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1
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Kang JW, Ki Chan KW, Vasudevan SG, Low JG. α-Glucosidase Inhibitors as Broad-Spectrum Antivirals: Current Knowledge and Future Prospects. Antiviral Res 2025:106147. [PMID: 40120858 DOI: 10.1016/j.antiviral.2025.106147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/17/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Affiliation(s)
- James Wj Kang
- Department of Infectious Diseases, Singapore General Hospital, Singapore 168753, Singapore.
| | - Kitti Wing Ki Chan
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Subhash G Vasudevan
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore; Institute of Biomedicine and Glycomics, Griffith University, Queensland, Australia
| | - Jenny G Low
- Department of Infectious Diseases, Singapore General Hospital, Singapore 168753, Singapore; Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore; Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore 169857, Singapore
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2
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Liu Q, Liu Y, Liu T, Fan J, Xia Z, Zhou Y, Deng X. Expanding horizons of iminosugars as broad-spectrum anti-virals: mechanism, efficacy and novel developments. NATURAL PRODUCTS AND BIOPROSPECTING 2024; 14:55. [PMID: 39325109 PMCID: PMC11427655 DOI: 10.1007/s13659-024-00477-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 09/14/2024] [Indexed: 09/27/2024]
Abstract
Iminosugars, a class of polyhydroxylated cyclic alkaloids with intriguing properties, hold promising therapeutic potentials against a broad spectrum of enveloped viruses, including DENV, HCV, HIV, and influenza viruses. Mechanistically, iminosugars act as the competitive inhibitors of host endoplasmic reticular α-glucosidases I and II to disrupt the proper folding of viral nascent glycoproteins, which thereby exerts antiviral effects. Remarkably, the glycoproteins of many enveloped viruses are significantly more dependent on the calnexin pathway of the protein folding than most host glycoproteins. Therefore, extensive interests and efforts have been devoted to exploit iminosugars as broad-spectrum antiviral agents. This review provides the summary and insights into the recent advancements in the development of novel iminosugars as effective and selective antiviral agents against a variety of enveloped viruses, as well as the understandings of their antiviral mechanisms.
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Affiliation(s)
- Qiantong Liu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Yanyun Liu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Tingting Liu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Jinbao Fan
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Zanxian Xia
- School of Life Science, Central South University, Changsha, 410013, Hunan, China
| | - Yingjun Zhou
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Xu Deng
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China.
- Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, Hunan, China.
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3
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Akram M, Hameed S, Hassan A, Khan KM. Development in the Inhibition of Dengue Proteases as Drug Targets. Curr Med Chem 2024; 31:2195-2233. [PMID: 37723635 DOI: 10.2174/0929867331666230918110144] [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: 03/20/2023] [Revised: 06/24/2023] [Accepted: 08/04/2023] [Indexed: 09/20/2023]
Abstract
BACKGROUND Viral infections continue to increase morbidity and mortality severely. The flavivirus genus has fifty different species, including the dengue, Zika, and West Nile viruses that can infect 40% of individuals globally, who reside in at least a hundred different countries. Dengue, one of the oldest and most dangerous human infections, was initially documented by the Chinese Medical Encyclopedia in the Jin period. It was referred to as "water poison," connected to flying insects, i.e., Aedes aegypti and Aedes albopictus. DENV causes some medical expressions like dengue hemorrhagic fever, acute febrile illness, and dengue shock syndrome. OBJECTIVE According to the World Health Organization report of 2012, 2500 million people are in danger of contracting dengue fever worldwide. According to a recent study, 96 million of the 390 million dengue infections yearly show some clinical or subclinical severity. There is no antiviral drug or vaccine to treat this severe infection. It can be controlled by getting enough rest, drinking plenty of water, and using painkillers. The first dengue vaccine created by Sanofi, called Dengvaxia, was previously approved by the USFDA in 2019. All four serotypes of the DENV1-4 have shown re-infection in vaccine recipients. However, the usage of Dengvaxia has been constrained by its adverse effects. CONCLUSION Different classes of compounds have been reported against DENV, such as nitrogen-containing heterocycles (i.e., imidazole, pyridine, triazoles quinazolines, quinoline, and indole), oxygen-containing heterocycles (i.e., coumarins), and some are mixed heterocyclic compounds of S, N (thiazole, benzothiazine, and thiazolidinediones), and N, O (i.e., oxadiazole). There have been reports of computationally designed compounds to impede the molecular functions of specific structural and non-structural proteins as potential therapeutic targets. This review summarized the current progress in developing dengue protease inhibitors.
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Affiliation(s)
- Muhammad Akram
- Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Shehryar Hameed
- H.E.J. Research Institute of Chemistry, International Centre for Chemical and Biological Sciences, University of Karachi, Karachi, 75720, Pakistan
| | - Abbas Hassan
- Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Khalid Mohammed Khan
- H.E.J. Research Institute of Chemistry, International Centre for Chemical and Biological Sciences, University of Karachi, Karachi, 75720, Pakistan
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4
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Wang X, Li J, Shang J, Bai J, Wu K, Liu J, Yang Z, Ou H, Shao L. Metabolites extracted from microorganisms as potential inhibitors of glycosidases (α-glucosidase and α-amylase): A review. Front Microbiol 2022; 13:1050869. [PMID: 36466660 PMCID: PMC9712454 DOI: 10.3389/fmicb.2022.1050869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/17/2022] [Indexed: 09/30/2023] Open
Abstract
α-Glucosidase and α-amylase are the two main glycosidases that participate in the metabolism of carbohydrates. Inhibitors of these two enzymes are considered an important medical treatment for carbohydrate uptake disorders, such as diabetes and obesity. Microbes are an important source of constituents that have the potential to inhibit glycosidases and can be used as sources of new drugs and dietary supplements. For example, the α-glucosidase inhibitor acarbose, isolated from Actinoplanes sp., has played an important role in adequately controlling type 2 diabetes, but this class of marketed drugs has many drawbacks, such as poor compliance with treatment and expense. This demonstrates the need for new microorganism-derived resources, as well as novel classes of drugs with better compliance, socioeconomic benefits, and safety. This review introduces the literature on microbial sources of α-glucosidase and α-amylase inhibitors, with a focus on endophytes and marine microorganisms, over the most recent 5 years. This paper also reviews the application of glycosidase inhibitors as drugs and dietary supplements. These studies will contribute to the future development of new microorganism-derived glycosidase inhibitors.
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Affiliation(s)
- Xiaojing Wang
- Affiliated Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, China
- Microbial Pharmacology Laboratory, Shanghai University of Medicine and Health Sciences, Shanghai, China
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Jiaying Li
- Microbial Pharmacology Laboratory, Shanghai University of Medicine and Health Sciences, Shanghai, China
- Shanghai University of Medicine and Health Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiaqi Shang
- Microbial Pharmacology Laboratory, Shanghai University of Medicine and Health Sciences, Shanghai, China
- School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Jing Bai
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, China
| | - Kai Wu
- Microbial Pharmacology Laboratory, Shanghai University of Medicine and Health Sciences, Shanghai, China
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Jing Liu
- Microbial Pharmacology Laboratory, Shanghai University of Medicine and Health Sciences, Shanghai, China
- School of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Zhijun Yang
- Microbial Pharmacology Laboratory, Shanghai University of Medicine and Health Sciences, Shanghai, China
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Hao Ou
- Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lei Shao
- Microbial Pharmacology Laboratory, Shanghai University of Medicine and Health Sciences, Shanghai, China
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
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5
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Dwek RA, Bell JI, Feldmann M, Zitzmann N. Host-targeting oral antiviral drugs to prevent pandemics. Lancet 2022; 399:1381-1382. [PMID: 35344736 PMCID: PMC8956295 DOI: 10.1016/s0140-6736(22)00454-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 11/05/2022]
Affiliation(s)
- Raymond A Dwek
- Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
| | - John I Bell
- Medical Sciences Division, University of Oxford, Oxford OX1 3QU, UK
| | - Marc Feldmann
- Kennedy Institute of Rheumatology, University of Oxford, Oxford OX1 3QU, UK; Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX1 3QU, UK
| | - Nicole Zitzmann
- Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK
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6
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Identification of an Antiviral Compound from the Pandemic Response Box that Efficiently Inhibits SARS-CoV-2 Infection In Vitro. Microorganisms 2020; 8:microorganisms8121872. [PMID: 33256227 PMCID: PMC7760777 DOI: 10.3390/microorganisms8121872] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/18/2020] [Accepted: 11/24/2020] [Indexed: 12/13/2022] Open
Abstract
With over 50 million currently confirmed cases worldwide, including more than 1.3 million deaths, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has a major impact on the economy and health care system. Currently, limited prophylactic or therapeutic intervention options are available against SARS-CoV-2. In this study, 400 compounds from the antimicrobial “pandemic response box” library were screened for inhibiting properties against SARS-CoV-2. An initial screen on Vero E6 cells identified five compounds that inhibited SARS-CoV-2 replication. However, validation of the selected hits in a human lung cell line highlighted that only a single compound, namely Retro-2.1, efficiently inhibited SARS-CoV-2 replication. Additional analysis revealed that the antiviral activity of Retro-2.1 occurs at a post-entry stage of the viral replication cycle. Combined, these data demonstrate that stringent in vitro screening of preselected compounds in multiple cell lines refines the rapid identification of new potential antiviral candidate drugs targeting SARS-CoV-2.
