and Middle East Respiratory Syndrome (MERS), have made an impact in China and the Arabian peninsula respectively. Both SARS and COVID-19 share similar symptoms such as fever, cough, and difficulty in breathing that can become fatal in later stages. However, SARS and MERS infections were epidemic diseases constrained to limited regions. By March 2020 the SARS-CoV-2 had spread across the globe and on March 11th, 2020 the World Health Organization (WHO) declared COVID-19 as pandemic disease. In severe SARS-CoV-2 infection, many patients succumbed to pneumonia. Higher rates of deaths were seen in older patients who had co-morbidities such as diabetes mellitus, hypertension, cardiovascular disease (CVD), and dementia. In this review paper, we discuss the effect of SARS-CoV-2 on CNS diseases, such as Alzheimer's-like dementia, and diabetes mellitus. We also focus on the virus genome, pathophysiology, theranostics, and autophagy mechanisms. We will assess the multiorgan failure reported in advanced stages of SARS-CoV-2 infection. Our paper will provide mechanistic clues and therapeutic targets for physicians and investigators to combat COVID-19.
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Affiliation(s)
| | - Albin John
- Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Willayat Yousuf Wani
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | | | | | - P Hemachandra Reddy
- Professor of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Internal Medicine, Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
| | - Ramesh Kandimalla
- Department of Biochemistry, Kakatiya Medical College, Warangal 506007, Telangana, India; Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India.
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Khare P, Sahu U, Pandey SC, Samant M. Current approaches for target-specific drug discovery using natural compounds against SARS-CoV-2 infection. Virus Res 2020; 290:198169. [PMID: 32979476 PMCID: PMC7513916 DOI: 10.1016/j.virusres.2020.198169] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 12/23/2022]
Abstract
The pandemic of COVID-19 remains to affect the whole world. Current remedies for COVID-19 is not satisfactory/available. The therapeutic efficacy of Natural Compounds is well explored in various viral infections. Natural Compounds could be explored as target specific therapeutic agents against COVID-19 infection. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) recently caused a pandemic outbreak called coronavirus disease 2019 (COVID-19). This disease has initially been reported in China and also now it is expeditiously spreading around the globe directly among individuals through coughing and sneezing. Since it is a newly emerging viral disease and obviously there is a lack of anti-SARS-CoV-2 therapeutic agents, it is urgently required to develop an effective anti-SARS-CoV-2-agent.Through recent advancements in computational biology and biological assays, several natural compounds and their derivatives have been reported to confirm their target specific antiviral potential against Middle East respiratory syndrome coronavirus (MERS-CoV) or Severe Acute Respiratory Syndrome(SARS-CoV).These targets including an important host cell receptor, i.e., angiotensin-converting enzyme ACE2 and several viral proteins e.g. spike glycoprotein (S) containing S1 and S2 domains, SARS CoV Chymotrypsin-like cysteine protease (3CLpro), papain-like cysteine protease (PLpro), helicases and RNA-dependent RNA polymerase (RdRp). Due to physical, chemical, and some genetic similarities of SARS CoV-2 with SARS−COV and MERS−COV, repurposing various anti-SARS−COV or anti-MERS−COV natural therapeutic agents could be helpful for the development of anti−COVID-19 herbal medicine. Here we have summarized various drug targets in SARS−COV and MERS−COV using several natural products and their derivatives, which could guide researchers to design and develop a safe and cost-effective anti-SARS−COV-2 drugs.
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Affiliation(s)
- Prashant Khare
- Department of Microbiology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Utkarsha Sahu
- Department of Microbiology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Satish Chandra Pandey
- Cell and Molecular Biology Laboratory, Department of Zoology, Kumaun University, SSJ Campus, Almora, Uttarakhand, India
| | - Mukesh Samant
- Cell and Molecular Biology Laboratory, Department of Zoology, Kumaun University, SSJ Campus, Almora, Uttarakhand, India.
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38
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Wondmkun YT, Mohammed OA. A Review on Novel Drug Targets and Future Directions for COVID-19 Treatment. Biologics 2020; 14:77-82. [PMID: 32921981 PMCID: PMC7457863 DOI: 10.2147/btt.s266487] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/04/2020] [Indexed: 12/22/2022]
Abstract
Severe acute respiratory syndrome coronavirus-2 causes coronavirus disease-19 (COVID-19) that spreads quickly in the world. Considering the impact of this pandemic, researchers have been racing to understand the peculiar nature of the virus and the pathogenesis of the disease to uncover possible drug targets, effective therapeutic agents, and vaccines. Accordingly, numerous drug targets are identified by scientists. Among them, structural glycoproteins, virulence factors, host-specific receptors and enzymes, non-structure proteins, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, and pro-inflammatory cytokines are discussed herein. This review summarizes the promising drug targets for COVID-19, and highlights antiviral strategies which depend on molecular interactions between viral small molecules and host biologic machinery for repurposing the available clinical drugs. In addition, it gives a strong rational basis for the ongoing discovery of new drugs and vaccines.
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Affiliation(s)
- Yohannes Tsegyie Wondmkun
- Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
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Abstract
A novel pathogen, named SARS-CoV-2, has caused an unprecedented worldwide pandemic in the first half of 2020. As the SARS-CoV-2 genome sequences have become available, one of the important focus of scientists has become tracking variations in the viral genome. In this study, 30366 SARS-CoV-2 isolate genomes were aligned using the software developed by our group (ODOTool) and 11 variations in SARS-CoV-2 genome over 10% of whole isolates were discussed. Results indicated that, frequency rates of these 11 variations change between 3.56%-88.44 % and these rates differ greatly depending on the continents they have been reported. Despite some variations being in low frequency rate in some continents, C14408T and A23403G variations on Nsp12 and S protein, respectively, observed to be the most prominent variations all over the world, in general, and both cause missense mutations. It is also notable that most of isolates carry C14408T and A23403 variations simultaneously and also nearly all isolates carrying the G25563T variation on ORF3a, also carry C14408T and A23403 variations, although their location distributions are not similar. All these data should be considered towards development of vaccine and antiviral treatment strategies as well as tracing diversity of virus in all over the world.
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Affiliation(s)
- Osman Mutluhan Ugurel
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yıldız Technical University, İstanbul Turkey.,Department of Basic Sciences, School of Engineering and Natural Sciences, Altınbaş University, İstanbul Turkey
| | - Oguz Ata
- Department of Software Engineering, School of Engineering and Natural Sciences, Altınbaş University, İstanbul Turkey
| | - Dilek Turgut-Balik
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yıldız Technical University, İstanbul Turkey
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40
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Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2020; 70:145-159. [PMID: 31955138 DOI: 10.2478/acph-2020-0024] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/08/2019] [Indexed: 01/19/2023]
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) had emerged and spread because of the worldwide travel and inefficient healthcare provided for the infected patients in several countries. Herein we investigated the anti-MERS-CoV activity of newly synthesized sixteen halogenated triazole compounds through the inhibition of helicase activity using the FRET assay. All new compounds underwent justification for their target structures via microanalytical and spectral data. SAR studies were performed. Biological results revealed that the most potent compounds were 4-(cyclopent-1-en-3-ylamino)-5-(2-(4-iodophenyl)hydrazinyl)-4H-1,2,4-triazole-3-thiol (16) and 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-chlorophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol (12). In silico molecular docking of the most potent compounds was performed to the active binding site of MERS-CoV helicase nsp13. Molecular docking results are in agreement with experimental findings.
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41
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Bhatia R, Narang RK, Rawal RK. A Summary of Viral Targets and Recently Released PDB IDs of SARS-CoV-2. Open Virol J 2020. [DOI: 10.2174/1874357902014010007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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42
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Prajapat M, Sarma P, Shekhar N, Avti P, Sinha S, Kaur H, Kumar S, Bhattacharyya A, Kumar H, Bansal S, Medhi B. Drug targets for corona virus: A systematic review. Indian J Pharmacol 2020; 52:56-65. [PMID: 32201449 PMCID: PMC7074424 DOI: 10.4103/ijp.ijp_115_20] [Citation(s) in RCA: 281] [Impact Index Per Article: 56.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/31/2022] Open
Abstract
The 2019-novel coronavirus (nCoV) is a major source of disaster in the 21th century. However, the lack of specific drugs to prevent/treat an attack is a major need at this current point of time. In this regard, we conducted a systematic review to identify major druggable targets in coronavirus (CoV). We searched PubMed and RCSB database with keywords HCoV, NCoV, corona virus, SERS-CoV, MERS-CoV, 2019-nCoV, crystal structure, X-ray crystallography structure, NMR structure, target, and drug target till Feb 3, 2020. The search identified seven major targets (spike protein, envelop protein, membrane protein, protease, nucleocapsid protein, hemagglutinin esterase, and helicase) for which drug design can be considered. There are other 16 nonstructural proteins (NSPs), which can also be considered from the drug design perspective. The major structural proteins and NSPs may serve an important role from drug design perspectives. However, the occurrence of frequent recombination events is a major deterrent factor toward the development of CoV-specific vaccines/drugs.
