The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase.
Screening of the in-house sample collection for compounds with HCV NS5B RNA dependent RNA polymerase inhibition led to the identification of a new lead. Afterwards, we discovered that the screening lead, rather than containing the expected structure 1, was comprised of roughly a 1:1 mixture of meconic acid 2 and its monoethyl ester 3, with all inhibitory potency residing with 3. We propose that this compound shares critical common features for activity with alpha,gamma-diketoacids inhibitors previously discovered by our group. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design.
Pace
Paola
P
Department of Medicinal Chemistry and Biochemistry, IRBM-MRL Rome, Via Pontina, Km 30.600, 00040 Pomezia (Rome), Italy. paola_pace@merck.com
Nizi
Emanuela
E
Pacini
Barbara
B
Pesci
Silvia
S
Matassa
Victor
V
De Francesco
Raffaele
R
Altamura
Sergio
S
Summa
Vincenzo
V
D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D011753:Pyrones / Q000737:chemistry* / Q000378:metabolism; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D011753:Pyrones; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C010603:meconic acid