title: The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Biochemistry, IRBM-MRL Rome, Via Pontina, Km 30.600, 00040 Pomezia (Rome), Italy. paola_pace@merck.com
authors.forename: Paola
authors.initials: P
authors.lastname: Pace
authors.forename: Emanuela
authors.initials: E
authors.lastname: Nizi
authors.forename: Barbara
authors.initials: B
authors.lastname: Pacini
authors.forename: Silvia
authors.initials: S
authors.lastname: Pesci
authors.forename: Victor
authors.initials: V
authors.lastname: Matassa
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
mesh_terms: 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
chemical_list: 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