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7
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N-Glycosylation and N-Glycan Processing in HBV Biology and Pathogenesis. Cells 2020; 9:cells9061404. [PMID: 32512942 PMCID: PMC7349502 DOI: 10.3390/cells9061404] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 05/29/2020] [Accepted: 06/03/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B Virus (HBV) glycobiology has been an area of intensive research in the last decades and continues to be an attractive topic due to the multiple roles that N-glycosylation in particular plays in the virus life-cycle and its interaction with the host that are still being discovered. The three HBV envelope glycoproteins, small (S), medium (M) and large (L) share a very peculiar N-glycosylation pattern, which distinctly regulates their folding, degradation, assembly, intracellular trafficking and antigenic properties. In addition, recent findings indicate important roles of N-linked oligosaccharides in viral pathogenesis and evasion of the immune system surveillance. This review focuses on N-glycosylation’s contribution to HBV infection and disease, with implications for development of improved vaccines and antiviral therapies.
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8
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Yang LF, Shimadate Y, Kato A, Li YX, Jia YM, Fleet GWJ, Yu CY. Synthesis and glycosidase inhibition of N-substituted derivatives of 1,4-dideoxy-1,4-imino-d-mannitol (DIM). Org Biomol Chem 2020; 18:999-1011. [DOI: 10.1039/c9ob02029b] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Four series of N-substituted DIMs have been synthesized and assayed against glycosidases to provide continuous and reliable inhibitory spectra.
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Affiliation(s)
- Lin-Feng Yang
- Beijing National Laboratory for Molecular Science (BNLMS)
- CAS Key Laboratory of Molecular Recognition and Function
- Institute of Chemistry
- Chinese Academy of Sciences
- Beijing 100190
| | - Yuna Shimadate
- Department of Hospital Pharmacy
- University of Toyama
- Toyama 930-0194
- Japan
| | - Atsushi Kato
- Department of Hospital Pharmacy
- University of Toyama
- Toyama 930-0194
- Japan
| | - Yi-Xian Li
- Beijing National Laboratory for Molecular Science (BNLMS)
- CAS Key Laboratory of Molecular Recognition and Function
- Institute of Chemistry
- Chinese Academy of Sciences
- Beijing 100190
| | - Yue-Mei Jia
- Beijing National Laboratory for Molecular Science (BNLMS)
- CAS Key Laboratory of Molecular Recognition and Function
- Institute of Chemistry
- Chinese Academy of Sciences
- Beijing 100190
| | - George W. J. Fleet
- Chemistry Research Laboratory
- Department of Chemistry
- University of Oxford
- Oxford
- UK
| | - Chu-Yi Yu
- Beijing National Laboratory for Molecular Science (BNLMS)
- CAS Key Laboratory of Molecular Recognition and Function
- Institute of Chemistry
- Chinese Academy of Sciences
- Beijing 100190
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9
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Akhundova FN, Kurbanova MM, Huseynzada AE, Alves MJ, Sujayev AR. Synthesis and Bioactivity of New Analogue of Bicyclic 1‐Azafagomine. ChemistrySelect 2019. [DOI: 10.1002/slct.201903190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Fidan N. Akhundova
- Baku State UniversityOrganic Chemistry Department Z. Khalilov 23 Baku AZ 1148
| | | | | | - Maria J. Alves
- Universidade do Minho de GualtarDepartment of Organic Chemistry 4710-057 Braga Portugal
| | - Afsun R. Sujayev
- Laboratory of Organic chemistryInstitute of Chemistry of AdditivesAzerbaijan National Academy of Sciences 1029 Baku, Azerbaijan
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10
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Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1062:277-301. [PMID: 29845540 PMCID: PMC7121742 DOI: 10.1007/978-981-10-8727-1_20] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The antiviral mechanism of action of iminosugars against many enveloped viruses, including dengue virus (DENV), HIV, influenza and hepatitis C virus, is believed to be mediated by inducing misfolding of viral N-linked glycoproteins through inhibition of host endoplasmic reticulum-resident α-glucosidase enzymes. This leads to reduced secretion and/or infectivity of virions and hence lower viral titres, both in vitro and in vivo. Free oligosaccharide analysis from iminosugar-treated cells shows that antiviral activity correlates with production of mono- and tri-glucosylated sugars, indicative of inhibition of ER α-glucosidases. We demonstrate that glucose-mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. Galactose-mimicking iminosugars that have been tested do not inhibit glycoprotein processing but do inhibit glycolipid processing, and are not antiviral against DENV. By comparison, the antiviral activity of glucose-mimetic iminosugars that inhibit endoplasmic reticulum-resident α-glucosidases, but not glycolipid processing, demonstrates that inhibition of α-glucosidases is responsible for iminosugar antiviral activity against DENV. This monograph will review the investigations of many researchers into the mechanisms of action of iminosugars and the contribution of our current understanding of these mechanisms for optimising clinical delivery of iminosugars. The effects of iminosugars on enzymes other than glucosidases, the induction of ER stress and viral receptors will be also put into context. Data suggest that inhibition of α-glucosidases results in inhibited release of virus and is the primary antiviral mechanism of action of iminosugars against DENV.
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11
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Wagatsuma T, Kuno A, Angata K, Tajiri K, Takahashi J, Korenaga M, Mizokami M, Narimatsu H. Highly Sensitive Glycan Profiling of Hepatitis B Viral Particles and a Simple Method for Dane Particle Enrichment. Anal Chem 2018; 90:10196-10203. [PMID: 30074767 DOI: 10.1021/acs.analchem.8b01030] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatitis B virus (HBV) is a double-stranded DNA virus composed of three types of viral particles. The virions are called Dane particles and the others are noninfectious subviral particles (SVPs). In blood, SVPs are detected in abundance, about 1000-10000 fold higher than Dane particles. Dane particles are hazardous because of their strong infectivity, unlike SVPs. Dane particles are covered with an envelope of glycoprotein called HBV surface antigen (HBsAg). HBsAg glycosylation is involved in viral particle formation and secretion. In this study, we established a novel and highly sensitive method for viral glycan profiling of HBsAg using small aliquots of patient serum. Our lectin microarray system could sensitively profile the glycans exposed on HBV while retaining the intact viral particle structure under nonreducing conditions. Several typical lectins were chosen from the lectin microarray results. Specifically, jacalin, which recognizes O-glycan, showed specific and strong reactivity to the M-HBsAg required for Dane particle secretion. Employing the lectin-fractionation method using jacalin, HBV particles were fractionated into jacalin-bound and unbound fractions from patient serum. We measured HBsAg titer and viral DNA load in each fraction using clinical tests. Interestingly, the jacalin-bound fraction contained a major fraction of the HBV viral DNA load. Thus, in this study we have presented a glycan profiling method for HBsAg on the intact HBV particle and an easy and simple method to enrich Dane particles from patient serum by jacalin fractionation.
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Affiliation(s)
- Takanori Wagatsuma
- Research Center for Medical Glycoscience (RCMG) , National Institute of Advanced Industrial Science and Technology , AIST Tsukuba Central 2, 1-1-1, Umezono , Tsukuba , Ibaraki 305-8568 , Japan
- The Research Center for Hepatitis and Immunology , National Center for Global Health and Medicine , 1-7-1, Kohnodai , Ichikawa , Chiba 272-8516 , Japan
| | - Atsushi Kuno
- Research Center for Medical Glycoscience (RCMG) , National Institute of Advanced Industrial Science and Technology , AIST Tsukuba Central 2, 1-1-1, Umezono , Tsukuba , Ibaraki 305-8568 , Japan
| | - Kiyohiko Angata
- Research Center for Medical Glycoscience (RCMG) , National Institute of Advanced Industrial Science and Technology , AIST Tsukuba Central 2, 1-1-1, Umezono , Tsukuba , Ibaraki 305-8568 , Japan
| | - Kazuto Tajiri
- The Third Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science , University of Toyama , 2630, Sugitani , Toyama , Toyama 930-0194 , Japan
| | - Junko Takahashi
- Japanese Red Cross Kinki Block Blood Center , Japanese Red Cross Society , 7-5-17, Saitoasagi , Ibaraki-city , Osaka 567-0085 , Japan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology , National Center for Global Health and Medicine , 1-7-1, Kohnodai , Ichikawa , Chiba 272-8516 , Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology , National Center for Global Health and Medicine , 1-7-1, Kohnodai , Ichikawa , Chiba 272-8516 , Japan
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience (RCMG) , National Institute of Advanced Industrial Science and Technology , AIST Tsukuba Central 2, 1-1-1, Umezono , Tsukuba , Ibaraki 305-8568 , Japan
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12
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Takizawa N, Yamasaki M. Current landscape and future prospects of antiviral drugs derived from microbial products. J Antibiot (Tokyo) 2017; 71:ja2017115. [PMID: 29018267 PMCID: PMC7091927 DOI: 10.1038/ja.2017.115] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 08/10/2017] [Accepted: 08/21/2017] [Indexed: 12/11/2022]
Abstract
Viral infections are a major global health threat. Over the last 50 years, significant efforts have been devoted to the development of antiviral drugs and great success has been achieved for some viruses. However, other virus infections, such as epidemic influenza, still spread globally and new threats continue to arise from emerging and re-emerging viruses and drug-resistant viruses. In this review, the contributions of microbial products isolated in Institute of Microbial Chemistry for antiviral research are summarized. In addition, the current state of development of antiviral drugs that target influenza virus and hepatitis B virus, and the future prospects for antivirals from natural products are described and discussed.The Journal of Antibiotics advance online publication, 11 October 2017; doi:10.1038/ja.2017.115.
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Affiliation(s)
- Naoki Takizawa
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Tokyo Japan
| | - Manabu Yamasaki
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Tokyo Japan
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13
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Tyrrell BE, Sayce AC, Warfield KL, Miller JL, Zitzmann N. Iminosugars: Promising therapeutics for influenza infection. Crit Rev Microbiol 2017; 43:521-545. [PMID: 27931136 PMCID: PMC5470110 DOI: 10.1080/1040841x.2016.1242868] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 09/02/2016] [Accepted: 09/27/2016] [Indexed: 01/11/2023]
Abstract
Influenza virus causes three to five million severe respiratory infections per year in seasonal epidemics, and sporadic pandemics, three of which occurred in the twentieth century and are a continuing global threat. Currently licensed antivirals exclusively target the viral neuraminidase or M2 ion channel, and emerging drug resistance necessitates the development of novel therapeutics. It is believed that a host-targeted strategy may combat the development of antiviral drug resistance. To this end, a class of molecules known as iminosugars, hydroxylated carbohydrate mimics with the endocyclic oxygen atom replaced by a nitrogen atom, are being investigated for their broad-spectrum antiviral potential. The influenza virus glycoproteins, hemagglutinin and neuraminidase, are susceptible to inhibition of endoplasmic reticulum α-glucosidases by certain iminosugars, leading to reduced virion production or infectivity, demonstrated by in vitro and in vivo studies. In some experiments, viral strain-specific effects are observed. Iminosugars may also inhibit other host and virus targets with antiviral consequences. While investigations of anti-influenza iminosugar activities have been conducted since the 1980s, recent successes of nojirimycin derivatives have re-invigorated investigation of the therapeutic potential of iminosugars as orally available, low cytotoxicity, effective anti-influenza drugs.
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Affiliation(s)
- Beatrice Ellen Tyrrell
- Department of Biochemistry, University of Oxford Medical Sciences DivisionOxfordUnited Kingdom of Great Britain and Northern Ireland
| | - Andrew Cameron Sayce
- Department of Biochemistry, University of Oxford Medical Sciences DivisionOxfordUnited Kingdom of Great Britain and Northern Ireland
| | - Kelly Lyn Warfield
- Antiviral Research and Development, Emergent BioSolutions IncGaithersburgMDUnited States
| | - Joanna Louise Miller
- Department of Biochemistry, University of Oxford Medical Sciences DivisionOxfordUnited Kingdom of Great Britain and Northern Ireland
| | - Nicole Zitzmann
- Department of Biochemistry, University of Oxford Medical Sciences DivisionOxfordUnited Kingdom of Great Britain and Northern Ireland
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14
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Simsek E, Lu X, Ouzounov S, Block TM, Mehta AS. α-Glucosidase Inhibitors Have a Prolonged Antiviral Effect against Hepatitis B Virus through the Sustained Inhibition of the Large and Middle Envelope Glycoproteins. ACTA ACUST UNITED AC 2016; 17:259-67. [PMID: 17176630 DOI: 10.1177/095632020601700503] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Previous work has shown that the secretion of enveloped hepatitis B virus (HBV) DNA and the HBV middle envelope protein (MHBs) are sensitive to glucosidase inhibition. Here, it is shown that HBV DNA secretion remains depressed after the removal of the glucosidase inhibitor and long after glucosidase function returns to normal. For example, glycoprocessing and the secretion of α-1 anti-trypsin returned to normal within 3 h of the removal of the glucosidase inhibitor. In contrast, the secretion of HBV did not return to normal for more than 7 days after the removal of the inhibitor. Consistent with the inhibition of HBV virion secretion, the levels of HBV L and HBV M proteins were also reduced by treatment with the glucosidase inhibitor and remained reduced for 7 days after compound withdrawal. The implications of the prolonged antiviral effect against HBV and the use of glucosidase inhibitors as antiviral agents are discussed.
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Affiliation(s)
- Ender Simsek
- Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University College of Medicine, Philadelphia, PA, USA
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15
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Mehta A, Comunale MA, Rawat S, Casciano JC, Lamontagne J, Herrera H, Ramanathan A, Betesh L, Wang M, Norton P, Steel LF, Bouchard MJ. Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation. Sci Rep 2016; 6:27965. [PMID: 27328854 PMCID: PMC4916422 DOI: 10.1038/srep27965] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 05/25/2016] [Indexed: 12/13/2022] Open
Abstract
Alterations in N-linked glycosylation have long been associated with cancer but for the most part, the reasons why have remained poorly understood. Here we show that increased core fucosylation is associated with de-differentiation of primary hepatocytes and with the appearance of markers indicative of a transition of cells from an epithelial to a mesenchymal state. This increase in core fucosylation was associated with increased levels of two enzymes involved in α-1,6 linked fucosylation, GDP-mannose 4, 6-dehydratase (Gmds) and to a lesser extent fucosyltransferase 8 (Fut8). In addition, the activation of cancer-associated cellular signaling pathways in primary rat hepatocytes can increase core fucosylation and induce additional glycoform alterations on hepatocyte proteins. Specifically, we show that increased levels of protein sialylation and α-1,6-linked core fucosylation are observed following activation of the β-catenin pathway. Activation of the Akt signaling pathway or induction of hypoxia also results in increased levels of fucosylation and sialylation. We believe that this knowledge will help in the better understanding of the genetic factors associated with altered glycosylation and may allow for the development of more clinically relevant biomarkers.
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Affiliation(s)
- Anand Mehta
- Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA
| | - Mary Ann Comunale
- Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA
| | - Siddhartha Rawat
- Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Molecular and Cellular Biology and Genetics Graduate Program, 245 North 15th Street, Philadelphia, PA 19102, USA
| | - Jessica C Casciano
- Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Molecular and Cellular Biology and Genetics Graduate Program, 245 North 15th Street, Philadelphia, PA 19102, USA
| | - Jason Lamontagne
- Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Microbiology and Immunology Graduate Program, 2900 Queen Lane, Philadelphia, PA 19129, USA
| | - Harmin Herrera
- Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Microbiology and Immunology Graduate Program, 2900 Queen Lane, Philadelphia, PA 19129, USA
| | - Aarti Ramanathan
- Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Microbiology and Immunology Graduate Program, 2900 Queen Lane, Philadelphia, PA 19129, USA
| | - Lucy Betesh
- Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA
| | - Mengjun Wang
- Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA
| | - Pamela Norton
- Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA
| | - Laura F Steel
- Drexel University College of Medicine, Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, 245 North 15th Street, Philadelphia, PA 19102, USA
| | - Michael J Bouchard
- Drexel University College of Medicine, Department of Biochemistry and Molecular Biology, 245 N. 15th Street, Philadelphia, PA 19102, USA
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16
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Roggendorf M, Kosinska AD, Liu J, Lu M. The Woodchuck, a Nonprimate Model for Immunopathogenesis and Therapeutic Immunomodulation in Chronic Hepatitis B Virus Infection. Cold Spring Harb Perspect Med 2015; 5:cshperspect.a021451. [PMID: 26511761 DOI: 10.1101/cshperspect.a021451] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The woodchuck hepatitis virus (WHV) and its host, the eastern woodchuck, is a very valuable model system for hepatitis B virus infection. Many aspects of WHV replication and pathogenesis resemble acute and chronic hepatitis B infection in patients. Since the establishment of immunological tools, woodchucks were used to develop new therapeutic vaccines and immunomodulatory approaches to treat chronic hepadnaviral infections. Combination therapy of nucleos(t)ide analogs, with prime-boost vaccination and triple therapy, including immunomodulatory strategies by blocking the interaction of the programmed death-1 (PD-1) receptor with its ligand inducing a potent T-cell response in chronic WHV carrier woodchucks, suppression of viral replication, and complete elimination of the virus in 30% of the animals. Both strategies may be used for future therapies in patients with chronic hepatitis B.
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Affiliation(s)
- Michael Roggendorf
- Institute for Virology, University of Duisburg-Essen, 45122 Essen, Germany
| | - Anna D Kosinska
- Institute for Virology, University of Duisburg-Essen, 45122 Essen, Germany
| | - Jia Liu
- Institute for Virology, University of Duisburg-Essen, 45122 Essen, Germany
| | - Mengji Lu
- Institute for Virology, University of Duisburg-Essen, 45122 Essen, Germany
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17
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Ahn SH, Kim DH, Lee AR, Kim BK, Park YK, Park ES, Ahn SH, Shin GC, Park S, Kang HS, Rhee JK, Yang SI, Chong Y, Kim KH. Substitution at rt269 in Hepatitis B Virus Polymerase Is a Compensatory Mutation Associated with Multi-Drug Resistance. PLoS One 2015; 10:e0136728. [PMID: 26322642 PMCID: PMC4556173 DOI: 10.1371/journal.pone.0136728] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 08/08/2015] [Indexed: 02/06/2023] Open
Abstract
The emergence of compensatory mutations in the polymerase gene of drug resistant hepatitis B virus (HBV) is associated with treatment failure. We previously identified a multi-drug resistant HBV mutant, which displayed resistance towards lamivudine (LMV), clevudine (CLV), and entecavir (ETV), along with a strong replication capacity. The aim of this study was to identify the previously unknown compensatory mutations, and to determine the clinical relevance of this mutation during antiviral therapy. In vitro mutagenesis, drug susceptibility assay, and molecular modeling studies were performed. The rtL269I substitution conferred 2- to 7-fold higher replication capacity in the wild-type (WT) or YMDD mutation backbone, regardless of drug treatment. The rtL269I substitution alone did not confer resistance to LMV, ETV, adefovir (ADV), or tenofovir (TDF). However, upon combination with YMDD mutation, the replication capacity under LMV or ETV treatment was enhanced by several folds. Molecular modeling studies suggested that the rtL269I substitution affects template binding, which may eventually lead to the enhanced activity of rtI269-HBV polymerase in both WT virus and YMDD mutant. The clinical relevance of the rtL269I substitution was validated by its emergence in association with YMDD mutation in chronic hepatitis B (CHB) patients with sub-optimal response or treatment failure to LMV or CLV. Our study suggests that substitution at rt269 in HBV polymerase is associated with multi-drug resistance, which may serve as a novel compensatory mutation for replication-defective multi-drug resistant HBV.
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Affiliation(s)
- Sung Hyun Ahn
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
| | - Doo Hyun Kim
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
| | - Ah Ram Lee
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Kwang Park
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
| | - Eun-Sook Park
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
- KU Open Innovation Center, Konkuk University, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Gu-Choul Shin
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
- KU Open Innovation Center, Konkuk University, Seoul, Korea
| | - Soree Park
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
| | - Hong Seok Kang
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
| | - Jin-Kyu Rhee
- Departments of Food Science and Engineering, Ewha Womans University, Seoul, Korea
| | - Sung-Il Yang
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
| | - Youhoon Chong
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Korea
| | - Kyun-Hwan Kim
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
- KU Open Innovation Center, Konkuk University, Seoul, Korea
- Research Institute of Medical Sciences, Konkuk University, Seoul, Korea
- * E-mail:
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18
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Koumbi L. Current and future antiviral drug therapies of hepatitis B chronic infection. World J Hepatol 2015; 7:1030-1040. [PMID: 26052392 PMCID: PMC4450180 DOI: 10.4254/wjh.v7.i8.1030] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/12/2015] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host’s immune system. Currently the approved therapeutic regimens include pegylated-interferon (IFN)-α and monotherapy with five nucleos(t)ide analogues (NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish long-term control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection.
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19
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Zoulim F, Durantel D. Antiviral therapies and prospects for a cure of chronic hepatitis B. Cold Spring Harb Perspect Med 2015; 5:5/4/a021501. [PMID: 25833942 DOI: 10.1101/cshperspect.a021501] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Current therapies of chronic hepatitis B (CHB) remain limited to either pegylated interferon-α (Peg-IFN-α), or one of the five approved nucleoside analog (NA) treatments. Although viral suppression can be achieved in the majority of patients with high-barrier-to-resistance new-generation NAs (i.e., entecavir and tenofovir), HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5 years. Attempts to improve the response by administering two different NAs or a combination of NA and Peg-IFN-α have been unsuccessful. Therefore, there is a renewed interest to investigate a number of steps in the hepatitis B virus (HBV) replication cycle and specific virus-host cell interactions as potential targets for new antivirals. Novel targets and compounds could readily be evaluated using both relevant in vitro and newly developed in vivo models of HBV infection. The addition of one or several new drugs to current regimens should offer the prospect of markedly improving the response to therapy, thus reducing the burden of drug resistance, as well as the incidence of cirrhosis and hepatocellular carcinoma (HCC).
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Affiliation(s)
- Fabien Zoulim
- INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Hospices Civils de Lyon, Lyon, France
| | - David Durantel
- INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Hospices Civils de Lyon, Lyon, France
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20
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The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment. Sci Rep 2015; 5:8421. [PMID: 25672227 PMCID: PMC4325332 DOI: 10.1038/srep08421] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 12/16/2014] [Indexed: 12/14/2022] Open
Abstract
Chronic infection caused by the hepatitis B virus (HBV), is strongly associated with hepatitis, fatty liver and hepatocellular carcinoma. To investigate the underlying mechanisms, we characterize the metabolic features of host cells infected with the virus using systems biological approach. The results show that HBV replication induces systematic metabolic alterations in host cells. HBV infection up-regulates the biosynthesis of hexosamine and phosphatidylcholine by activating glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1) and choline kinase alpha (CHKA) respectively, which were reported for the first time for HBV infection. Importantly suppressing hexosamine biosynthesis and phosphatidylcholine biosynthesis can inhibit HBV replication and expression. In addition, HBV induces oxidative stress and stimulates central carbon metabolism and nucleotide synthesis. Our results also indicate that HBV associated hepatocellular carcinoma could be attributed to GFAT1 activated hexosamine biosynthesis and CHKA activated phosphatidylcholine biosynthesis. This study provides further insights into the pathogenesis of HBV-induced diseases, and sheds new light on drug target for treating HBV infection.
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21
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Kosinska AD, Liu J, Lu M, Roggendorf M. Therapeutic vaccination and immunomodulation in the treatment of chronic hepatitis B: preclinical studies in the woodchuck. Med Microbiol Immunol 2014; 204:103-14. [PMID: 25535101 PMCID: PMC4305085 DOI: 10.1007/s00430-014-0379-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Accepted: 09/18/2014] [Indexed: 12/12/2022]
Abstract
Infection with hepatitis B virus (HBV) may lead to subclinical, acute or chronic hepatitis. In the prevaccination era, HBV infections were endemic due to frequent mother to child transmission in large regions of the world. However, there are still estimated 240 million chronic HBV carriers today and ca. 620,000 patients die per year due to HBV-related liver diseases. Recommended treatment of chronic hepatitis B with interferon-α and/or nucleos(t)ide analogues does not lead to satisfactory results. Induction of HBV-specific T cells by therapeutic vaccination or immunomodulation may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients with or without therapeutic reduction of viral load did not result in effective immune control of HBV infection, suggesting that combination of antiviral treatment with new formulations of therapeutic vaccines is needed. The woodchuck (Marmota monax) and its HBV-like woodchuck hepatitis virus are a useful preclinical animal model for developing new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments using nucleos(t)ide analogues, with prime-boost vaccination using DNA vaccines, new hepadnaviral antigens or recombinant adenoviral vectors were tested in the woodchuck model. In this review, we summarize these encouraging results obtained with these therapeutic vaccines. In addition, we present potential innovations in immunostimulatory strategies by blocking the interaction of the inhibitory programmed death receptor 1 with its ligand in this animal model.
