Your browser doesn't support javascript.
loading
Cidofovir Diphosphate Inhibits Adenovirus 5 DNA Polymerase via both Nonobligate Chain Termination and Direct Inhibition, and Polymerase Mutations Confer Cidofovir Resistance on Intact Virus.
Chamberlain, Jeffrey M; Sortino, Katherine; Sethna, Phiroze; Bae, Andrew; Lanier, Randall; Bambara, Robert A; Dewhurst, Stephen.
Afiliación
  • Chamberlain JM; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
  • Sortino K; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
  • Sethna P; Chimerix, Durham, North Carolina, USA.
  • Bae A; Chimerix, Durham, North Carolina, USA.
  • Lanier R; Chimerix, Durham, North Carolina, USA.
  • Bambara RA; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
  • Dewhurst S; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA Stephen_Dewhurst@urmc.rochester.edu.
Antimicrob Agents Chemother ; 63(1)2019 01.
Article en En | MEDLINE | ID: mdl-30397065
Human adenovirus (AdV) can cause fatal disease in immune-suppressed individuals, but treatment options are limited, in part because the antiviral cytidine analog cidofovir (CDV) is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, nonnephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. Therefore, we have examined the effect of CDVpp on DNA synthesis by a purified adenovirus 5 (AdV5) DNA polymerase (Pol). CDVpp was incorporated into nascent DNA strands and promoted a nonobligate form of chain termination (i.e., AdV5 Pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 Pol. At elevated concentrations, CDVpp inhibited AdV5 Pol in a manner consistent with both chain termination and direct inhibition of Pol activity. Finally, a recombinant AdV5 was constructed, containing Pol mutations (V303I and T87I) that were selected following an extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated 50% effective concentration (EC50) for BCV and a 1.9-fold increased EC50 for CDV; thus, these results confirmed that viral resistance to BCV and CDV can be attributed to mutations in the viral Pol. These findings show that the anti-AdV5 activity of CDV and BCV is mediated through the viral DNA Pol and that their antiviral activity may occur via both (nonobligate) chain termination and (at high concentration) direct inhibition of AdV5 Pol activity.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Proteínas Virales / ADN Viral / Adenovirus Humanos / Citosina / ADN Polimerasa Dirigida por ADN / Organofosfonatos / Cidofovir Límite: Humans Idioma: En Revista: Antimicrob Agents Chemother Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Proteínas Virales / ADN Viral / Adenovirus Humanos / Citosina / ADN Polimerasa Dirigida por ADN / Organofosfonatos / Cidofovir Límite: Humans Idioma: En Revista: Antimicrob Agents Chemother Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos