title: Inhibition of hepatitis C virus NS5B polymerase by S-trityl-L-cysteine derivatives.
abstract: Structure-based studies led to the identification of a constrained derivative of S-trityl-l-cysteine (STLC) scaffold as a candidate inhibitor of hepatitis C virus (HCV) NS5B polymerase. A panel of STLC derivatives were synthesized and investigated for their activity against HCV NS5B. Three STLC derivatives, 9, F-3070, and F-3065, were identified as modest HCV NS5B inhibitors with IC(50) values between 22.3 and 39.7 μM. F-3070 and F-3065 displayed potent inhibition of intracellular NS5B activity in the BHK-NS5B-FRLuc reporter and also inhibited HCV RNA replication in the Huh7/Rep-Feo1b reporter system. Binding mode investigations suggested that the STLC scaffold can be used to develop new NS5B inhibitors by further chemical modification at one of the trityl phenyl group.
authors.affiliation: Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Nichols
authors.forename: Guy
authors.initials: G
authors.lastname: Fournet
authors.forename: K R
authors.initials: KR
authors.lastname: Gurukumar
authors.forename: Amartya
authors.initials: A
authors.lastname: Basu
authors.forename: Jin-Ching
authors.initials: JC
authors.lastname: Lee
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Frank
authors.initials: F
authors.lastname: Kozielski
authors.forename: Ira
authors.initials: I
authors.lastname: Musmuca
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Neerja
authors.initials: N
authors.lastname: Kaushik-Basu
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D012367:RNA, Viral / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012367:RNA, Viral; C003724:3-tritylthio-L-alanine; D012324:RNA-Dependent RNA Polymerase; D003545:Cysteine