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Affiliation(s)
- Anna D Kosinska
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Virchowstrasse 179, 45122, Essen, Germany
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22
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Aguilar AL, Escribano J, Wentworth P, Butters TD. Synthetic 1-Deoxynojirimycin N-Substituted Peptides Offer Prolonged Disruption to N-Linked Glycan Processing. ChemMedChem 2014; 9:2809-13. [DOI: 10.1002/cmdc.201402186] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Indexed: 11/08/2022]
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23
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Therapeutic strategies for a functional cure of chronic hepatitis B virus infection. Acta Pharm Sin B 2014; 4:248-57. [PMID: 26579392 PMCID: PMC4629125 DOI: 10.1016/j.apsb.2014.05.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 05/20/2014] [Accepted: 05/23/2014] [Indexed: 02/07/2023] Open
Abstract
Treatment of chronic hepatitis B virus (HBV) infection with the viral DNA polymerase inhibitors or pegylated alpha-interferon has led to a significant retardation in HBV-related disease progression and reduction in mortality related to chronic hepatitis B associated liver decompensation and hepatocellular carcinoma. However, chronic HBV infection remains not cured. The reasons for the failure to eradicate HBV infection by long-term antiviral therapy are not completely understood. However, clinical studies suggest that the intrinsic stability of the nuclear form of viral genome, the covalently closed circular (ccc) DNA, sustained low level viral replication under antiviral therapy and homeostatic proliferation of hepatocytes are the critical virological and pathophysiological factors that affect the persistence and therapeutic outcomes of HBV infection. More importantly, despite potent suppression of HBV replication in livers of the treated patients, the dysfunction of HBV-specific antiviral immunity persists. The inability of the immune system to recognize cells harboring HBV infection and to cure or eliminate cells actively producing virus is the biggest challenge to finding a cure. Unraveling the complex virus–host interactions that lead to persistent infection should facilitate the rational design of antivirals and immunotherapeutics to cure chronic HBV infection.
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24
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Xu YB, Yang L, Wang GF, Tong XK, Wang YJ, Yu Y, Jing JF, Feng CL, He PL, Lu W, Tang W, Zuo JP. Benzimidazole derivative, BM601, a novel inhibitor of hepatitis B virus and HBsAg secretion. Antiviral Res 2014; 107:6-15. [DOI: 10.1016/j.antiviral.2014.04.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 03/13/2014] [Accepted: 04/06/2014] [Indexed: 12/15/2022]
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25
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Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, Iwamoto M, Nakajima S, Tsukuda S, Borroto‐Esoda K, Sugiyama M, Tanaka Y, Kanai Y, Kusuhara H, Mizokami M, Wakita T. Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP). Hepatology 2014; 59:1726-37. [PMID: 24375637 PMCID: PMC4265264 DOI: 10.1002/hep.26982] [Citation(s) in RCA: 196] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 12/17/2013] [Indexed: 12/11/2022]
Abstract
UNLABELLED Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. Although nucleos(t)ide analogs inhibiting viral reverse transcriptase are clinically available as anti-HBV agents, emergence of drug-resistant viruses highlights the need for new anti-HBV agents interfering with other targets. Here we report that cyclosporin A (CsA) can inhibit HBV entry into cultured hepatocytes. The anti-HBV effect of CsA was independent of binding to cyclophilin and calcineurin. Rather, blockade of HBV infection correlated with the ability to inhibit the transporter activity of sodium taurocholate cotransporting polypeptide (NTCP). We also found that HBV infection-susceptible cells, differentiated HepaRG cells and primary human hepatocytes expressed NTCP, while nonsusceptible cell lines did not. A series of compounds targeting NTCP could inhibit HBV infection. CsA inhibited the binding between NTCP and large envelope protein in vitro. Evaluation of CsA analogs identified a compound with higher anti-HBV potency, having a median inhibitory concentration <0.2 μM. CONCLUSION This study provides a proof of concept for the novel strategy to identify anti-HBV agents by targeting the candidate HBV receptor, NTCP, using CsA as a structural platform.
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Affiliation(s)
- Koichi Watashi
- Department of Virology IINational Institute of Infectious DiseasesTokyoJapan
| | | | - Takuji Daito
- Department of Virology IINational Institute of Infectious DiseasesTokyoJapan,SCYNEXIS, Inc.DurhamNCUSA
| | - Satoko Matsunaga
- Department of MicrobiologyYokohama City University School of MedicineYokohamaJapan
| | - Akihide Ryo
- Department of MicrobiologyYokohama City University School of MedicineYokohamaJapan
| | | | - Masashi Iwamoto
- Department of Virology IINational Institute of Infectious DiseasesTokyoJapan
| | - Syo Nakajima
- Department of Virology IINational Institute of Infectious DiseasesTokyoJapan
| | - Senko Tsukuda
- Department of Virology IINational Institute of Infectious DiseasesTokyoJapan,Micro‐signaling Regulation Technology UnitRIKEN Center for Life Science TechnologiesWakoJapan
| | | | - Masaya Sugiyama
- Research Center for Hepatitis and ImmunologyNational Center for Global Health and MedicineIchikawaJapan
| | - Yasuhito Tanaka
- Department of Virology and Liver UnitNagoya City University Graduate School of Medicinal SciencesNagoyaJapan
| | | | - Hiroyuki Kusuhara
- University of Tokyo Graduate School of Pharmaceutical SciencesTokyoJapan
| | - Masashi Mizokami
- Research Center for Hepatitis and ImmunologyNational Center for Global Health and MedicineIchikawaJapan
| | - Takaji Wakita
- Department of Virology IINational Institute of Infectious DiseasesTokyoJapan
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26
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Bin BH, Seo J, Yang SH, Lee E, Choi H, Kim KH, Cho EG, Lee TR. Novel inhibitory effect of the antidiabetic drug voglibose on melanogenesis. Exp Dermatol 2014; 22:541-6. [PMID: 23879813 DOI: 10.1111/exd.12195] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2013] [Indexed: 12/18/2022]
Abstract
Overproduction of melanin can lead to medical disorders such as postinflammatory melanoderma and melasma. Therefore, developing antimelanogenic agents is important for both medical and cosmetic purposes. In this report, we demonstrated for the first time that the antidiabetic drug voglibose is a potent antimelanogenic agent. Voglibose is a representative antidiabetic drug possessing inhibitory activity towards human α-glucosidase; it blocked the proper N-glycan modification of tyrosinase, resulting in a dramatic reduction of the tyrosinase protein level by altering its stability and subsequently decreasing melanin production. Acarbose, another antihyperglycaemic drug that has a lower inhibitory effect on human intracellular α-glucosidase compared with voglibose, did not cause any changes in either the N-glycan modification of tyrosinase or the tyrosinase protein level, indicating that voglibose was the most efficient antimelanogenic agent among the widely used antihyperglycaemic agents. Considering that voglibose was originally selected from the valiolamine derivatives in a screen for an oral antidiabetic drug with a strong inhibitory activity towards intestinal α-glucosidase and low cell permeability, we propose an alternative strategy for screening compounds from valiolamine derivatives that show high inhibitory activity towards human intracellular α-glucosidases and high cell permeability, with the goal of obtaining antimelanogenic agents that are effective inside the cells.
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Affiliation(s)
- Bum-Ho Bin
- Bioscience Research Institute, AmorePacific Corporation R&D Center, Yongin, Korea
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27
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Zhang F, Wang G. A review of non-nucleoside anti-hepatitis B virus agents. Eur J Med Chem 2014; 75:267-81. [PMID: 24549242 DOI: 10.1016/j.ejmech.2014.01.046] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 01/12/2014] [Accepted: 01/17/2014] [Indexed: 12/14/2022]
Abstract
Hepatitis B Virus is the most common cause of chronic liver disease worldwide. Currently approved agents of chronic HBV infection treatment include interferon and nucleoside analogues. However, the side effects of interferon and the viral resistance of nucleoside analogues make the current treatment far from satisfactory. Therefore, new drugs with novel structures and mechanisms are needed. Recently, a number of non-nucleoside HBV inhibitors have been obtained from natural sources or prepared by synthesis/semi-synthesis. Some of them exhibited potent anti-HBV activity with novel mechanisms. These compounds provide useful information for the medicinal chemist to develop novel non-nucleoside compounds as anti-HBV agents.
