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Biochemical Effect of Resistance Mutations against Synergistic Inhibitors of RSV RNA Polymerase.
Deval, Jerome; Fung, Amy; Stevens, Sarah K; Jordan, Paul C; Gromova, Tatiana; Taylor, Joshua S; Hong, Jin; Meng, Jia; Wang, Guangyi; Dyatkina, Natalia; Prhavc, Marija; Symons, Julian A; Beigelman, Leo.
Afiliación
  • Deval J; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Fung A; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Stevens SK; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Jordan PC; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Gromova T; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Taylor JS; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Hong J; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Meng J; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Wang G; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Dyatkina N; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Prhavc M; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Symons JA; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
  • Beigelman L; Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, United States of America.
PLoS One ; 11(5): e0154097, 2016.
Article en En | MEDLINE | ID: mdl-27163448
ABSTRACT
ALS-8112 is the parent molecule of ALS-8176, a first-in-class nucleoside analog prodrug effective in the clinic against respiratory syncytial virus (RSV) infection. The antiviral activity of ALS-8112 is mediated by its 5'-triphosphate metabolite (ALS-8112-TP, or 2'F-4'ClCH2-cytidine triphosphate) inhibiting the RNA polymerase activity of the RSV L-P protein complex through RNA chain termination. Four amino acid mutations in the RNA-dependent RNA polymerase (RdRp) domain of L (QUAD M628L, A789V, L795I, and I796V) confer in vitro resistance to ALS-8112-TP by increasing its discrimination relative to natural CTP. In this study, we show that the QUAD mutations specifically recognize the ClCH2 group of ALS-8112-TP. Among the four mutations, A789V conferred the greatest resistance phenotype, which was consistent with its putative position in the active site of the RdRp domain. AZ-27, a non-nucleoside inhibitor of RSV, also inhibited the RdRp activity, with decreased inhibition potency in the presence of the Y1631H mutation. The QUAD mutations had no effect on the antiviral activity of AZ-27, and the Y1631H mutation did not significantly increase the discrimination of ALS-8112-TP. Combining ALS-8112 with AZ-27 in vitro resulted in significant synergistic inhibition of RSV replication. Overall, this is the first mechanistic study showing a lack of cross-resistance between mutations selected by different classes of RSV polymerase inhibitors acting in synergy, opening the door to future potential combination therapies targeting different regions of the L protein.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Proteínas Virales / Benzazepinas / ARN Polimerasas Dirigidas por ADN / Mutación Puntual / Niacinamida / Citidina Trifosfato / Farmacorresistencia Viral Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Proteínas Virales / Benzazepinas / ARN Polimerasas Dirigidas por ADN / Mutación Puntual / Niacinamida / Citidina Trifosfato / Farmacorresistencia Viral Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos