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Pal R, Teli G, Akhtar MJ, Matada GSP. Synthetic product-based approach toward potential antileishmanial drug development. Eur J Med Chem 2024; 263:115927. [PMID: 37976706 DOI: 10.1016/j.ejmech.2023.115927] [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: 08/19/2023] [Revised: 10/27/2023] [Accepted: 10/30/2023] [Indexed: 11/19/2023]
Abstract
Leishmaniasis is a parasitic disease and is categorized as a tropically neglected disease (NTD) with no effective vaccines available. The available chemotherapeutics against leishmaniasis are associated with an increase in the incidence of toxicity and drug resistance. Consequently, targeting metabolic pathways and enzymes of parasites which differs from the mammalian host can be exploited to treat and overcome the resistance. The classical methods of identifying the structural fragments and the moieties responsible for the biological activities from the standard compounds and their modification are options for developing more effective novel compounds. Significant progress has been made in refining the development of potent non-toxic molecules and addressing the limitations of the current treatment available. Several examples of synthetic product-based approach utilizing their core heterocyclic rings including furan, pyrrole, thiazole, imidazole, pyrazole, triazole, quinazoline, quinoline, pyrimidine, coumarin, indole, acridine, oxadiazole, purine, chalcone, carboline, phenanthrene and metal containing derivatives and their structure-activity relationships are discussed in this review. It also analyses the groups/fragments interacting with the host cell receptors and will support the medicinal chemists with novel antileishmanial agents.
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Affiliation(s)
- Rohit Pal
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - Ghanshyam Teli
- School of Pharmacy, Sangam University, Atoon, Bhilwara, 311001, Rajasthan, India
| | - Md Jawaid Akhtar
- Department of Pharmaceutical Chemistry, National University of Science and Technology, PO 620, PC 130, Azaiba Bousher, Muscat, Sultanate of Oman
| | - Gurubasavaraja Swamy Purawarga Matada
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India.
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2
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González-González A, Vázquez C, Encalada R, Saavedra E, Vázquez-Jiménez LK, Ortiz-Pérez E, Bolognesi ML, Rivera G. Phenothiazine-based virtual screening, molecular docking, and molecular dynamics of new trypanothione reductase inhibitors of Trypanosoma cruzi. Mol Inform 2023; 42:e2300069. [PMID: 37490403 DOI: 10.1002/minf.202300069] [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: 03/21/2023] [Revised: 06/26/2023] [Accepted: 07/25/2023] [Indexed: 07/27/2023]
Abstract
Phenothiazine derivatives can unselectively inhibit the trypanothione-dependent antioxidant system enzyme trypanothione reductase (TR). A virtual screening of 2163 phenothiazine derivatives from the ZINC15 and PubChem databases docked on the active site of T. cruzi TR showed that 285 compounds have higher affinity than the natural ligand trypanothione disulfide. 244 compounds showed higher affinity toward the parasite's enzyme than to its human homolog glutathione reductase. Protein-ligand interaction profiling predicted that the main interactions for the top scored compounds were with residues important for trypanothione disulfide binding: Phe396, Pro398, Leu399, His461, Glu466, and Glu467, particularly His461, which participates in catalysis. Two compounds with the desired profiles, ZINC1033681 (Zn_C687) and ZINC10213096 (Zn_C216), decreased parasite growth by 20 % and 50 %, respectively. They behaved as mixed-type inhibitors of recombinant TR, with Ki values of 59 and 47 μM, respectively. This study provides a further understanding of the potential of phenothiazine derivatives as TR inhibitors.
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Affiliation(s)
- Alonzo González-González
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710, Reynosa, México
| | - Citlali Vázquez
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, 14080, Mexico City, Mexico
| | - Rusely Encalada
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, 14080, Mexico City, Mexico
| | - Emma Saavedra
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, 14080, Mexico City, Mexico
| | - Lenci K Vázquez-Jiménez
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710, Reynosa, México
| | - Eyra Ortiz-Pérez
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710, Reynosa, México
| | - María Laura Bolognesi
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy
| | - Gildardo Rivera
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710, Reynosa, México
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Ali V, Behera S, Nawaz A, Equbal A, Pandey K. Unique thiol metabolism in trypanosomatids: Redox homeostasis and drug resistance. ADVANCES IN PARASITOLOGY 2022; 117:75-155. [PMID: 35878950 DOI: 10.1016/bs.apar.2022.04.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Trypanosomatids are mainly responsible for heterogeneous parasitic diseases: Leishmaniasis, Sleeping sickness, and Chagas disease and control of these diseases implicates serious challenges due to the emergence of drug resistance. Redox-active biomolecules are the endogenous substances in organisms, which play important role in the regulation of redox homeostasis. The redox-active substances like glutathione, trypanothione, cysteine, cysteine persulfides, etc., and other inorganic intermediates (hydrogen peroxide, nitric oxide) are very useful as defence mechanism. In the present review, the suitability of trypanothione and other essential thiol molecules of trypanosomatids as drug targets are described in Leishmania and Trypanosoma. We have explored the role of tryparedoxin, tryparedoxin peroxidase, ascorbate peroxidase, superoxide dismutase, and glutaredoxins in the anti-oxidant mechanism and drug resistance. Up-regulation of some proteins in trypanothione metabolism helps the parasites in survival against drug pressure (sodium stibogluconate, Amphotericin B, etc.) and oxidative stress. These molecules accept electrons from the reduced trypanothione and donate their electrons to other proteins, and these proteins reduce toxic molecules, neutralize reactive oxygen, or nitrogen species; and help parasites to cope with oxidative stress. Thus, a better understanding of the role of these molecules in drug resistance and redox homeostasis will help to target metabolic pathway proteins to combat Leishmaniasis and trypanosomiases.
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Affiliation(s)
- Vahab Ali
- Laboratory of Molecular Biochemistry and Cell Biology, Department of Biochemistry, ICMR-Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna, Bihar, India.
| | - Sachidananda Behera
- Laboratory of Molecular Biochemistry and Cell Biology, Department of Biochemistry, ICMR-Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna, Bihar, India
| | - Afreen Nawaz
- Laboratory of Molecular Biochemistry and Cell Biology, Department of Biochemistry, ICMR-Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna, Bihar, India
| | - Asif Equbal
- Laboratory of Molecular Biochemistry and Cell Biology, Department of Biochemistry, ICMR-Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna, Bihar, India; Department of Botany, Araria College, Purnea University, Purnia, Bihar, India
| | - Krishna Pandey
- Department of Clinical Medicine, ICMR-Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna, Bihar, India
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Docampo R, Vercesi AE. Mitochondrial Ca 2+ and Reactive Oxygen Species in Trypanosomatids. Antioxid Redox Signal 2022; 36:969-983. [PMID: 34218689 PMCID: PMC9125514 DOI: 10.1089/ars.2021.0058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/31/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023]
Abstract
Significance: Millions of people are infected with trypanosomatids and new therapeutic approaches are needed. Trypanosomatids possess one mitochondrion per cell and its study has led to discoveries of general biological interest. These mitochondria, as in their animal counterparts, generate reactive oxygen species (ROS) and have evolved enzymatic and nonenzymatic defenses against them. Mitochondrial calcium ion (Ca2+) overload leads to generation of ROS and its study could lead to relevant information on the biology of trypanosomatids and to novel drug targets. Recent Advances: Mitochondrial Ca2+ is normally involved in maintaining the bioenergetics of trypanosomes, but when Ca2+ overload occurs, it is associated with cell death. Trypanosomes lack key players in the mechanism of cell death described in mammalian cells, although mitochondrial Ca2+ overload results in collapse of their membrane potential, production of ROS, and cytochrome c release. They are also very resistant to mitochondrial permeability transition, and cell death after mitochondrial Ca2+ overload depends on generation of ROS. Critical Issues: In this review, we consider the mechanisms of mitochondrial oxidant generation and removal and the involvement of Ca2+ in trypanosome cell death. Future Directions: More studies are required to determine the reactions involved in generation of ROS by the mitochondria of trypanosomatids, their enzymatic and nonenzymatic defenses against ROS, and the occurrence and composition of a mitochondrial permeability transition pore. Antioxid. Redox Signal. 36, 969-983.
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Affiliation(s)
- Roberto Docampo
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, USA
- Department of Cellular Biology, University of Georgia, Athens, Georgia, USA
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Santana W, de Oliveira SSC, Ramos MH, Santos ALS, Dolabella SS, Souto EB, Severino P, Jain S. Exploring Innovative Leishmaniasis Treatment: Drug Targets from Pre-Clinical to Clinical Findings. Chem Biodivers 2021; 18:e2100336. [PMID: 34369662 DOI: 10.1002/cbdv.202100336] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/13/2021] [Indexed: 12/28/2022]
Abstract
Leishmaniasis is a group of tropical diseases caused by parasitic protozoa belonging to the genus Leishmania. The disease is categorized in cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL). The conventional treatment is complex and can present high toxicity and therapeutic failures. Thus, there is a continuing need to develop new treatments. In this review, we focus on the novel molecules described in the literature with potential leishmanicidal activity, categorizing them in pre-clinical (in vitro, in vivo), drug repurposing and clinical research.
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Affiliation(s)
- Wanessa Santana
- Post-Graduation Program in Industrial Biotechnology, University of Tiradentes, Aracaju, Sergipe, Brazil
| | - Simone S C de Oliveira
- Institute of Microbiology Paulo de Góes, Department of General Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mariana H Ramos
- Post-Graduation Program in Industrial Biotechnology, University of Tiradentes, Aracaju, Sergipe, Brazil
| | - André L S Santos
- Institute of Microbiology Paulo de Góes, Department of General Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Silvio S Dolabella
- Laboratory of Entomology and Tropical Parasitology, Department of Morphology, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil
| | - Eliana B Souto
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, Portugal.,CEB - Center of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
| | - Patrícia Severino
- Post-Graduation Program in Industrial Biotechnology, University of Tiradentes, Aracaju, Sergipe, Brazil.,Institute of Technology and Research (ITP), University of Tiradentes, Aracaju, Sergipe, Brazil
| | - Sona Jain
- Post-Graduation Program in Industrial Biotechnology, University of Tiradentes, Aracaju, Sergipe, Brazil
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da Silva MA, Fokoue HH, Fialho SN, Dos Santos APDA, Rossi NRDLP, Gouveia ADJ, Ferreira AS, Passarini GM, Garay AFG, Alfonso JJ, Soares AM, Zanchi FB, Kato MJ, Teles CBG, Kuehn CC. Antileishmanial activity evaluation of a natural amide and its synthetic analogs against Leishmania (V.) braziliensis: an integrated approach in vitro and in silico. Parasitol Res 2021; 120:2199-2218. [PMID: 33963899 DOI: 10.1007/s00436-021-07169-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 04/21/2021] [Indexed: 10/21/2022]
Abstract
Leishmaniasis is considered a neglected disease, which makes it an unattractive market for the pharmaceutical industry; hence, efforts in the search for biologically active substances are hampered by this lack of financial motivation. Thus, in the present study, we report the leishmanicidal activity and the possible mechanisms of action of compounds with promising activity against the species Leishmania (V.) braziliensis, the causative agent of the skin disease leishmaniasis. The natural compound 1a (piplartine) and the analog 2a were the most potent against promastigote forms with growth inhibition values for 50% of the parasite population (IC50) = 8.58 and 11.25 μM, respectively. For amastigote forms, the ICa50 values were 1.46 and 16.7 μM, respectively. In the molecular docking study, piplartine showed favorable binding energy (-7.13 kcal/mol) and with 50% inhibition of trypanothione reductase (IC50) = 91.1 μM. Preliminary investigations of the mechanism of action indicate that piplartine increased ROS levels, induced loss of cell membrane integrity, and caused accumulation of lipid bodies after 24 h of incubation at its lowest effective concentration (IC50), which was not observed for the synthetic analog 2a. The mode of action for the leishmanicidal activity of piplartine (1a) was assigned to involve affinity for the trypanothione reductase of Leishmania (V.) braziliensis TR.
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Affiliation(s)
- Minelly A da Silva
- Federal Institute of Education, Science and Technology of Rondônia - IFRO, Porto Velho, Rondônia, Brazil.
- Federal University of Rondônia - UNIR, Porto Velho, Rondônia, Brazil.
- Instituto Federal de Rondônia - Porto Velho-Calama, Av. Calama, 4985 - Flodoaldo Pontes Pinto, Porto Velho, RO, 76820-441, Brazil.
| | - Harold H Fokoue
- Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - FIOCRUZ/RJ, Rio de Janeiro, Brazil
| | - Saara N Fialho
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Rede de Biodiversidade e Biotecnologia da Amazônia Legal - BIONORTE, Porto Velho, Rondônia, Brazil
| | | | - Norton R D L P Rossi
- Federal University of Rondônia - UNIR, Porto Velho, Rondônia, Brazil
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
| | | | - Amália S Ferreira
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
| | - Guilherme M Passarini
- Federal University of Rondônia - UNIR, Porto Velho, Rondônia, Brazil
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
| | - Ana F G Garay
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Centro para el Desarrollo de la Investigación Científica - CEDIC, Asunción, Paraguay
| | - Jorge J Alfonso
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Centro para el Desarrollo de la Investigación Científica - CEDIC, Asunción, Paraguay
| | - Andreimar M Soares
- Federal University of Rondônia - UNIR, Porto Velho, Rondônia, Brazil
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Rede de Biodiversidade e Biotecnologia da Amazônia Legal - BIONORTE, Porto Velho, Rondônia, Brazil
- National Institute of Science and Technology of Epidemiology in the Western Amazon - INCT-EpiAmO, Rondônia, Brazil
| | - Fernando B Zanchi
- Federal University of Rondônia - UNIR, Porto Velho, Rondônia, Brazil
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Rede de Biodiversidade e Biotecnologia da Amazônia Legal - BIONORTE, Porto Velho, Rondônia, Brazil
| | - Massuo J Kato
- Institute of Chemistry, University of São Paulo - USP, São Paulo, Brazil
| | - Carolina B G Teles
- Federal University of Rondônia - UNIR, Porto Velho, Rondônia, Brazil
- Fundação Oswaldo Cruz - Rondônia - FIOCRUZ/RO, Porto Velho, Rondônia, Brazil
- Rede de Biodiversidade e Biotecnologia da Amazônia Legal - BIONORTE, Porto Velho, Rondônia, Brazil
- National Institute of Science and Technology of Epidemiology in the Western Amazon - INCT-EpiAmO, Rondônia, Brazil
| | - Christian C Kuehn
- Federal University of Rondônia - UNIR, Porto Velho, Rondônia, Brazil
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Quinolizidine-Derived Lucanthone and Amitriptyline Analogues Endowed with Potent Antileishmanial Activity. Pharmaceuticals (Basel) 2020; 13:ph13110339. [PMID: 33113777 PMCID: PMC7694037 DOI: 10.3390/ph13110339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 10/21/2020] [Accepted: 10/21/2020] [Indexed: 12/11/2022] Open
Abstract
Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against Leishmania tropica and L. infantum promastigotes. All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety. All compounds displayed activity against both species of Leishmania with IC50 values in the low micromolar range, resulting in several fold more potency than miltefosine, comparable to that of lucanthone, and endowed with substantially lower cytotoxicity to Vero-76 cells, for the best of them. Thus, 4-amino-1-(quinolizidinylethyl)aminothioxanthen-9-one (14) and 9-(quinolizidinylmethylidene)fluorene (17), with selectivity index (SI) in the range 16-24, represent promising leads for the development of improved antileishmanial agents. These two compounds also exhibited comparable activity against intramacrophagic amastigotes of L. infantum. Docking studies have suggested that the inhibition of trypanothione reductase (TryR) may be at the basis (eventually besides other mechanisms) of the observed antileishmanial activity. Therefore, these investigated derivatives may deserve further structural improvements and more in-depth biological studies of their mechanisms of action in order to develop more efficient antiparasitic agents.
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Altamura F, Rajesh R, Catta-Preta CMC, Moretti NS, Cestari I. The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets. Drug Dev Res 2020; 83:225-252. [PMID: 32249457 DOI: 10.1002/ddr.21664] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/05/2020] [Accepted: 03/13/2020] [Indexed: 12/11/2022]
Abstract
Human trypanosomiasis and leishmaniasis are vector-borne neglected tropical diseases caused by infection with the protozoan parasites Trypanosoma spp. and Leishmania spp., respectively. Once restricted to endemic areas, these diseases are now distributed worldwide due to human migration, climate change, and anthropogenic disturbance, causing significant health and economic burden globally. The current chemotherapy used to treat these diseases has limited efficacy, and drug resistance is spreading. Hence, new drugs are urgently needed. Phenotypic compound screenings have prevailed as the leading method to discover new drug candidates against these diseases. However, the publication of the complete genome sequences of multiple strains, advances in the application of CRISPR/Cas9 technology, and in vivo bioluminescence-based imaging have set the stage for advancing target-based drug discovery. This review analyses the limitations of the narrow pool of available drugs presently used for treating these diseases. It describes the current drug-based clinical trials highlighting the most promising leads. Furthermore, the review presents a focused discussion on the most important biological and pharmacological challenges that target-based drug discovery programs must overcome to advance drug candidates. Finally, it examines the advantages and limitations of modern research tools designed to identify and validate essential genes as drug targets, including genomic editing applications and in vivo imaging.