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Affiliation(s)
- Manisha Prajapat
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Phulen Sarma
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Nishant Shekhar
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pramod Avti
- Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shweta Sinha
- Department of Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Hardeep Kaur
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Subodh Kumar
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anusuya Bhattacharyya
- Departments of Ophthalmology, Government Medical College and Hospital, Chandigarh, India
| | - Harish Kumar
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Seema Bansal
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Bikash Medhi
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Zika viral proteome analysis reveals an epitope cluster within NS3 helicase as a potential vaccine candidate: An in silico study. INFORMATICS IN MEDICINE UNLOCKED 2020. [DOI: 10.1016/j.imu.2020.100434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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44
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Prajapat M, Sarma P, Shekhar N, Avti P, Sinha S, Kaur H, Kumar S, Bhattacharyya A, Kumar H, Bansal S, Medhi B. Drug targets for corona virus: A systematic review. Indian J Pharmacol 2020. [PMID: 32201449 DOI: 10.4103/ijp.ijp.115-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/15/2023] Open
Abstract
The 2019-novel coronavirus (nCoV) is a major source of disaster in the 21th century. However, the lack of specific drugs to prevent/treat an attack is a major need at this current point of time. In this regard, we conducted a systematic review to identify major druggable targets in coronavirus (CoV). We searched PubMed and RCSB database with keywords HCoV, NCoV, corona virus, SERS-CoV, MERS-CoV, 2019-nCoV, crystal structure, X-ray crystallography structure, NMR structure, target, and drug target till Feb 3, 2020. The search identified seven major targets (spike protein, envelop protein, membrane protein, protease, nucleocapsid protein, hemagglutinin esterase, and helicase) for which drug design can be considered. There are other 16 nonstructural proteins (NSPs), which can also be considered from the drug design perspective. The major structural proteins and NSPs may serve an important role from drug design perspectives. However, the occurrence of frequent recombination events is a major deterrent factor toward the development of CoV-specific vaccines/drugs.
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Affiliation(s)
- Manisha Prajapat
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Phulen Sarma
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Nishant Shekhar
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pramod Avti
- Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shweta Sinha
- Department of Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Hardeep Kaur
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Subodh Kumar
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anusuya Bhattacharyya
- Departments of Ophthalmology, Government Medical College and Hospital, Chandigarh, India
| | - Harish Kumar
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Seema Bansal
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Bikash Medhi
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Karger A, Pérez-Núñez D, Urquiza J, Hinojar P, Alonso C, Freitas FB, Revilla Y, Le Potier MF, Montoya M. An Update on African Swine Fever Virology. Viruses 2019; 11:v11090864. [PMID: 31533244 PMCID: PMC6784044 DOI: 10.3390/v11090864] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/05/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
Animal diseases constitute a continuing threat to animal health, food safety, national economy, and the environment. Among those, African swine fever (ASF) is one of the most devastating viruses affecting pigs and wild suids due to the lack of vaccine or effective treatment. ASF is endemic in countries in sub-Saharan Africa, but since its introduction to the Caucasus region in 2007, a highly virulent strain of ASF virus (ASFV) has continued to circulate and spread into Eastern Europe and Russia, and most recently into Western Europe, China, and various countries of Southeast Asia. Given the importance of this disease, this review will highlight recent discoveries in basic virology with special focus on proteomic analysis, replication cycle, and some recent data on genes involved in cycle progression and viral–host interactions, such as I215L (E2 ubiquitin-conjugating enzyme), EP402R (CD2v), A104R (histone-like protein), QP509L, and Q706L (RNA helicases) or P1192R (Topoisomerase II). Taking into consideration the large DNA genome of ASFV and its complex interactions with the host, more studies and new approaches are to be taken to understand the basic virus–host interaction for ASFV. Proteomic studies are just paving the way for future research.
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Affiliation(s)
- Axel Karger
- Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany;
| | - Daniel Pérez-Núñez
- Virology Department, Centro Biología Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain; (D.P.-N.); (Y.R.)
| | - Jesús Urquiza
- INIA, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, 28040 Madrid, Spain; (J.U.); (P.H.); (C.A.)
| | - Patricia Hinojar
- INIA, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, 28040 Madrid, Spain; (J.U.); (P.H.); (C.A.)
| | - Covadonga Alonso
- INIA, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, 28040 Madrid, Spain; (J.U.); (P.H.); (C.A.)
| | - Ferdinando B. Freitas
- Centre for Interdisciplinary Research in Animal Health (CIISA), Faculty of Veterinary Medicine, University of Lisbon, 1649-004 Lisboa, Portugal;
| | - Yolanda Revilla
- Virology Department, Centro Biología Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain; (D.P.-N.); (Y.R.)
| | - Marie-Frédérique Le Potier
- ANSES, Laboratoire de Ploufragan/Plouzané/Niort, Unité Virologie Immunologie Porcines, Anses, 22440 Ploufragan, France;
| | - Maria Montoya
- Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
- Correspondence:
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Badshah SL, Ahmad N, Ur Rehman A, Khan K, Ullah A, Alsayari A, Muhsinah AB, N Mabkhot Y. Molecular docking and simulation of Zika virus NS3 helicase. BMC Chem 2019; 13:67. [PMID: 31384814 PMCID: PMC6661806 DOI: 10.1186/s13065-019-0582-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 05/02/2019] [Indexed: 02/06/2023] Open
Abstract
The Zika virus (ZIKV) has gained attention for the last few years due to the congenital microcephaly and Guillain–Barre Syndrome that resulted in humans. The non-structural protein-3 (NS3) helicase of ZIKV play an important role in viral RNA replication. In this article, we performed hundred nanosecond molecular dynamics simulation and molecular docking of the NS3 helicase of ZIKV with 1,4-benzothiazine derivatives. The root mean square deviation (RMSD) analyses showed the stability of the NS3 helicase. The simulation showed that the flexible and rigid domains of the protein play a crucial role during the RNA replication process. All such domains with ligand binding pockets can be targeted for drug design. The molecular docking showed that the strong hydrogen bonding and arene-cation interactions are responsible for the binding between NS3 and 1,4-benzothiazine derivatives, which provides a new dimension for potent drug design for ZIKV.
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Affiliation(s)
- Syed Lal Badshah
- 1Department of Chemistry, Islamia College University, Peshawar, Khyber Pakhtunkhwa Pakistan
| | - Nasir Ahmad
- 1Department of Chemistry, Islamia College University, Peshawar, Khyber Pakhtunkhwa Pakistan
| | - Ashfaq Ur Rehman
- 2State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240 China
| | - Khalid Khan
- 1Department of Chemistry, Islamia College University, Peshawar, Khyber Pakhtunkhwa Pakistan
| | - Asad Ullah
- 1Department of Chemistry, Islamia College University, Peshawar, Khyber Pakhtunkhwa Pakistan
| | - Abdulrhman Alsayari
- 3Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, 62529 Saudi Arabia
| | - Abdullatif Bin Muhsinah
- 3Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, 62529 Saudi Arabia
| | - Yahia N Mabkhot
- 4Department of Pharmaceutical Chemistry, College of Pharamacy, King Khalid University, Abha, 61441 Saudi Arabia
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de Lima LP, Calderano SG, da Silva MS, de Araujo CB, Vasconcelos EJR, Iwai LK, Pereira CA, Fragoso SP, Elias MC. Ortholog of the polymerase theta helicase domain modulates DNA replication in Trypanosoma cruzi. Sci Rep 2019; 9:2888. [PMID: 30814563 PMCID: PMC6393585 DOI: 10.1038/s41598-019-39348-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 11/19/2018] [Indexed: 01/05/2023] Open
Abstract
DNA polymerase theta (Polθ), a member of the DNA polymerase family A, exhibits a polymerase C-terminal domain, a central domain, and an N-terminal helicase domain. Polθ plays important roles in DNA repair via its polymerase domain, regulating genome integrity. In addition, in mammals, Polθ modulates origin firing timing and MCM helicase recruitment to chromatin. In contrast, as a model eukaryote, Trypanosoma cruzi exhibits two individual putative orthologs of Polθ in different genomic loci; one ortholog is homologous to the Polθ C-terminal polymerase domain, and the other is homologous to the Polθ helicase domain, called Polθ-polymerase and Polθ-helicase, respectively. A pull-down assay using the T. cruzi component of the prereplication complex Orc1/Cdc6 as bait captured Polθ-helicase from the nuclear extract. Orc1/Cdc6 and Polθ-helicase directly interacted, and Polθ-helicase presented DNA unwinding and ATPase activities. A T. cruzi strain overexpressing the Polθ-helicase domain exhibited a significantly decreased amount of DNA-bound MCM7 and impaired replication origin firing. Taken together, these data suggest that Polθ-helicase modulates DNA replication by directly interacting with Orc1/Cdc6, which reduces the binding of MCM7 to DNA and thereby impairs the firing of replication origins.