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Affiliation(s)
- Fan Zhang
- School of Pharmacy, Liaoning Medical University, No. 40, Section 3, Songpo Road, Linghe District, Jinzhou 121001, PR China.
| | - Gang Wang
- School of Pharmacy, Liaoning Medical University, No. 40, Section 3, Songpo Road, Linghe District, Jinzhou 121001, PR China
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28
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Chang J, Guo JT, Du Y, Block T. Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents. Emerg Microbes Infect 2013; 2:e77. [PMID: 26038444 PMCID: PMC3924557 DOI: 10.1038/emi.2013.77] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 09/16/2013] [Accepted: 09/22/2013] [Indexed: 12/12/2022]
Abstract
Ebola virus and Marburg virus are members of the family of Filoviridae and are etiological agents of a deadly hemorrhagic fever disease. The clinical symptoms of Ebola and Marburg hemorrhagic fevers are difficult to distinguish and there are currently no specific antiviral therapies against either of the viruses. Therefore, a drug that is safe and effective against both would be an enormous breakthrough. We and others have shown that the folding of the glycoproteins of many enveloped viruses, including the filoviruses, is far more dependent upon the calnexin pathway of protein folding than are most host glycoproteins. Drugs that inhibit this pathway would be expected to be selectively antiviral. Indeed, as we summarize in this review, imino sugars that are competitive inhibitors of the host endoplasmic reticular α-glucosidases I and II, which are enzymes that process N-glycan on nascent glycoproteins and thereby inhibit calnexin binding to the nascent glycoproteins, have been shown to have antiviral activity against a number of enveloped viruses including filoviruses. In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations.
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Affiliation(s)
- Jinhong Chang
- The Department of Microbiology and Immunology, Drexel University College of Medicine , Doylestown, PA 18902, USA ; The Institute of Hepatitis and Virus Research , Doylestown, PA 18902, USA
| | - Ju-Tao Guo
- The Department of Microbiology and Immunology, Drexel University College of Medicine , Doylestown, PA 18902, USA ; The Institute of Hepatitis and Virus Research , Doylestown, PA 18902, USA
| | - Yanming Du
- The Institute of Hepatitis and Virus Research , Doylestown, PA 18902, USA
| | - Timothy Block
- The Department of Microbiology and Immunology, Drexel University College of Medicine , Doylestown, PA 18902, USA ; The Institute of Hepatitis and Virus Research , Doylestown, PA 18902, USA
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29
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Chang J, Block TM, Guo JT. Antiviral therapies targeting host ER alpha-glucosidases: current status and future directions. Antiviral Res 2013; 99:251-60. [PMID: 23816430 PMCID: PMC7114303 DOI: 10.1016/j.antiviral.2013.06.011] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 06/15/2013] [Accepted: 06/19/2013] [Indexed: 12/18/2022]
Abstract
ER α-glucosidases are essential host factors for the morphogenesis of many enveloped viruses. Imino sugars are competitive inhibitors of the ER α-glucosidases I and II. Broad-spectrum antiviral efficacies of imino sugars have been demonstrated in vitro, and in vivo. Strategies for development of potent and specific ER α-glucosidase inhibitors have been proposed. Targeting glucosidase is promising for viral hemorrhagic fever and respiratory infections. Endoplasmic reticulum (ER)-resident α-glucosidases I and II sequentially trim the three terminal glucose moieties on N-linked glycans attached to nascent glycoproteins. These reactions are the first steps of N-linked glycan processing and are essential for proper folding and function of many glycoproteins. Because most viral envelope glycoproteins contain N-linked glycans, inhibition of ER α-glucosidases with derivatives of 1-deoxynojirimycin (DNJ) or castanospermine (CAST), two well-studied pharmacophores of α-glucosidase inhibitors, efficiently disrupts the morphogenesis of a broad spectrum of enveloped viruses. Moreover, both DNJ and CAST derivatives have been demonstrated to prevent the death of mice infected with several distinct flaviviruses and filoviruses and suppress the multiplication of several other species of viruses in infected animals. N-Butyl derivative of DNJ (NB-DNJ) and 6 O-bytanoyl prodrug of CAST (Bu-CAST) have been evaluated in human clinical trials for their antiviral activities against human immunodeficiency virus and hepatitis C virus, and there is an ongoing trial of treating dengue patients with Bu-CAST. This article summarizes the current status of ER α-glucosidase-targeted antiviral therapy and proposes strategies for development of more efficacious and specific ER α-glucosidase inhibitors as broad-spectrum, drug resistance-refractory antiviral therapeutics. These host function-targeted, broad-spectrum antiviral agents do not rely on time-consuming etiologic diagnosis, and should therefore be particularly promising in the management of viral hemorrhagic fever and respiratory tract viral infections, medical conditions that can be caused by many different enveloped RNA viruses, with a short window for medical intervention.
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Affiliation(s)
- Jinhong Chang
- Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, USA.
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Abstract
Hepatitis delta virus (HDV) is a defective RNA virus that depends on hepatitis B virus (HBV) for its lifecycle. Treatment of chronic HDV infection is difficult as it does not have an enzymatic function as a target, such as polymerases and proteases of HBV and hepatitis C virus. Recently, it has been suggested that farnesyl transferase could be an enzymatic target. Currently, interferon is the only agent against HDV infection. Virological response has risen to 20-47% with pegylated interferon. Monotherapy of nucleos(t)ide analogs are ineffective against the HDV infection, but adefovir and pegylated interferon combination therapy have had some advantages for reduction of HBV surface antigen (HBsAg) levels. Recent studies suggest that measuring HBsAg levels during treatment could be more meaningful than HDV RNA negativity to predict virological response. Prenylation inhibitors that can affect the interactions between the large HDV antigen and HBsAg in the HDV virion are expected treatments for HDV infection. More studies are needed to understand the molecular mechanisms of HDV to manage the disease.
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Affiliation(s)
- Fulya Gunsar
- Department of Gastroenterology, Ege University, Bornova, Izmir 35100, Turkey.
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31
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Zoulim F. Are novel combination therapies needed for chronic hepatitis B? Antiviral Res 2012; 96:256-9. [PMID: 22999818 DOI: 10.1016/j.antiviral.2012.09.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 09/06/2012] [Accepted: 09/07/2012] [Indexed: 01/14/2023]
Abstract
The treatment of chronic hepatitis B remains limited to monotherapy with pegInterferon-alpha or one of 5 different nucleoside analogues (NUC). While viral suppression can be achieved in approximately 95% of patients with new-generation NUCs, the rate of HBeAg seroconversion ranges from only 20% with NUCs to 30% with pegInterferon-alpha. HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5years. Attempts to improve the response by administering two different NUCs or a combination of NUC and pegInterferon-alpha have been unsuccessful. This situation has led researchers to investigate a number of steps in the HBV replication cycle as potential targets for new antiviral drugs. Novel targets and compounds could readily be evaluated in in vitro and in vivo models of HBV infection. The addition of one or more new drugs to the current regimen should offer the prospect of markedly improving the response to therapy, reducing the future burden of drug resistance, cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Fabien Zoulim
- INSERM U1052, UMR CNRS 5268, Cancer Research Center of Lyon, F-69003 Lyon, France.
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32
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Dandri M, Lütgehetmann M, Petersen J. Experimental models and therapeutic approaches for HBV. Semin Immunopathol 2012; 35:7-21. [PMID: 22898798 DOI: 10.1007/s00281-012-0335-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2012] [Accepted: 07/31/2012] [Indexed: 12/12/2022]
Abstract
Liver disease associated to persistent infection with the hepatitis B virus (HBV) continues to be a major health problem of global impact. In spite of the existence of an effective vaccine, approximately 360 million people are chronically infected worldwide, who are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Although current therapeutic regimens can efficiently suppress viral replication, the unique replication strategies employed by HBV permit the virus to persist within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment with polymerase inhibitors. The narrow host range of HBV has hindered progresses in understanding specific steps of HBV replication and the development of more effective therapeutic strategies aiming at achieving sustained viral control and, eventually, virus eradication. This review will focus on summarizing recent advances obtained with well-established and more innovative experimental models, giving emphasis on the strength of the different systems as tools for elucidating distinct aspects of HBV persistence and for the development of new therapeutic approaches.