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Affiliation(s)
- Fernando Altamura
- Institute of Parasitology, McGill University, Ste Anne de Bellevue, Quebec, Canada
| | - Rishi Rajesh
- Institute of Parasitology, McGill University, Ste Anne de Bellevue, Quebec, Canada
| | | | - Nilmar S Moretti
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Igor Cestari
- Institute of Parasitology, McGill University, Ste Anne de Bellevue, Quebec, Canada
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Ribeiro V, Dias N, Paiva T, Hagström-Bex L, Nitz N, Pratesi R, Hecht M. Current trends in the pharmacological management of Chagas disease. Int J Parasitol Drugs Drug Resist 2020; 12:7-17. [PMID: 31862616 PMCID: PMC6928327 DOI: 10.1016/j.ijpddr.2019.11.004] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/06/2019] [Accepted: 11/28/2019] [Indexed: 12/12/2022]
Abstract
Chagas disease (CD) is a tropical neglected illness, affecting mainly populations of low socioeconomic status in Latin America. An estimated 6 to 8 million people worldwide are infected with Trypanosoma cruzi, the etiological agent of CD. Despite being one of the main global health problems, this disease continues without effective treatment during the chronic phase of the infection. The limitation of therapeutic strategies has been one of the biggest challenges on the fight against CD. Nifurtimox and benznidazole, developed in the 1970s, are still the only commercial options with established efficacy on CD. However, the efficacy of these drugs have a proven efficacy only during early infection and the benefits in the chronic phase are questionable. Consequently, there is a growing need for new pharmacological alternatives, either by optimization of existing drugs or by the formulation of new compounds. In the present study, a literature review of the currently adopted therapy, its concomitant combination with other drugs, and potential future treatments for CD was performed, considering articles published from 2012. The revised articles were selected according to the protocol of treatment: evaluation of drug association, drug repositioning and research of new drugs. As a result of the present revision, it was possible to conclude that the use of benznidazole in combination with other compounds showed better results when compared with its use as a single therapy. The search of new drugs has been the strategy most used in pursuing more effective forms of treatment for CD. However, studies have still focused on basic research, that is, they are still in a pre-clinical stage, using methodologies based on in vitro or in animal studies.
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Affiliation(s)
- Vanessa Ribeiro
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil.
| | - Nayra Dias
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil.
| | - Taís Paiva
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil.
| | - Luciana Hagström-Bex
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil.
| | - Nadjar Nitz
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil.
| | - Riccardo Pratesi
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil.
| | - Mariana Hecht
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil.
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10
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Santos SS, de Araújo RV, Giarolla J, Seoud OE, Ferreira EI. Searching for drugs for Chagas disease, leishmaniasis and schistosomiasis: a review. Int J Antimicrob Agents 2020; 55:105906. [PMID: 31987883 DOI: 10.1016/j.ijantimicag.2020.105906] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 01/14/2020] [Accepted: 01/18/2020] [Indexed: 12/16/2022]
Abstract
Chagas disease, leishmaniasis and schistosomiasis are neglected diseases (NDs) and are a considerable global challenge. Despite the huge number of people infected, NDs do not create interest from pharmaceutical companies because the associated revenue is generally low. Most of the research on these diseases has been conducted in academic institutions. The chemotherapeutic armamentarium for NDs is scarce and inefficient and better drugs are needed. Researchers have found some promising potential drug candidates using medicinal chemistry and computational approaches. Most of these compounds are synthetic but some are from natural sources or are semi-synthetic. Drug repurposing or repositioning has also been greatly stimulated for NDs. This review considers some potential drug candidates and provides details of their design, discovery and activity.
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Affiliation(s)
- Soraya Silva Santos
- Laboratory of Design and Synthesis of Chemotherapeutics Potentially Active in Neglected Diseases (LAPEN), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo-USP, Avenue Professor Lineu Prestes, 580-Building 13, São Paulo SP, 05508-900, Brazil
| | - Renan Vinicius de Araújo
- Laboratory of Design and Synthesis of Chemotherapeutics Potentially Active in Neglected Diseases (LAPEN), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo-USP, Avenue Professor Lineu Prestes, 580-Building 13, São Paulo SP, 05508-900, Brazil
| | - Jeanine Giarolla
- Laboratory of Design and Synthesis of Chemotherapeutics Potentially Active in Neglected Diseases (LAPEN), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo-USP, Avenue Professor Lineu Prestes, 580-Building 13, São Paulo SP, 05508-900, Brazil
| | - Omar El Seoud
- Laboratory of Design and Synthesis of Chemotherapeutics Potentially Active in Neglected Diseases (LAPEN), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo-USP, Avenue Professor Lineu Prestes, 580-Building 13, São Paulo SP, 05508-900, Brazil
| | - Elizabeth Igne Ferreira
- Laboratory of Design and Synthesis of Chemotherapeutics Potentially Active in Neglected Diseases (LAPEN), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo-USP, Avenue Professor Lineu Prestes, 580-Building 13, São Paulo SP, 05508-900, Brazil.
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Talevi A, Carrillo C, Comini M. The Thiol-polyamine Metabolism of Trypanosoma cruzi: Molecular Targets and Drug Repurposing Strategies. Curr Med Chem 2019; 26:6614-6635. [PMID: 30259812 DOI: 10.2174/0929867325666180926151059] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/23/2018] [Accepted: 09/10/2018] [Indexed: 12/18/2022]
Abstract
Chagas´ disease continues to be a challenging and neglected public health problem in many American countries. The etiologic agent, Trypanosoma cruzi, develops intracellularly in the mammalian host, which hinders treatment efficacy. Progress in the knowledge of parasite biology and host-pathogen interaction has not been paralleled by the development of novel, safe and effective therapeutic options. It is then urgent to seek for novel therapeutic candidates and to implement drug discovery strategies that may accelerate the discovery process. The most appealing targets for pharmacological intervention are those essential for the pathogen and, whenever possible, absent or significantly different from the host homolog. The thiol-polyamine metabolism of T. cruzi offers interesting candidates for a rational design of selective drugs. In this respect, here we critically review the state of the art of the thiolpolyamine metabolism of T. cruzi and the pharmacological potential of its components. On the other hand, drug repurposing emerged as a valid strategy to identify new biological activities for drugs in clinical use, while significantly shortening the long time and high cost associated with de novo drug discovery approaches. Thus, we also discuss the different drug repurposing strategies available with a special emphasis in their applications to the identification of drug candidates targeting essential components of the thiol-polyamine metabolism of T. cruzi.
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Affiliation(s)
- Alan Talevi
- Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata, La Plata, Argentina
| | - Carolina Carrillo
- Instituto de Ciencias y Tecnología Dr. César Milstein (ICT Milstein) - CONICET. Ciudad Autónoma de Buenos Aires, Argentina
| | - Marcelo Comini
- Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay
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12
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Aguilera E, Alvarez G, Cerecetto H, González M. Polypharmacology in the Treatment of Chagas Disease. Curr Med Chem 2019; 26:4476-4489. [PMID: 29637852 DOI: 10.2174/0929867325666180410101728] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 03/28/2018] [Accepted: 04/28/2018] [Indexed: 01/06/2023]
Abstract
The current treatment of Chagas disease is based on monopharmacology where the used drugs have limited efficacy and severe side effects. In order to overcome these limitations, some tools have been described including the development or isolation of new drugs, drug repositioning, and polypharmacology. Here, we review the polypharmacology strategy where compounds belonging to different structural chemotypes were combined in order to affect different biochemical pathways of T. cruzi parasite. Therefore ergosterol biosynthesis inhibitors, anti-inflammatory agents, cardiac dysfunction drugs, trypanothione reductase inhibitors, vitamins, between others, were combined looking for new anti-Chagas treatment. Natural products were also used in the application of this strategy.
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Affiliation(s)
- Elena Aguilera
- Grupo de Quimica Medicinal, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Guzmán Alvarez
- Grupo de Quimica Medicinal, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.,Laboratorio de Moléculas Bioactivas, Centro Universitario Regional Litoral Norte, Universidad de la República, Paysandú, Uruguay
| | - Hugo Cerecetto
- Grupo de Quimica Medicinal, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.,Area de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Montevideo, Uruguay
| | - Mercedes González
- Grupo de Quimica Medicinal, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
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13
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Villalta F, Rachakonda G. Advances in preclinical approaches to Chagas disease drug discovery. Expert Opin Drug Discov 2019; 14:1161-1174. [PMID: 31411084 PMCID: PMC6779130 DOI: 10.1080/17460441.2019.1652593] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/02/2019] [Indexed: 12/21/2022]
Abstract
Introduction: Chagas disease affects 8-10 million people worldwide, mainly in Latin America. The current therapy for Chagas disease is limited to nifurtimox and benznidazole, which are effective in treating only the acute phase of the disease but with severe side effects. Therefore, there is an unmet need for new drugs and for the exploration of innovative approaches which may lead to the discovery of new effective and safe drugs for its treatment. Areas covered: The authors report and discuss recent approaches including structure-based design that have led to the discovery of new promising small molecule candidates for Chagas disease which affect prime targets that intervene in the sterol pathway of T. cruzi. Other trypanosome targets, phenotypic screening, the use of artificial intelligence and the challenges with Chagas disease drug discovery are also discussed. Expert opinion: The application of recent scientific innovations to the field of Chagas disease have led to the discovery of new promising drug candidates for Chagas disease. Phenotypic screening brought new hits and opportunities for drug discovery. Artificial intelligence also has the potential to accelerate drug discovery in Chagas disease and further research into this is warranted.
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Affiliation(s)
- Fernando Villalta
- Department of Microbiology, Immunology and Physiology, School of Medicine, Meharry Medical College , Nashville , TN , USA
| | - Girish Rachakonda
- Department of Microbiology, Immunology and Physiology, School of Medicine, Meharry Medical College , Nashville , TN , USA
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14
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The antidepressant clomipramine induces programmed cell death in Leishmania amazonensis through a mitochondrial pathway. Parasitol Res 2019; 118:977-989. [DOI: 10.1007/s00436-018-06200-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 12/28/2018] [Indexed: 12/14/2022]
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15
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Mendonça AAS, Coelho CM, Veloso MP, Caldas IS, Gonçalves RV, Teixeira AL, de Miranda AS, Novaes RD. Relevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection: A Systematic Review, Meta-Analysis, and In Silico Integrated Approach. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:8676578. [PMID: 30473742 PMCID: PMC6220389 DOI: 10.1155/2018/8676578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 08/14/2018] [Indexed: 02/08/2023]
Abstract
Due to the rudimentary antioxidant defenses in Trypanosoma cruzi, disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac β-adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro, and in vivo findings indicated that the anti-T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence.
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Affiliation(s)
- Andréa Aparecida Santos Mendonça
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, 37130-001 Minas Gerais, Brazil
- Department of Structural Biology, Federal University of Alfenas, Alfenas, 37130-001 Minas Gerais, Brazil
| | - Camila Morais Coelho
- Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, 37130-001 Minas Gerais, Brazil
| | - Marcia Paranho Veloso
- Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, 37130-001 Minas Gerais, Brazil
| | - Ivo Santana Caldas
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, 37130-001 Minas Gerais, Brazil
- Department of Pathology and Parasitology, Federal University of Alfenas, Alfenas, 37130-001 Minas Gerais, Brazil
| | | | - Antônio Lucio Teixeira
- Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, 30130-100 Minas Gerais, Brazil
| | - Aline Silva de Miranda
- Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, 30130-100 Minas Gerais, Brazil
- Institute of Biological Sciences, Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, 30130-100 Minas Gerais, Brazil
| | - Rômulo Dias Novaes
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, 37130-001 Minas Gerais, Brazil
- Department of Structural Biology, Federal University of Alfenas, Alfenas, 37130-001 Minas Gerais, Brazil
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16
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Tiwari N, Tanwar N, Munde M. Molecular insights into trypanothione reductase-inhibitor interaction: A structure-based review. Arch Pharm (Weinheim) 2018; 351:e1700373. [DOI: 10.1002/ardp.201700373] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 03/20/2018] [Accepted: 03/23/2018] [Indexed: 11/06/2022]
Affiliation(s)
- Neha Tiwari
- School of Physical Sciences; Jawaharlal Nehru University; New Delhi India
| | - Neetu Tanwar
- School of Physical Sciences; Jawaharlal Nehru University; New Delhi India
| | - Manoj Munde
- School of Physical Sciences; Jawaharlal Nehru University; New Delhi India
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17
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Strauss M, Rodrigues JHS, Lo Presti MS, Bazán PC, Báez AL, Paglini-Oliva P, Nakamura CV, Bustamante JM, Rivarola HW. In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach. Exp Parasitol 2018; 189:19-27. [PMID: 29726395 DOI: 10.1016/j.exppara.2018.04.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/18/2018] [Accepted: 04/15/2018] [Indexed: 01/07/2023]
Abstract
Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.
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Affiliation(s)
- Mariana Strauss
- Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro de Estudios e Investigación de la Enfermedad de Chagas y Leishmaniasis, Cátedra de Física Biomédica, Facultad de Ciencias Médicas, Santa Rosa 1085, Córdoba X5000ESU, Argentina
| | - Jean Henrique S Rodrigues
- Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Colombo 5790, Paraná, Brazil
| | - María Silvina Lo Presti
- Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro de Estudios e Investigación de la Enfermedad de Chagas y Leishmaniasis, Cátedra de Física Biomédica, Facultad de Ciencias Médicas, Santa Rosa 1085, Córdoba X5000ESU, Argentina
| | - Paola Carolina Bazán
- Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro de Estudios e Investigación de la Enfermedad de Chagas y Leishmaniasis, Cátedra de Física Biomédica, Facultad de Ciencias Médicas, Santa Rosa 1085, Córdoba X5000ESU, Argentina
| | - Alejandra Lidia Báez
- Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro de Estudios e Investigación de la Enfermedad de Chagas y Leishmaniasis, Cátedra de Física Biomédica, Facultad de Ciencias Médicas, Santa Rosa 1085, Córdoba X5000ESU, Argentina
| | - Patricia Paglini-Oliva
- Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro de Estudios e Investigación de la Enfermedad de Chagas y Leishmaniasis, Cátedra de Física Biomédica, Facultad de Ciencias Médicas, Santa Rosa 1085, Córdoba X5000ESU, Argentina
| | - Celso Vataru Nakamura
- Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Colombo 5790, Paraná, Brazil
| | - Juan Manuel Bustamante
- University of Georgia, Center for Tropical and Emerging Global Diseases, D.W. Brooks Dr. S310 Coverdell Center, Athens, GA 30602, USA
| | - Héctor Walter Rivarola
- Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro de Estudios e Investigación de la Enfermedad de Chagas y Leishmaniasis, Cátedra de Física Biomédica, Facultad de Ciencias Médicas, Santa Rosa 1085, Córdoba X5000ESU, Argentina.
