title: Benzothiazepinecarboxamides: Novel hepatitis C virus inhibitors that interfere with viral entry and the generation of infectious virions.
abstract: Upon screening synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified a benzothiazepinecarboxamide (BTC) scaffold that inhibits HCV. A structure-activity relationship (SAR) study with BTCs was performed, and modifications that led to nanomolar antiviral activity and improved the selective index (CC50/EC50) by more than 1000-fold were identified. In addition, a pharmacophore modeling study determined that the tricyclic core and positive charge on the piperidine moiety were essential for antiviral activity. Furthermore, we demonstrated that BTC interferes with HCV glycoprotein E1/E2-mediated viral entry and the generation of infectious virions by using HCV pseudoparticle and cell culture supernatant transfer assays, respectively. BTC showed potent antiviral activity against HCV genotype 2 (EC50 = 0.01 ± 0.01 μM), but was less potent against a genotype 1/2 chimeric virus (EC50 = 2.71 ± 0.05 μM), which expressed the structural proteins of HCV genotype 1. In summary, we identified, optimized, and characterized novel BTC inhibitors that interfere with early and late steps of the HCV viral life cycle.
authors: Hepatitis Research Laboratory, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Hee-Young
authors: HY
authors: Kim
authors: Chemistry Platform, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Sunju
authors: S
authors: Kong
authors: Chemistry Platform, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Sangmi
authors: S
authors: Oh
authors: Hepatitis Research Laboratory, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Jaewon
authors: J
authors: Yang
authors: Hepatitis Research Laboratory, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Eunji
authors: E
authors: Jo
authors: Cheminformatics, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Yoonae
authors: Y
authors: Ko
authors: Hepatitis Research Laboratory, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Soo-Hyun
authors: SH
authors: Kim
authors: Chemistry Platform, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Jong Yeon
authors: JY
authors: Hwang
authors: Chemistry Platform, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea.
authors: Rita
authors: R
authors: Song
authors: Hepatitis Research Laboratory, Institut Pasteur Korea, Seongnam, Gyeonggi, 463-400 South Korea. Electronic address: marc.windisch@ip-korea.org.
authors: Marc P
authors: MP
authors: Windisch
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D054852:Small Molecule Libraries / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014771:Virion / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D054852:Small Molecule Libraries; D013841:Thiazepines
keywords: Antiviral activity; Benzothiazepinecarboxamide (BTC); Hepatitis C virus (HCV); Mechanisms of action (MoA); Pharmacophore; Structure-activity relationship study