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Affiliation(s)
- Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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33
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Yu W, Gill T, Wang L, Du Y, Ye H, Qu X, Guo JT, Cuconati A, Zhao K, Block TM, Xu X, Chang J. Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection. J Med Chem 2012; 55:6061-75. [PMID: 22712544 DOI: 10.1021/jm300171v] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC(50) > 500 μM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).
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Affiliation(s)
- Wenquan Yu
- Institute for Hepatitis and Virus Research, Hepatitis B Foundation, Doylestown, PA 18902, USA
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Chang J, Schul W, Yip A, Xu X, Guo JT, Block TM. Competitive inhibitor of cellular α-glucosidases protects mice from lethal dengue virus infection. Antiviral Res 2011; 92:369-71. [PMID: 21854808 DOI: 10.1016/j.antiviral.2011.08.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Revised: 07/07/2011] [Accepted: 08/03/2011] [Indexed: 10/17/2022]
Abstract
Dengue virus infection causes diseases in people, ranging from the acute febrile illness dengue fever, to life-threatening dengue hemorrhagic fever/dengue shock syndrome. We previously reported that a host cellular α-glucosidases I and II inhibitor, imino sugar CM-10-18, potently inhibited dengue virus replication in cultured cells, and significantly reduced viremia in dengue virus infected AG129 mice. In this report we show that CM-10-18 also significantly protects mice from death and/or disease progress in two mouse models of lethal dengue virus infection. Our results thus provide a strong support for the development of CM-10-18 or its derivatives as antiviral agents to treat servere dengue virus infections.
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Affiliation(s)
- Jinhong Chang
- Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, PA 18902, United States.
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35
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McLaughlin M, Vandenbroeck K. The endoplasmic reticulum protein folding factory and its chaperones: new targets for drug discovery? Br J Pharmacol 2011; 162:328-45. [PMID: 20942857 DOI: 10.1111/j.1476-5381.2010.01064.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Cytosolic heat shock proteins have received significant attention as emerging therapeutic targets. Much of this excitement has been triggered by the discovery that HSP90 plays a central role in the maintenance and stability of multifarious oncogenic membrane receptors and their resultant tyrosine kinase activity. Numerous studies have dealt with the effects of small molecules on chaperone- and stress-related pathways of the endoplasmic reticulum (ER). However, unlike cytosolic chaperones, relatively little emphasis has been placed upon translational avenues towards targeting of the ER for inhibition of folding/secretion of disease-promoting proteins. Here, we summarise existing small molecule inhibitors and potential future targets of ER chaperone-mediated inhibition. Client proteins of translational relevance in disease treatment are outlined, alongside putative future disease treatment modalities based on ER-centric targeted therapies. Particular attention is paid to cancer and autoimmune disorders via the effects of the GRP94 inhibitor geldanamycin and its population of client proteins, overloading of the unfolded protein response, and inhibition of members of the IL-12 family of cytokines by celecoxib and non-coxib analogues.
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Stachulski AV, Pidathala C, Row EC, Sharma R, Berry NG, Iqbal M, Bentley J, Allman SA, Edwards G, Helm A, Hellier J, Korba BE, Semple JE, Rossignol JF. Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication. J Med Chem 2011; 54:4119-32. [PMID: 21553812 DOI: 10.1021/jm200153p] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.
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Affiliation(s)
- Andrew V Stachulski
- Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
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37
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38
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39
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Abstract
Chronic hepatitis B virus (HBV) infections remain a major public health problem worldwide. According to World Health Organization estimates, more than 300 million people are chronically infected and exposed to the risk of developing severe complications including cirrhosis and hepatocellular carcinoma (HCC). Major progress in the treatment of chronic hepatitis B (CHB) has been made during the last decade with the development of antivirals that inhibit viral polymerase activity. Antiviral drug resistance is an important factor in determining the success of long-term therapy for CHB. The development of resistance to nucleoside analogues (NUCs) has been associated with exacerbations of liver disease. Sequential therapy increases the risk of the emergence of multidrug resistance. The selection of a potent antiviral with a high barrier to resistance as a first-line therapy provides the best chance of achieving long-term treatment goals and should be used whenever possible. This has led to a significant decrease in drug resistance in countries where this strategy is affordable. However, the barrier to resistance of a given antiviral agent is influenced by the genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, the drug mechanisms of action and cross resistance. Furthermore, because of specific viral kinetics, prolonged treatment with NUCs does not result in the clearance of the viral genome from the infected liver. It is therefore important to continue research to identify new viral and immune targets and develop novel antiviral strategies for controlling viral replication as well as preventing drug resistance and its complications in the long term.
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Affiliation(s)
- Fabien Zoulim
- INSERM, U871, Lyon, France Université de Lyon, 69001 Lyon, France.
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Inhibitors of endoplasmic reticulum alpha-glucosidases potently suppress hepatitis C virus virion assembly and release. Antimicrob Agents Chemother 2010; 55:1036-44. [PMID: 21173177 DOI: 10.1128/aac.01319-10] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
α-Glucosidases I and II are endoplasmic reticulum-resident enzymes that are essential for N-linked glycan processing and subsequent proper folding of glycoproteins. In this report, we first demonstrate that downregulation of the expression of α-glucosidase I, II, or both in Huh7.5 cells by small hairpin RNA technology inhibited the production of hepatitis C virus (HCV). In agreement with the essential role of α-glucosidases in HCV envelope glycoprotein processing and folding, treatment of HCV-infected cells with a panel of imino sugar derivatives, which are competitive inhibitors of α-glucosidases, did not affect intracellular HCV RNA replication and nonstructural protein expression but resulted in the inhibition of glycan processing and subsequent degradation of HCV E2 glycoprotein. As a consequence, HCV virion assembly and secretion were inhibited. In searching for imino sugars with better antiviral activity, we found that a novel imino sugar, PBDNJ0804, had a superior ability to inhibit HCV virion assembly and secretion. In summary, we demonstrated that glucosidases are important host factor-based antiviral targets for HCV infection. The low likelihood of drug-resistant virus emergence and potent antiviral efficacy of the novel glucosidase inhibitor hold promise for its development as a therapeutic agent for the treatment of chronic hepatitis C.
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41
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Chang J, Schul W, Butters TD, Yip A, Liu B, Goh A, Lakshminarayana SB, Alonzi D, Reinkensmeier G, Pan X, Qu X, Weidner JM, Wang L, Yu W, Borune N, Kinch MA, Rayahin JE, Moriarty R, Xu X, Shi PY, Guo JT, Block TM. Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antiviral Res 2010; 89:26-34. [PMID: 21073903 DOI: 10.1016/j.antiviral.2010.11.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Revised: 10/26/2010] [Accepted: 11/03/2010] [Indexed: 10/18/2022]
Abstract
Cellular α-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of α-glucosidases I and II. In this report, we show that two oxygenated alkyl imino sugar derivatives, CM-9-78 and CM-10-18, are potent inhibitors of both α-glucosidases I and II in vitro and in treated animals, and efficiently inhibit DENV infection of cultured human cells. Pharmacokinetic studies reveal that both compounds are well tolerated at doses up to 100mg/kg in rats and have favorable pharmacokinetic properties and bioavailability in mice. Moreover, we showed that oral administration of either CM-9-78 or CM-10-18 reduces the peak viremia of DENV in mice. Interestingly, while treatment of DENV infected mice with ribavirin alone did not reduce the viremia, combination therapy of ribavirin with sub-effective dose of CM-10-18 demonstrated a significantly enhanced antiviral activity, as indicated by a profound reduction of the viremia. Our findings thus suggest that combination therapy of two broad-spectrum antiviral agents may provide a practically useful approach for the treatment of DENV infection.
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Affiliation(s)
- Jinhong Chang
- Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, United States.