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18
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Uliassi E, Fiorani G, Krauth-Siegel RL, Bergamini C, Fato R, Bianchini G, Carlos Menéndez J, Molina MT, López-Montero E, Falchi F, Cavalli A, Gul S, Kuzikov M, Ellinger B, Witt G, Moraes CB, Freitas-Junior LH, Borsari C, Costi MP, Bolognesi ML. Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase ( Tb GAPDH) and Trypanosoma cruzi trypanothione reductase ( Tc TR) and display trypanocidal activity. Eur J Med Chem 2017; 141:138-148. [DOI: 10.1016/j.ejmech.2017.10.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 09/18/2017] [Accepted: 10/02/2017] [Indexed: 01/23/2023]
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19
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Khan MOF. Trypanothione Reductase: A Viable Chemotherapeutic Target for Antitrypanosomal and Antileishmanial Drug Design. Drug Target Insights 2017. [DOI: 10.1177/117739280700200007] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- M. Omar F. Khan
- College of Pharmacy, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, U.S.A
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20
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Kumar A, Saha B, Singh S. Dataset generated for Dissection of mechanisms of Trypanothione Reductase and Tryparedoxin Peroxidase through dynamic network analysis and simulations in leishmaniasis. Data Brief 2017; 15:757-769. [PMID: 29159213 PMCID: PMC5675996 DOI: 10.1016/j.dib.2017.10.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 09/26/2017] [Accepted: 10/12/2017] [Indexed: 01/01/2023] Open
Abstract
Leishmaniasis is the second largest parasitic killer disease caused by the protozoan parasite Leishmania, transmitted by the bite of sand flies. It's endemic in the eastern India with 165.4 million populations at risk with the current drug regimen. Three forms of leishmaniasis exist in which cutaneous is the most common form caused by Leishmania major. Trypanothione Reductase (TryR), a flavoprotein oxidoreductase, unique to thiol redox system, is considered as a potential target for chemotherapy for trypanosomatids infection. It is involved in the NADPH dependent reduction of Trypanothione disulphide to Trypanothione. Similarly, is Tryparedoxin Peroxidase (Txnpx), for detoxification of peroxides, an event pivotal for survival of Leishmania in two disparate biological environment. Fe-S plays a major role in regulating redox balance. To check for the closeness between human homologs of these proteins, we have carried the molecular clock analysis followed by molecular modeling of 3D structure of this protein, enabling us to design and test the novel drug like molecules. Molecular clock analysis suggests that human homologs of TryR i.e. Glutathione Reductase and Txnpx respectively are highly diverged in phylogenetic tree, thus, they serve as good candidates for chemotherapy of leishmaniasis. Furthermore, we have done the homology modeling of TryR using template of same protein from Leishmania infantum (PDB ID: 2JK6). This was done using Modeller 9.18 and the resultant models were validated. To inhibit this target, molecular docking was done with various screened inhibitors in which we found Taxifolin acts as common inhibitors for both TryR and Txnpx. We constructed the protein-protein interaction network for the proteins that are involved in the redox metabolism from various Interaction databases and the network was statistically analysed.
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Key Words
- BIND, Biomolecular Network Interaction Database
- DIP, Database of Interacting Protein
- GRID, General repository for Interaction Database
- Homology modeling
- KEGG, Kyoto Encyclopaedia of Genes and Genomes
- L.major
- MINT, Molecular Interaction Database
- MIPS, Munich Information Centre for Protein sequence
- Molecular clock analysis
- Network analysis
- ProSA, Protein Structure Analysis
- SAVES, Structure Analysis and Verification Server
- T(SH)2, Trypanothione
- TryR, Trypanothione Reductase
- TryS, Trypanothione synthetase
- Trypanothione Reductase
- Tryparedoxin Peroxidase
- Txnpx, Tryparedoxin Peroxidase
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Affiliation(s)
- Anurag Kumar
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - Bhaskar Saha
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - Shailza Singh
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
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21
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Rodríguez-Becerra J, Cáceres-Jensen L, Hernández-Ramos J, Barrientos L. Identification of potential trypanothione reductase inhibitors among commercially available
$$\upbeta $$
β
-carboline derivatives using chemical space, lead-like and drug-like filters, pharmacophore models and molecular docking. Mol Divers 2017; 21:697-711. [DOI: 10.1007/s11030-017-9747-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 04/16/2017] [Indexed: 10/19/2022]
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New iminodibenzyl derivatives with anti-leishmanial activity. J Inorg Biochem 2017; 172:9-15. [PMID: 28414928 DOI: 10.1016/j.jinorgbio.2017.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 02/06/2017] [Accepted: 04/02/2017] [Indexed: 01/27/2023]
Abstract
Leishmaniasis is an infection caused by protozoa of the genus Leishmania and transmitted by sandflies. Current treatments are expensive and time-consuming, involving Sb(V)-based compounds, lipossomal amphotericin B and miltefosine. Recent studies suggest that inhibition of trypanothione reductase (TR) could be a specific target in the development of new drugs because it is essential and exclusive to trypanosomatids. This work presents the synthesis and characterization of new iminodibenzyl derivatives (dado) with ethylenediamine (ea), ethanolamine (en) and diethylenetriamine (dien) and their copper(II) complexes. Computational methods indicated that the complexes were highly lipophilic. Pro-oxidant activity assays by oxidation of the dihydrorhodamine (DHR) fluorimetric probe showed that [Cu(dado-ea)]2+ has the highest rate of oxidation, independent of H2O2 concentration. The toxicity to L. amazonensis promastigotes and RAW 264,7 macrophages was assessed, showing that dado-en was the most active new compound. Complexation to copper did not have an appreciable effect on the toxicity of the compounds.
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Sueth-Santiago V, Decote-Ricardo D, Morrot A, Freire-de-Lima CG, Lima MEF. Challenges in the chemotherapy of Chagas disease: Looking for possibilities related to the differences and similarities between the parasite and host. World J Biol Chem 2017; 8:57-80. [PMID: 28289519 PMCID: PMC5329715 DOI: 10.4331/wjbc.v8.i1.57] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 12/30/2016] [Accepted: 01/14/2017] [Indexed: 02/05/2023] Open
Abstract
Almost 110 years after the first studies by Dr. Carlos Chagas describing an infectious disease that was named for him, Chagas disease remains a neglected illness and a death sentence for infected people in poor countries. This short review highlights the enormous need for new studies aimed at the development of novel and more specific drugs to treat chagasic patients. The primary tool for facing this challenge is deep knowledge about the similarities and differences between the parasite and its human host.
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Romero AH, Medina R, Alcala A, García-Marchan Y, Núñez-Duran J, Leañez J, Mijoba A, Ciangherotti C, Serrano-Martín X, López SE. Design, synthesis, structure-activity relationship and mechanism of action studies of a series of 4-chloro-1-phthalazinyl hydrazones as a potent agent against Leishmania braziliensis. Eur J Med Chem 2017; 127:606-620. [DOI: 10.1016/j.ejmech.2017.01.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 01/12/2017] [Accepted: 01/13/2017] [Indexed: 11/29/2022]
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25
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Cunha-Júnior EF, Andrade-Neto VV, Lima ML, da Costa-Silva TA, Galisteo Junior AJ, Abengózar MA, Barbas C, Rivas L, Almeida-Amaral EE, Tempone AG, Torres-Santos EC. Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. PLoS Negl Trop Dis 2017; 11:e0005281. [PMID: 28045892 PMCID: PMC5234845 DOI: 10.1371/journal.pntd.0005281] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 01/13/2017] [Accepted: 12/21/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The leishmanicidal action of tricyclic antidepressants has been studied and evidences have pointed that their action is linked to inhibition of trypanothione reductase, a key enzyme in the redox metabolism of pathogenic trypanosomes. Cyclobenzaprine (CBP) is a tricyclic structurally related to the antidepressant amitriptyline, differing only by the presence of a double bond in the central ring. This paper describes the effect of CBP in experimental visceral leishmaniasis, its inhibitory effect in trypanothione reductase and the potential immunomodulatory activity. METHODOLOGY/PRINCIPAL FINDINGS In vitro antileishmanial activity was determined in promastigotes and in L. infantum-infected macrophages. For in vivo studies, L. infantum-infected BALB/c mice were treated with CBP by oral gavage for five days and the parasite load was estimated. Trypanothione reductase activity was assessed in the soluble fraction of promastigotes of L. infantum. For evaluation of cytokines, L. infantum-infected macrophages were co-cultured with BALB/c splenocytes and treated with CBP for 48 h. The supernatant was analyzed for IL-6, IL-10, MCP-1, IFN-γ and TNF-α. CBP demonstrated an IC50 of 14.5±1.1μM and an IC90 of 74.5±1.2 μM in promastigotes and an IC50 of 12.6±1.05 μM and an IC90 of 28.7±1.3 μM in intracellular amastigotes. CBP also reduced the parasite load in L. infantum-infected mice by 40.4±10.3% and 66.7±10.5% in spleen at 24.64 and 49.28 mg/kg, respectively and by 85.6±5.0 and 89.3±4.8% in liver at 24.64 and 49.28mg/kg, after a short-term treatment. CBP inhibited the trypanothione reductase activity with a Ki of 86 ± 7.7 μM and increased the ROS production in promastigotes. CBP inhibited in 53% the production of IL-6 in infected macrophages co-culture. CONCLUSION/SIGNIFICANCE To the best of our knowledge, this study is the first report of the in vivo antileishmanial activity of the FDA-approved drug CBP. Modulation of immune response and induction of oxidative stress in parasite seem to contribute to this efficacy.
