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Hepatitis C virus nucleotide inhibitors PSI-352938 and PSI-353661 exhibit a novel mechanism of resistance requiring multiple mutations within replicon RNA.
Lam, Angela M; Espiritu, Christine; Bansal, Shalini; Micolochick Steuer, Holly M; Zennou, Veronique; Otto, Michael J; Furman, Phillip A.
Afiliación
  • Lam AM; Pharmasset, Inc., 303A College Road East, Princeton, NJ 08540, USA. alam@pharmasset.com
J Virol ; 85(23): 12334-42, 2011 Dec.
Article en En | MEDLINE | ID: mdl-21957306
ABSTRACT
PSI-352938, a cyclic phosphate nucleotide, and PSI-353661, a phosphoramidate nucleotide, are prodrugs of ß-D-2'-deoxy-2'-α-fluoro-2'-ß-C-methylguanosine-5'-monophosphate. Both compounds are metabolized to the same active 5'-triphosphate, PSI-352666, which serves as an alternative substrate inhibitor of the NS5B RNA-dependent RNA polymerase during HCV replication. PSI-352938 and PSI-353661 retained full activity against replicons containing the S282T substitution, which confers resistance to certain 2'-substituted nucleoside/nucleotide analogs. PSI-352666 was also similarly active against both wild-type and S282T NS5B polymerases. In order to identify mutations that confer resistance to these compounds, in vitro selection studies were performed using HCV replicon cells. While no resistant genotype 1a or 1b replicons could be selected, cells containing genotype 2a JFH-1 replicons cultured in the presence of PSI-352938 or PSI-353661 developed resistance to both compounds. Sequencing of the NS5B region identified a number of amino acid changes, including S15G, R222Q, C223Y/H, L320I, and V321I. Phenotypic evaluation of these mutations indicated that single amino acid changes were not sufficient to significantly reduce the activity of PSI-352938 and PSI-353661. Instead, a combination of three amino acid changes, S15G/C223H/V321I, was required to confer a high level of resistance. No cross-resistance exists between the 2'-F-2'-C-methylguanosine prodrugs and other classes of HCV inhibitors, including 2'-modified nucleoside/-tide analogs such as PSI-6130, PSI-7977, INX-08189, and IDX-184. Finally, we determined that in genotype 1b replicons, the C223Y/H mutation failed to support replication, and although the A15G/C223H/V321I triple mutation did confer resistance to PSI-352938 and PSI-353661, this mutant replicated at only about 10% efficiency compared to the wild type.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Replicón / ARN Viral / Guanosina Monofosfato / Hepacivirus / Óxidos P-Cíclicos / Farmacorresistencia Viral / Mutación / Nucleósidos Límite: Humans Idioma: En Revista: J Virol Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Replicón / ARN Viral / Guanosina Monofosfato / Hepacivirus / Óxidos P-Cíclicos / Farmacorresistencia Viral / Mutación / Nucleósidos Límite: Humans Idioma: En Revista: J Virol Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos