A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease.
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).
Narjes
Frank
F
Department of Chemistry, IRBM, MRL Rome, Via Pontina Km 30.600, Pomezia, 00040, Rome, Italy. frank_narjes@merck.com
Koehler
Konrad F
KF
Koch
Uwe
U
Gerlach
Benjamin
B
Colarusso
Stefania
S
Steinkühler
Christian
C
Brunetti
Mirko
M
Altamura
Sergio
S
De Francesco
Raffaele
R
Matassa
Victor G
VG
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
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