Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.

Autor:	Byrn RA; Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Jones SM; Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Bennett HB; Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Bral C; Department of Drug Safety Evaluation, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Clark MP; Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Jacobs MD; Department of Protein Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Kwong AD; InnovaTID Pharmaceuticals, Cambridge, Massachusetts, USA., Ledeboer MW; Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Leeman JR; Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., McNeil CF; Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Murcko MA; Disruptive Biomedical, LLC, Holliston, Massachusetts, USA., Nezami A; Department of Protein Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Perola E; Department of Computational Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Rijnbrand R; Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Saxena K; Department of Protein Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Tsai AW; Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Zhou Y; Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA., Charifson PS; Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA paul_charifson@vrtx.com.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Mar; Vol. 59 (3), pp. 1569-82. Date of Electronic Publication: 2014 Dec 29.
DOI:	10.1128/AAC.04623-14
Abstrakt:	VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection. (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
Databáze:	MEDLINE
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