title: A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease.
abstract: The difluoromethyl group was designed by computational chemistry methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor 4 (K(i) 30 nM) and reversible covalent inhibitors (6, K(i) 0.5 nM; and 8 K*(i) 10 pM).
authors.affiliation: Department of Chemistry, IRBM, MRL Rome, Via Pontina Km 30.600, Pomezia, 00040, Rome, Italy. frank_narjes@merck.com
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
authors.forename: Konrad F
authors.initials: KF
authors.lastname: Koehler
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gerlach
authors.forename: Stefania
authors.initials: S
authors.lastname: Colarusso
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Mirko
authors.initials: M
authors.lastname: Brunetti
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Victor G
authors.initials: VG
authors.lastname: Matassa
mesh_terms: D003545:Cysteine; D015195:Drug Design; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D003545:Cysteine; D009842:Oligopeptides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases