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Exploring small molecules with pan-genotypic inhibitory activities against hepatitis C virus NS3/4A serine protease
journal contributionposted on 06.05.2022, 16:52 by Jinhong Ren, Isabel Ojeda, Maulik Patel, Michael JohnsonMichael Johnson, Hyun LeeHyun Lee
Among the many Hepatitis C virus (HCV) genotypes and subtypes, genotypes 1b and 3a are most prevalent in United States and Asia, respectively. A total of 132 commercially available analogs of a previous lead compound were initially investigated against wild-type HCV genotype 1b NS3/4A protease. Ten compounds showed inhibitory activities (IC50 values) below 10 µM with comparable direct binding affinities (KD values) determined by surface plasmon resonance (SPR). To identify pan-genotypic inhibitors, these ten selected compounds were tested against four additional genotypes (1a, 2a, 3a, and 4) and three drug-resistant mutants (A156S, R155K, and V36M). Four new analogs have been identified with better activities against all five tested genotypes than the prior lead compound. Further, the original lead compound did not show activity against genotype 3a NS3/4A, whereas four newly identified compounds exhibited IC50 values below 33 µM against genotype 3a NS3/4A. Encouragingly, the best new compound F1813-0710 possessed promising activity toward genotype 3a, which is a huge improvement over the previous lead compound that had no effect on genotype 3a. This intriguing observation was further analyzed by molecular docking and molecular dynamics (MD) simulations to understand their different binding interactions, which should benefit future pan-genotypic inhibitor design and drug discovery.
Center for Natural Product Technologies at UIC | Funder: National Institutes of Health (National Center for Complementary and Integrative Health) | Grant ID: U41AT008706
Development of broad spectrum Hepatitis C Virus NS3/4A protease inhibitors | Funder: National Institute of Allergy and Infectious Diseases | Grant ID: R41AI112114
CitationRen, J., Ojeda, I., Patel, M., Johnson, M. E.Lee, H. (2019). Exploring small molecules with pan-genotypic inhibitory activities against hepatitis C virus NS3/4A serine protease. Bioorganic & Medicinal Chemistry Letters, 29(16), 2349-2353. https://doi.org/10.1016/j.bmcl.2019.06.009
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Liver DiseaseEmerging Infectious DiseasesDigestive DiseasesGeneticsHIV/AIDSChronic Liver Disease and CirrhosisHepatitisInfectious DiseasesHepatitis - C5.1 PharmaceuticalsHepatitis C virusNS3/4A proteasePan-genotypic inhibitorsMolecular dockingMolecular dynamics simulationsAntiviral AgentsDose-Response Relationship, DrugGenotypeHepacivirusHumansMicrobial Sensitivity TestsMolecular StructureProtease InhibitorsSerine ProteasesSmall Molecule LibrariesStructure-Activity RelationshipViral Nonstructural ProteinsMedicinal & Biomolecular ChemistryMedicinal and Biomolecular ChemistryOrganic ChemistryPharmacology and Pharmaceutical Sciences