Discovery of Potent Non-nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from Fragment Screening and Structure-Guided Design.
Adv Exp Med Biol
; 1062: 187-198, 2018.
Article
em En
| MEDLINE
| ID: mdl-29845534
ABSTRACT
Flavivirus NS5 RNA-dependent RNA polymerase (RdRp) is an important drug target. Whilst a number of allosteric inhibitors have been described for Hepatitis C virus RdRp, few have been described for DENV RdRp. In addition, compound screening campaigns have not yielded suitable leads for this enzyme. Using fragment-based screening via X-ray crystallography, we identified a biphenyl acetic acid fragment that binds to a novel pocket of the dengue virus (DENV) RdRp, in the thumb/palm interface, close to its active site (termed "N pocket"). Structure-guided optimization yielded nanomolar inhibitors of the RdRp de novo initiation activity, with low micromolar EC50 in DENV cell-based assays. Compound-resistant DENV replicons exhibited amino acid mutations that mapped to the N pocket. This is the first report of a class of pan-serotype and cell-active DENV RdRp inhibitors and provides a significant opportunity for rational design of novel therapeutics against this proven antiviral target.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Proteínas Virais
/
RNA Polimerase Dependente de RNA
/
Dengue
/
Vírus da Dengue
/
Inibidores Enzimáticos
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Adv Exp Med Biol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Singapura