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Affiliation(s)
| | - Valter Viana Andrade-Neto
- Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brasil
| | - Marta Lopes Lima
- Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, São Paulo, Brazil
- Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, São Paulo, São Paulo, Brazil
| | | | | | - Maria A. Abengózar
- Centro de Investigaciones Biológicas (CSIC), Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU, Madrid, Spain
| | - Coral Barbas
- Center for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad CEU San Pablo, Madrid, Spain
| | - Luis Rivas
- Centro de Investigaciones Biológicas (CSIC), Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU, Madrid, Spain
| | | | - Andre Gustavo Tempone
- Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, São Paulo, São Paulo, Brazil
| | - Eduardo Caio Torres-Santos
- Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brasil
- * E-mail:
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26
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Drug repositioning approaches to parasitic diseases: a medicinal chemistry perspective. Drug Discov Today 2016; 21:1699-1710. [PMID: 27365271 DOI: 10.1016/j.drudis.2016.06.021] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Revised: 05/20/2016] [Accepted: 06/21/2016] [Indexed: 01/25/2023]
Abstract
Identifying new indications for clinically useful drugs is a worthwhile approach for neglected tropical diseases. The number of successful repurposing cases in the field is growing as not-for-profit organizations, in association with academia and pharmaceutical companies, enable screening campaigns for the identification of new repositioning candidates. Current programs have delivered encouraging results as the use of state-of-the-art technologies, such as genomic and structural biology tools, and high-throughput screening platforms have become increasingly common in infectious disease research. Drug repositioning has played a key part in improving the lives of those suffering from these conditions, as evidenced by successful precedents and recent studies on preeminent parasitic disorders.
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27
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Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease. Antimicrob Agents Chemother 2016; 60:3700-8. [PMID: 27067322 DOI: 10.1128/aac.00404-16] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 03/28/2016] [Indexed: 10/21/2022] Open
Abstract
Chagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.
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28
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Argüelles AJ, Cordell GA, Maruenda H. Molecular Docking and Binding Mode Analysis of Plant Alkaloids as in Vitro and in silico Inhibitors of Trypanothione Reductase from Trypanosoma cruzi. Nat Prod Commun 2016. [DOI: 10.1177/1934578x1601100118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Trypanothione reductase (TryR) is a key enzyme in the metabolism of Trypanosoma cruzi, the parasite responsible for Chagas disease. The available repertoire of TryR inhibitors relies heavily on synthetic substrates of limited structural diversity, and less on plant-derived natural products. In this study, a molecular docking procedure using a Lamarckian Genetic Algorithm was implemented to examine the protein-ligand binding interactions of strong in vitro inhibitors for which no X-ray data is available. In addition, a small, skeletally diverse, set of natural alkaloids was assessed computationally against T. cruzi TryR in search of new scaffolds for lead development. The preferential binding mode (low number of clusters, high cluster population), together with the deduced binding interactions were used to discriminate among the virtual inhibitors. This study confirms the prior in vitro data and proposes quebrachamine, cephalotaxine, cryptolepine, (22 S,25 S)-tomatidine, (22 R,25 S)-solanidine, and (22 R,25 R)-solasodine as new alkaloid scaffold leads in the search for more potent and selective TryR inhibitors.
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Affiliation(s)
- Alonso J. Argüelles
- Pontificia Universidad Católica del Perú, Departamento de Ciencias - Sección Química, Lima, Perú
| | - Geoffrey A. Cordell
- Pontificia Universidad Católica del Perú, Departamento de Ciencias - Sección Química, Lima, Perú
- Natural Products Inc., Evanston, IL 60203, USA
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
| | - Helena Maruenda
- Pontificia Universidad Católica del Perú, Departamento de Ciencias - Sección Química, Lima, Perú
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29
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Marcu A, Schurigt U, Müller K, Moll H, Krauth-Siegel RL, Prinz H. Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase. Eur J Med Chem 2015; 108:436-443. [PMID: 26708110 DOI: 10.1016/j.ejmech.2015.11.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 09/23/2015] [Accepted: 11/16/2015] [Indexed: 10/22/2022]
Abstract
A number of phenothiazine-, phenoxazine- and related tricyclics-derived chloroacetamides were synthesized and evaluated in vitro for antiprotozoal activities against Leishmania major (L. major) promastigotes. Several analogs were remarkably potent inhibitors, with antileishmanial activities being comparable or superior to those of the reference antiprotozoal drugs. Furthermore, we explored the structure-activity relationships of N-10 haloacetamides that influence the potency of such analogs toward inhibition of L. major promastigote growth in vitro. With respect to the mechanism of action, selected compounds were evaluated for time-dependent inactivation of Trypanosoma brucei trypanothione reductase. Our results are indicative of a covalent interaction which could account for potent antiprotozoal activities.
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Affiliation(s)
- Ana Marcu
- Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany
| | - Uta Schurigt
- Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany.
| | - Klaus Müller
- Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany
| | - Heidrun Moll
- Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany
| | - R Luise Krauth-Siegel
- Biochemistry Center of Heidelberg University (BZH), Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany
| | - Helge Prinz
- Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany.
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30
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Saccoccia F, Angelucci F, Boumis G, Carotti D, Desiato G, Miele AE, Bellelli A. Thioredoxin reductase and its inhibitors. Curr Protein Pept Sci 2015; 15:621-46. [PMID: 24875642 PMCID: PMC4275836 DOI: 10.2174/1389203715666140530091910] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 05/28/2014] [Accepted: 05/28/2014] [Indexed: 01/13/2023]
Abstract
Thioredoxin plays a crucial role in a wide number of physiological processes, which span from reduction of nucleotides to deoxyriboucleotides to the detoxification from xenobiotics, oxidants and radicals. The redox function of Thioredoxin is critically dependent on the enzyme Thioredoxin NADPH Reductase (TrxR). In view of its indirect involvement in the above mentioned physio/pathological processes, inhibition of TrxR is an important clinical goal. As a general rule, the affinities and mechanisms of binding of TrxR inhibitors to the target enzyme are known with scarce precision and conflicting results abound in the literature. A relevant analysis of published results as well as the experimental procedures is therefore needed, also in view of the critical interest of TrxR inhibitors. We review the inhibitors of TrxR and related flavoreductases and the classical treatment of reversible, competitive, non competitive and uncompetitive inhibition with respect to TrxR, and in some cases we are able to reconcile contradictory results generated by oversimplified data analysis.
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Affiliation(s)
| | | | | | | | | | | | - Andrea Bellelli
- Istituto Pasteur - Fondazione Cenci-Bolognetti, Istituto di Biologia e Medicina Molecolare del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Piazzale A. Moro 5, 00185 Rome, Italy.
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31
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O’Sullivan MC, Durham TB, Valdes HE, Dauer KL, Karney NJ, Forrestel AC, Bacchi CJ, Baker JF. Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities. Bioorg Med Chem 2015; 23:996-1010. [DOI: 10.1016/j.bmc.2015.01.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 01/04/2015] [Accepted: 01/09/2015] [Indexed: 12/15/2022]
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32
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Kaiser M, Maes L, Tadoori LP, Spangenberg T, Ioset JR. Repurposing of the Open Access Malaria Box for Kinetoplastid Diseases Identifies Novel Active Scaffolds against Trypanosomatids. ACTA ACUST UNITED AC 2015; 20:634-45. [PMID: 25690568 DOI: 10.1177/1087057115569155] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 01/02/2015] [Indexed: 01/06/2023]
Abstract
Phenotypic screening had successfully been used for hit generation, especially in the field of neglected diseases, in which feeding the drug pipeline with new chemotypes remains a constant challenge. Here, we catalyze drug discovery research using a publicly available screening tool to boost drug discovery. The Malaria Box, assembled by the Medicines for Malaria Venture, is a structurally diverse set of 200 druglike and 200 probelike compounds distilled from more than 20,000 antimalarial hits from corporate and academic libraries. Repurposing such compounds has already identified new scaffolds against cryptosporidiosis and schistosomiasis. In addition to initiating new hit-to-lead activities, screening the Malaria Box against a plethora of other parasites would enable the community to better understand the similarities and differences between them. We describe the screening of the Malaria Box and triaging of the identified hits against kinetoplastids responsible for human African trypanosomiasis (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and visceral leishmaniasis (Leishmania donovani and Leishmania infantum). The in vitro and in vivo profiling of the most promising active compounds with respect to efficacy, toxicity, pharmacokinetics, and complementary druggable properties are presented and a collaborative model used as a way to accelerate the discovery process discussed.
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Affiliation(s)
- Marcel Kaiser
- Parasite Chemotherapy, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland
| | - Louis Maes
- Laboratory of Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Antwerp University, Antwerp, Belgium
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33
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Keenan M, Chaplin JH. A New Era for Chagas Disease Drug Discovery? PROGRESS IN MEDICINAL CHEMISTRY 2015; 54:185-230. [DOI: 10.1016/bs.pmch.2014.12.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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34
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Sánchez-Murcia PA, Ruiz-Santaquiteria M, Toro MA, de Lucio H, Jiménez MÁ, Gago F, Jiménez-Ruiz A, Camarasa MJ, Velázquez S. Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase. RSC Adv 2015. [DOI: 10.1039/c5ra06853c] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Helical peptides stabilizedviaall-hydrocarbon or lactam side-chain bridging were investigated as disruptors ofLeishmania infantumtrypanothione reductase.
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Affiliation(s)
| | | | - Miguel A. Toro
- Departamento de Biología de Sistemas
- Universidad de Alcalá
- Madrid
- Spain
| | - Héctor de Lucio
- Departamento de Biología de Sistemas
- Universidad de Alcalá
- Madrid
- Spain
| | | | - Federico Gago
- Departamento de Ciencias Biomédicas
- Unidad Asociada al CSIC
- Universidad de Alcalá
- Madrid
- Spain
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35
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Nagle A, Khare S, Kumar AB, Supek F, Buchynskyy A, Mathison CJN, Chennamaneni N, Pendem N, Buckner FS, Gelb M, Molteni V. Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Chem Rev 2014; 114:11305-47. [PMID: 25365529 PMCID: PMC4633805 DOI: 10.1021/cr500365f] [Citation(s) in RCA: 250] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Indexed: 02/08/2023]
Affiliation(s)
- Advait
S. Nagle
- Genomics
Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Shilpi Khare
- Genomics
Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Arun Babu Kumar
- Departments of Chemistry, Biochemistry, and Medicine, University
of Washington, Seattle, Washington 98195, United States
| | - Frantisek Supek
- Genomics
Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Andriy Buchynskyy
- Departments of Chemistry, Biochemistry, and Medicine, University
of Washington, Seattle, Washington 98195, United States
| | - Casey J. N. Mathison
- Genomics
Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Naveen
Kumar Chennamaneni
- Departments of Chemistry, Biochemistry, and Medicine, University
of Washington, Seattle, Washington 98195, United States
| | - Nagendar Pendem
- Departments of Chemistry, Biochemistry, and Medicine, University
of Washington, Seattle, Washington 98195, United States
| | - Frederick S. Buckner
- Departments of Chemistry, Biochemistry, and Medicine, University
of Washington, Seattle, Washington 98195, United States
| | - Michael
H. Gelb
- Departments of Chemistry, Biochemistry, and Medicine, University
of Washington, Seattle, Washington 98195, United States
| | - Valentina Molteni
- Genomics
Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
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36
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Persch E, Bryson S, Todoroff NK, Eberle C, Thelemann J, Dirdjaja N, Kaiser M, Weber M, Derbani H, Brun R, Schneider G, Pai EF, Krauth-Siegel RL, Diederich F. Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase. ChemMedChem 2014; 9:1880-91. [PMID: 24788386 DOI: 10.1002/cmdc.201402032] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Indexed: 01/16/2023]
Abstract
The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so-called "mepacrine binding site". The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.
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Affiliation(s)
- Elke Persch
- Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zurich (Switzerland)
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37
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Ketanserin, an antidepressant, exerts its antileishmanial action via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme of Leishmania donovani. Parasitol Res 2014; 113:2161-8. [PMID: 24728519 DOI: 10.1007/s00436-014-3868-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 03/21/2014] [Indexed: 12/11/2022]
Abstract
Leishmaniasis is one of the major health problems existing globally. The current chemotherapy for leishmaniasis presents several drawbacks like toxicity and increased resistance to existing drugs, and hence, there is a necessity to look out for the novel drug targets and new chemical entities. Current trend in drug discovery arena is the "repurposing" of old drugs for the treatment of diseases. In the present study, an antidepressant, ketanserin, was found lethal to both Leishmania donovani promastigotes and intracellular amastigotes with no apparent toxicity to the cells. Ketanserin killed promastigotes and amastigotes with an IC50 value of 37 μM and 28 μM respectively, in a dose-dependent manner. Ketanserin was found to inhibit L. donovani recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme with an IC50 value of 43 μM. Ketanserin treated promastigotes were exogenously supplemented with sterols like ergosterol and cholesterol to rescue cell death. Ergosterol could recover the inhibition partially, whereas cholesterol supplementation completely failed to rescue the inhibited parasites. Further, HMGR-overexpressing parasites were generated by transfecting Leishmania promastigotes with an episomal pspα hygroα-HMGR construct. Wild-type and HMGR overexpressors of L. donovani were used to study the effect and mode of action of this inhibitor. The HMGR overexpressors showed twofold resistance to ketanserin. These observations suggest that the lethal effect of ketanserin is due to inhibition of HMGR, the rate-limiting enzyme of the ergosterol biosynthetic pathway. Since targeting of the sterol biosynthetic pathway enzymes may be useful therapeutically, the present study may have implications in treatment of leishmaniasis.
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38
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Abstract
The potential of flavoproteins as targets of pharmacological treatments is immense. In this review we present an overview of the current research progress on medical interventions based on flavoproteins with a special emphasis on cancer, infectious diseases, and neurological disorders.
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Affiliation(s)
- Esther Jortzik
- Interdisciplinary Research Center, Justus Liebig University, Giessen, Germany
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39
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Simple colorimetric trypanothione reductase-based assay for high-throughput screening of drugs against Leishmania intracellular amastigotes. Antimicrob Agents Chemother 2013; 58:527-35. [PMID: 24189262 DOI: 10.1128/aac.00751-13] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Critical to the search for new anti-leishmanial drugs is the availability of high-throughput screening (HTS) methods to test chemical compounds against the relevant stage for pathogenesis, the intracellular amastigotes. Recent progress in automated microscopy and genetic recombination has produced powerful tools for drug discovery. Nevertheless, a simple and efficient test for measuring drug activity against Leishmania clinical isolates is lacking. Here we describe a quantitative colorimetric assay in which the activity of a Leishmania native enzyme is used to assess parasite viability. Enzymatic reduction of disulfide trypanothione, monitored by a microtiter plate reader, was used to quantify the growth of Leishmania parasites. An excellent correlation was found between the optical density at 412 nm and the number of parasites inoculated. Pharmacological validation of the assay was performed against the conventional alamarBlue method for promastigotes and standard microscopy for intracellular amastigotes. The activity of a selected-compound panel, including several anti-leishmanial reference drugs, demonstrated high consistency between the newly developed assay and the reference method and corroborated previously published data. Quality assessment with standard measures confirmed the robustness and reproducibility of the assay, which performed in compliance with HTS requirements. This simple and rapid assay provides a reliable, accurate method for screening anti-leishmanial agents, with high throughput. The basic equipment and manipulation required to perform the assay make it easy to implement, simplifying the method for scoring inhibitor assays.
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40
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Lu J, Vodnala SK, Gustavsson AL, Gustafsson TN, Sjöberg B, Johansson HA, Kumar S, Tjernberg A, Engman L, Rottenberg ME, Holmgren A. Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei. J Biol Chem 2013; 288:27456-27468. [PMID: 23900839 DOI: 10.1074/jbc.m113.495101] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis.
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Affiliation(s)
- Jun Lu
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics
| | | | - Anna-Lena Gustavsson
- Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden
| | - Tomas N Gustafsson
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics
| | - Birger Sjöberg
- Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden
| | - Henrik A Johansson
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics; Department of Chemistry-BMC, Uppsala University, SE-751 23 Uppsala, Sweden
| | | | | | - Lars Engman
- Department of Chemistry-BMC, Uppsala University, SE-751 23 Uppsala, Sweden
| | | | - Arne Holmgren
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics.
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41
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Abstract
Chagas infection is a major endemic disease affecting Latin American countries. The persistence of Trypanosoma cruzi generates a chronic inflammatory reactivity that induces an immune response directed to the host's tissues. The effectiveness of the treatment in the chronic phase is still unsatisfactory due, amongst other reasons, to the collateral effects of the drugs used. We investigated the effect of clomipramine, a tricyclic antidepressant that, when used as a treatment of T. cruzi-chronically infected mice, inhibits trypanothione reductase, an exclusive and vital enzyme of T. cruzi. Clomipramine improved survival (P<0.05) by diminishing the parasite intensity as demonstrated by PCR studies in the heart and skeletal muscle, and significantly prevented the evolution to fibrosis of the inflammatory infiltrates. Clomipramine could be a good candidate for the treatment of chronic Chagas disease.
