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

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

  • Antimicrob Agents Chemother. 2015 Mar;59(3):1569-82. doi: 10.1128/AAC.04623-14.
Randal A Byrn 1,  Steven M Jones 1,  Hamilton B Bennett 1,  Chris Bral 2,  Michael P Clark 3,  Marc D Jacobs 4,  Ann D Kwong 5,  Mark W Ledeboer 3,  Joshua R Leeman 1,  Colleen F McNeil 1,  Mark A Murcko 6,  Azin Nezami 4,  Emanuele Perola 7,  Rene Rijnbrand 1,  Kumkum Saxena 4,  Alice W Tsai 8,  Yi Zhou 1,  Paul S Charifson 9
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
  • 2 Department of Drug Safety Evaluation, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
  • 3 Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
  • 4 Department of Protein Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
  • 5 InnovaTID Pharmaceuticals, Cambridge, Massachusetts, USA.
  • 6 Disruptive Biomedical, LLC, Holliston, Massachusetts, USA.
  • 7 Department of Computational Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
  • 8 Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
  • 9 Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA paul_charifson@vrtx.com.
PMID: 25547360 DOI: 10.1128/AAC.04623-14
Abstract

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.

Figures
Products