title: Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.
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.
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Randal A
authors.initials: RA
authors.lastname: Byrn
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Hamilton B
authors.initials: HB
authors.lastname: Bennett
authors.affiliation: Department of Drug Safety Evaluation, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Bral
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.affiliation: Department of Protein Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Jacobs
authors.affiliation: InnovaTID Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Ann D
authors.initials: AD
authors.lastname: Kwong
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Ledeboer
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Leeman
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Colleen F
authors.initials: CF
authors.lastname: McNeil
authors.affiliation: Disruptive Biomedical, LLC, Holliston, Massachusetts, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Murcko
authors.affiliation: Department of Protein Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Azin
authors.initials: A
authors.lastname: Nezami
authors.affiliation: Department of Computational Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Rijnbrand
authors.affiliation: Department of Protein Sciences, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Kumkum
authors.initials: K
authors.lastname: Saxena
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Alice W
authors.initials: AW
authors.lastname: Tsai
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA paul_charifson@vrtx.com.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000821:virology; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D012321:DNA-Directed RNA Polymerases