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42
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Mukherjee S, Mukherjee B, Mukhopadhyay R, Naskar K, Sundar S, Dujardin JC, Das AK, Roy S. Imipramine is an orally active drug against both antimony sensitive and resistant Leishmania donovani clinical isolates in experimental infection. PLoS Negl Trop Dis 2012; 6:e1987. [PMID: 23301108 PMCID: PMC3531496 DOI: 10.1371/journal.pntd.0001987] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 11/15/2012] [Indexed: 01/20/2023] Open
Abstract
Background In an endeavor to find an orally active and affordable antileishmanial drug, we tested the efficacy of a cationic amphiphilic drug, imipramine, commonly used for the treatment of depression in humans. The only available orally active antileishmanial drug is miltefosine with long half life and teratogenic potential limits patient compliance. Thus there is a genuine need for an orally active antileishmanial drug. Previously it was shown that imipramine, a tricyclic antidepressant alters the protonmotive force in promastigotes, but its in vivo efficacy was not reported. Methodology/Principal Findings Here we show that the drug is highly active against antimony sensitive and resistant Leishmania donovani in both promastigotes and intracellular amastigotes and in LD infected hamster model. The drug was found to decrease the mitochondrial transmembrane potential of Leishmania donovani (LD) promastigotes and purified amastigotes after 8 h of treatment, whereas miltefosine effected only a marginal change even after 24 h. The drug restores defective antigen presenting ability of the parasitized macrophages. The status of the host protective factors TNF α, IFN γ and iNOS activity increased with the concomitant decrease in IL 10 and TGF β level in imipramine treated infected hamsters and evolution of matured sterile hepatic granuloma. The 10-day therapeutic window as a monotherapy, showing about 90% clearance of organ parasites in infected hamsters regardless of their SSG sensitivity. Conclusions This study showed that imipramine possibly qualifies for a new use of an old drug and can be used as an effective orally active drug for the treatment of Kala-azar. The disease Kala-azar or visceral leishmaniasis is still a big problem in the Indian subcontinent. The antimonials were used for the chemotherapy of Kala-azar but with time its efficacy has reduced dramatically. The newer version of orally active drug miltefosine has been introduced, but its efficacy has decreased considerably as relapse cases are on the rise. Other drugs like liposomal form of amphotericin B is expensive and the patients require hospitalization. Thus there is a genuine need for an orally active antileishmanial drug. There are reports that the cationic amphiphilic molecule, imipramine, a drug used for the treatment of depression in humans, kills the promastigotes of Leishmania donovani. We tested the efficacy of imipramine in experimental infection in hamster and mouse model. Our study showed that the drug is highly effective against antimony sensitive and antimony resistant Leishmania donovani infected hamsters as well as mouse and offered almost sterile cure.
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Affiliation(s)
- Sandip Mukherjee
- CSIR-Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India
| | - Budhaditya Mukherjee
- CSIR-Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India
| | - Rupkatha Mukhopadhyay
- CSIR-Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India
| | - Kshudiram Naskar
- CSIR-Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India
| | - Shyam Sundar
- Institute of Medical Sciences, Benaras Hindu University, Varanasi, India
| | | | - Anjan Kumar Das
- Calcutta National Medical College and Hospital, Kolkata, India
| | - Syamal Roy
- CSIR-Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India
- * E-mail:
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The receptor-dependent LQTA-QSAR: application to a set of trypanothione reductase inhibitors. J Comput Aided Mol Des 2012; 26:1055-65. [PMID: 22972559 DOI: 10.1007/s10822-012-9598-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 08/29/2012] [Indexed: 11/27/2022]
Abstract
A new Receptor-Dependent LQTA-QSAR approach, RD-LQTA-QSAR, is proposed as a new 4D-QSAR method. It is an evolution of receptor independent LQTA-QSAR. This approach uses the free GROMACS package to carry out molecular dynamics simulations and generates a conformational ensemble profile for each compound. Such an ensemble is used to build molecular interaction field-based QSAR models, as in CoMFA. To show the potential of this methodology, a set of 38 phenothiazine derivatives that are specific competitive T. cruzi trypanothione reductase inhibitors, was chosen. Using a combination of molecular docking and molecular dynamics simulations, the binding mode of the phenotiazine derivatives was evaluated in a simulated induced fit approach. The ligands alignments were performed using both ligand and binding site atoms, enabling unbiased alignment. The models obtained were extensively validated by leave-N-out cross-validation and y-randomization techniques to test for their robustness and absence of chance correlation. The final model presented Q(2) LOO of 0.87 and R² of 0.92 and a suitable external prediction of [Formula: see text]= 0.78. The adapted binding site obtained is useful to perform virtual screening and ligand structure-based design and the descriptors in the final model can aid in the design new inhibitors.
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Da Rocha Pita SS, Batista PR, Albuquerque MG, Pascutti PG. Molecular Dynamics Simulations of Peptide Inhibitors Complexed WithTrypanosoma cruziTrypanothione Reductase. Chem Biol Drug Des 2012; 80:561-71. [DOI: 10.1111/j.1747-0285.2012.01429.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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da Rocha Pita SS, Albuquerque MG, Rodrigues CR, Castro HC, Hopfinger AJ. Receptor-dependent 4D-QSAR analysis of peptidemimetic inhibitors of Trypanosoma cruzi trypanothione reductase with receptor-based alignment. Chem Biol Drug Des 2012; 79:740-8. [PMID: 22269140 DOI: 10.1111/j.1747-0285.2012.01338.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591) approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D-QSAR models that were highly predictive (q(2) above 0.71). The 3D-QSAR models can be visualized as a spatial map of atom types that are important on the comprehension of the ligand-enzyme interaction mechanism, pointing main pharmacophoric groups and TR subsites described in the literature. We were able also to identify some TR subsites for further development in the drug discovery process against tropical diseases not yet studied.
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Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH. Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography. J Med Chem 2011; 54:6514-30. [PMID: 21851087 PMCID: PMC3188286 DOI: 10.1021/jm200312v] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.
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Affiliation(s)
- Stephen Patterson
- Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K
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Increasing the activity of copper(II) complexes against Leishmania through lipophilicity and pro-oxidant ability. J Biol Inorg Chem 2011; 17:107-12. [DOI: 10.1007/s00775-011-0834-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Accepted: 08/08/2011] [Indexed: 02/06/2023]
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Van Assche T, Deschacht M, da Luz RAI, Maes L, Cos P. Leishmania-macrophage interactions: insights into the redox biology. Free Radic Biol Med 2011; 51:337-51. [PMID: 21620959 DOI: 10.1016/j.freeradbiomed.2011.05.011] [Citation(s) in RCA: 165] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 04/24/2011] [Accepted: 05/07/2011] [Indexed: 11/19/2022]
Abstract
Leishmaniasis is a neglected tropical disease that affects about 350 million individuals worldwide. The protozoan parasite has a relatively simple life cycle with two principal stages: the flagellated mobile promastigote living in the gut of the sandfly vector and the intracellular amastigote within phagolysosomal vesicles of the vertebrate host macrophage. This review presents a state-of-the-art overview of the redox biology at the parasite-macrophage interface. Although Leishmania species are susceptible in vitro to exogenous superoxide radical, hydrogen peroxide, nitric oxide, and peroxynitrite, they manage to survive the endogenous oxidative burst during phagocytosis and the subsequent elevated nitric oxide production in the macrophage. The parasite adopts various defense mechanisms to cope with oxidative stress: the lipophosphoglycan membrane decreases superoxide radical production by inhibiting NADPH oxidase assembly and the parasite also protects itself by expressing antioxidant enzymes and proteins. Some of these enzymes could be considered potential drug targets because they are not expressed in mammals. In respect to antileishmanial therapy, the effects of current drugs on parasite-macrophage redox biology and its involvement in the development of drug resistance and treatment failure are presented.
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Affiliation(s)
- Tim Van Assche
- Laboratory of Microbiology Parasitology, and Hygiene, University of Antwerp, B-2020 Antwerp, Belgium
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Venkatesan SK, Shukla AK, Dubey VK. Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantum. J Comput Chem 2011; 31:2463-75. [PMID: 20340105 DOI: 10.1002/jcc.21538] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol-redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9-aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9-aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed.
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50
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Eberle C, Lauber BS, Fankhauser D, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities. ChemMedChem 2010; 6:292-301. [DOI: 10.1002/cmdc.201000420] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2010] [Indexed: 11/05/2022]
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