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42
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Norton PA, Menne S, Sinnathamby G, Betesh L, Cote PJ, Philip R, Mehta AS, Tennant BC, Block TM. Glucosidase inhibition enhances presentation of de-N-glycosylated hepatitis B virus epitopes by major histocompatibility complex class I in vitro and in woodchucks. Hepatology 2010; 52:1242-50. [PMID: 20658465 PMCID: PMC2947625 DOI: 10.1002/hep.23806] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
UNLABELLED In this report, the possibility of pharmacologically altering the hepatitis B virus (HBV) epitopes presented by major histocompatibility complex class I on infected cells is demonstrated. The HBV middle envelope glycoprotein (MHBs) maturation appears to require calnexin-mediated folding. This interaction is dependent on glucosidases in the endoplasmic reticulum. Prevention of HBV envelope protein maturation in cultured cells through use of glucosidase inhibitors, such as 6-O-butanoyl castanospermine and N-nonyl deoxynorjirimycin, resulted in MHBs degradation by proteasomes. The de-N-glycosylation associated with polypeptide degradation was predicted to result in conversion of asparagine residues into aspartic acid residues. This prediction was confirmed by showing that peptides corresponding to the N-glycosylation sequons of MHBs, but with aspartic acid replacing asparagine, (1) can prime human cytotoxic T lymphocytes that recognize HBV-producing cells and (2) that the presentation of these envelope motifs by major histocompatibility complex class I is enhanced by incubation with glucosidase inhibitors. Moreover, although peripheral blood mononuclear cells isolated from woodchucks chronically infected with woodchuck hepatitis virus and vaccinated with woodchuck hepatitis virus surface antigen could be induced to recognize the natural MHBs asparagine-containing peptides, only cells isolated from animals treated with glucosidase inhibitor recognized the aspartic acid-containing peptides. CONCLUSION These data suggest that pharmacological intervention with glucosidase inhibitors can alter the MHBs epitopes presented. This editing of the amino acid sequence of the polypeptide results in a new epitope, or "editope", with possible medical significance.
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Affiliation(s)
- Pamela A Norton
- Drexel Institute for Biotechnology and Virology Research and Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, PA, USA.
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Abstract
A basic understanding of the molecular events involved in the hepatitis B virus (HBV) life cycle is essential to better appreciate the natural history and atypical presentations of the disease and to develop individual management plans based on readily available virologic tests. With the improved knowledge gained from studying the molecular biology of HBV, novel approaches to inhibition of viral replication are being explored, such as viral entry inhibitors, nucleocapsid inhibitors, and inhibitors of viral assembly. However, the ultimate goal of therapy is to identify strategies to eliminate covalently closed circular DNA from infected hepatocytes. This article serves to introduce the clinically relevant aspects of the HBV life cycle as they pertain to patient management.
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Affiliation(s)
- Edward C. Doo
- Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, National Insti- tute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Two Democ- racy Plaza, Room 651, MSC 5450, 6707 Democracy Boulevard, Bethesda, MD 20892-5450, USA
| | - Marc G. Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10 Room 9B-16, 10 Center Drive, MSC 1800, Bethesda, MD 20892-1800, USA,Corresponding author:
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44
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Xie YH, Hong R, Liu W, Liu J, Zhai JW. Development of novel therapeutics for chronic hepatitis B. Virol Sin 2010; 25:294-300. [PMID: 20960302 DOI: 10.1007/s12250-010-3138-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Accepted: 05/30/2010] [Indexed: 12/27/2022] Open
Abstract
Chronic infection of hepatitis B virus (HBV) presents one of the serious public health challenges worldwide. Current treatment of chronic hepatitis B (CHB) is limited, and is composed of interferon and nucleoside/nucleotide reverse transcriptase inhibitors (NRTI). Interferon is poorly tolerated and is only responsive in a small fraction of CHB patients and NRTIs often face the problem of emergence of drug resistance during long-term treatment. The current treatment of CHB can be improved in several ways including genotyping mutations associated with drug resistance before treatment to guide the choice of NRTIs and suitable combinations among NRTIs and interferon. It is important to continue research in the identification of novel therapeutic targets in the life cycle of HBV or in the host immune system to stimulate the development of new antiviral agents and immunotherapies. Several antiviral agents targeting HBV entry, cccDNA, capsid formation, viral morphogenesis and virion secretion, as well as two therapeutic vaccines are currently being evaluated in preclinical studies or in clinical trials to assess their anti-HBV efficacy.
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Affiliation(s)
- You-hua Xie
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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45
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Antiviral treatment of chronic hepatitis B virus (HBV) infections. Viruses 2010; 2:1279-1305. [PMID: 21994680 PMCID: PMC3185710 DOI: 10.3390/v2061279] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Revised: 05/18/2010] [Accepted: 05/25/2010] [Indexed: 12/21/2022] Open
Abstract
While 25 compounds have been formally licensed for the treatment of HIV infection (AIDS), only seven licensed products are currently available for the treatment of chronic hepatitis B virus (HBV) infection: interferon-α, pegylated interferon-α, lamivudine, adefovir (dipivoxil), entecavir, telbivudine and tenofovir (disoproxil fumarate). In contrast to the treatment of HIV infections where the individual drugs are routinely used in combination, for the treatment of chronic HBV infection the individual drugs are generally used in monotherapy. In principle, combination drug therapy should allow reducing the likelihood of drug-resistant development.
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46
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Zhu X, Zhao G, Zhou X, Xu X, Xia G, Zheng Z, Wang L, Yang X, Li S. 2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives as anti-HBV agents targeting at capsid assembly. Bioorg Med Chem Lett 2010; 20:299-301. [DOI: 10.1016/j.bmcl.2009.10.119] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2009] [Revised: 09/29/2009] [Accepted: 10/27/2009] [Indexed: 11/25/2022]
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Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 2009; 137:1593-608.e1-2. [PMID: 19737565 DOI: 10.1053/j.gastro.2009.08.063] [Citation(s) in RCA: 524] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2009] [Revised: 08/28/2009] [Accepted: 08/28/2009] [Indexed: 02/07/2023]
Abstract
Patients with chronic hepatitis B (CHB) can be successfully treated using nucleos(t)ide analogs (NA), but drug-resistant hepatitis B virus (HBV) mutants frequently arise, leading to treatment failure and progression to liver disease. There has been much research into the mechanisms of resistance to NA and selection of these mutants. Five NA have been approved by the US Food and Drug Administration for treatment of CHB; it is unlikely that any more NA will be developed in the near future, so it is important to better understand mechanisms of cross-resistance (when a mutation that mediates resistance to one NA also confers resistance to another) and design more effective therapeutic strategies for these 5 agents. The genes that encode the polymerase and envelope proteins of HBV overlap, so resistance mutations in polymerase usually affect the hepatitis B surface antigen; these alterations affect infectivity, vaccine efficacy, pathogenesis of liver disease, and transmission throughout the population. Associations between HBV genotype and resistance phenotype have allowed cross-resistance profiles to be determined for many commonly detected mutants, so genotyping assays can be used to adapt therapy. Patients that experience virologic breakthrough or partial response to their primary therapy can often be successfully treated with a second NA, if this drug is given at early stages of these events. However, best strategies for preventing NA resistance include first-line use of the most potent antivirals with a high barrier to resistance. It is important to continue basic research into HBV replication and pathogenic mechanisms to identify new therapeutic targets, develop novel antiviral agents, design combination therapies that prevent drug resistance, and decrease the incidence of complications of CHB.
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48
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Alonzi DS, Dwek RA, Butters TD. Improved cellular inhibitors for glycoprotein processing α-glucosidases: biological characterisation of alkyl- and arylalkyl-N-substituted deoxynojirimycins. ACTA ACUST UNITED AC 2009. [DOI: 10.1016/j.tetasy.2009.03.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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49
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Novel imino sugar derivatives demonstrate potent antiviral activity against flaviviruses. Antimicrob Agents Chemother 2009; 53:1501-8. [PMID: 19223639 DOI: 10.1128/aac.01457-08] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Imino sugars, such as N-butyl-deoxynojirimycin and N-nonyl-deoxynojirimycin (NNDNJ), are glucose analogues that selectively inhibit cellular alpha-glucosidase I and II in the endoplasmic reticulum and exhibit antiviral activities against many types of enveloped viruses. Although these molecules have broad-spectrum antiviral activity, their development has been limited by a lack of efficacy and/or selectivity. We have previously reported that a DNJ derivative with a hydroxylated cyclohexyl side chain, called OSL-95II, has an antiviral efficacy similar to that of NNDNJ but significantly less toxicity. Building upon this observation, a family of imino sugar derivatives containing an oxygenated side chain and terminally restricted ring structures were synthesized and shown to have low cytotoxicity and superior antiviral activity against members of the Flaviviridae family, including bovine viral diarrhea virus, dengue virus (DENV), and West Nile virus. Of particular interest is that several of these novel imino sugar derivatives, such as PBDNJ0801, PBDNJ0803, and PBDNJ0804, potently inhibit DENV infection in vitro, with 90% effective concentration values at submicromolar concentrations and selectivity indices greater than 800. Therefore, these compounds represent the best in their class and may offer realistic candidates for the development of antiviral therapeutics against human DENV infections.
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