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Affiliation(s)
- Loyze P de Lima
- Laboratorio Especial de Ciclo Celular, Instituto Butantan, São Paulo, Brazil
- Center of Toxins, Immune Response and Cell Signaling (CeTICS), Instituto Butantan, São Paulo, Brazil
| | | | - Marcelo S da Silva
- Laboratorio Especial de Ciclo Celular, Instituto Butantan, São Paulo, Brazil
- Center of Toxins, Immune Response and Cell Signaling (CeTICS), Instituto Butantan, São Paulo, Brazil
| | - Christiane B de Araujo
- Laboratorio Especial de Ciclo Celular, Instituto Butantan, São Paulo, Brazil
- Center of Toxins, Immune Response and Cell Signaling (CeTICS), Instituto Butantan, São Paulo, Brazil
| | - Elton J R Vasconcelos
- College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, 91766, USA
| | - Leo K Iwai
- Laboratório Especial de Toxinologia Aplicada, Instituto Butantan, São Paulo, Brazil
| | - Claudio A Pereira
- Laboratorio de Parasitología Molecular, Instituto de Investigaciones Médicas A. Lanari, Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Combatientes de Malvinas, (C1427ARO) Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | | | - M Carolina Elias
- Laboratorio Especial de Ciclo Celular, Instituto Butantan, São Paulo, Brazil.
- Center of Toxins, Immune Response and Cell Signaling (CeTICS), Instituto Butantan, São Paulo, Brazil.
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Freitas FB, Frouco G, Martins C, Ferreira F. The QP509L and Q706L superfamily II RNA helicases of African swine fever virus are required for viral replication, having non-redundant activities. Emerg Microbes Infect 2019; 8:291-302. [PMID: 30866783 PMCID: PMC6455146 DOI: 10.1080/22221751.2019.1578624] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/15/2019] [Accepted: 01/21/2019] [Indexed: 01/06/2023]
Abstract
African swine fever virus is complex DNA virus that infects pigs with mortality rates up to 100% leading to devastating socioeconomic effected in the affected countries. There is neither a vaccine nor a treatment to control ASF. African swine fever virus genome encodes two putative SF2 RNA helicases (QP509L and Q706L). In the present study, we found that these two RNA helicases do not share a common ancestral besides sharing a sequence overlap. Although, our phylogenetic studies revealed that they are conserved among virulent and non-virulent isolates, it was possible to observe a degree of variation between isolates corresponding to different genotypes occurring in distinct geographic regions. Further experiments showed that QP509L and Q706L are actively transcribed from 4 h post infection. The immunoblot analysis revealed that both protein co-localized in the viral factories at 12 h post infection, however, QP509L was also detected in the cell nucleus. Finally, siRNA assays uncover the relevant role of these proteins during viral cycle progression, in particular, for the late transcription, genome replication, and viral progeny (a reduction of infectious particles up to 99.4% when siRNA against QP509L was used and 98.4% for siRNA against Q706L). Thus, our results suggest that both helicases are essential during viral infection, highlighting the potential use of these enzymes as target for drug and vaccine development against African swine fever.
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Affiliation(s)
- Ferdinando B. Freitas
- CIISA – Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
| | - Gonçalo Frouco
- CIISA – Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
| | - Carlos Martins
- CIISA – Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
| | - Fernando Ferreira
- CIISA – Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
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Anang S, Kaushik N, Surjit M. Recent Advances Towards the Development of a Potent Antiviral Against the Hepatitis E Virus. J Clin Transl Hepatol 2018; 6:310-316. [PMID: 30271744 PMCID: PMC6160310 DOI: 10.14218/jcth.2018.00005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 02/19/2018] [Accepted: 03/23/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatitis E virus (HEV) is one of the leading causes of acute viral hepatitis. It also causes acute liver failure and acute-on-chronic liver failure in many patients, such as those suffering from other infections/liver injuries or organ transplant/chemotherapy recipients. Despite widespread sporadic and epidemic incidents, there is no specific treatment against HEV, justifying an urgent need for developing a potent antiviral against it. This review summarizes the known antiviral candidates and provides an overview of the potential targets for the development of specific antivirals against HEV.
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Affiliation(s)
- Saumya Anang
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Nidhi Kaushik
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Milan Surjit
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
- *Correspondence to: Milan Surjit, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, PO Box No. 04, Faridabad-121001, Haryana, India. Tel: +91-129-2876-318, Fax: +91-129-2876400, E-mail:
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50
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Molecular Recognition Features in Zika Virus Proteome. J Mol Biol 2018; 430:2372-2388. [DOI: 10.1016/j.jmb.2017.10.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 10/18/2017] [Accepted: 10/18/2017] [Indexed: 12/23/2022]
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