tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2014 Dec 29. pii: AAC.04623-14. [Epub ahead of print]
[h=1]Preclinical activity of VX-787, a first in class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.[/h] Byrn RA[SUP]1[/SUP], Jones SM[SUP]1[/SUP], Bennett HB[SUP]1[/SUP], Bral CM[SUP]2[/SUP], Clark MP[SUP]3[/SUP], Jacobs MD[SUP]4[/SUP], Kwong AD[SUP]5[/SUP], Ledeboer MW[SUP]3[/SUP], Leeman JR[SUP]1[/SUP], McNeil CF[SUP]1[/SUP], Murcko MA[SUP]6[/SUP], Nezami A[SUP]4[/SUP], Perola E[SUP]7[/SUP], Rijnbrand R[SUP]1[/SUP], Saxena K[SUP]4[/SUP], Tsai AW[SUP]8[/SUP], Zhou Y[SUP]1[/SUP], Charifson PS[SUP]9[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] VX-787 is a novel inhibitor of influenza replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support that VX-787 occupies the m[SUP]7[/SUP]GTP cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a K[SUB]D[/SUB] of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC[SUB]50[/SUB] for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC[SUB]50[/SUB] in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A 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 delayed start-to-treat experiments, with 100% survival up to 96 h post infection and partial survival in groups where the initiation of therapy was delayed up to 120 h post infection. At different doses, VX-787 showed a 1- to >5-log reduction in lung 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 ? 2014, American Society for Microbiology. All Rights Reserved.
PMID: 25547360 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25547360
[h=1]Preclinical activity of VX-787, a first in class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.[/h] Byrn RA[SUP]1[/SUP], Jones SM[SUP]1[/SUP], Bennett HB[SUP]1[/SUP], Bral CM[SUP]2[/SUP], Clark MP[SUP]3[/SUP], Jacobs MD[SUP]4[/SUP], Kwong AD[SUP]5[/SUP], Ledeboer MW[SUP]3[/SUP], Leeman JR[SUP]1[/SUP], McNeil CF[SUP]1[/SUP], Murcko MA[SUP]6[/SUP], Nezami A[SUP]4[/SUP], Perola E[SUP]7[/SUP], Rijnbrand R[SUP]1[/SUP], Saxena K[SUP]4[/SUP], Tsai AW[SUP]8[/SUP], Zhou Y[SUP]1[/SUP], Charifson PS[SUP]9[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] VX-787 is a novel inhibitor of influenza replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support that VX-787 occupies the m[SUP]7[/SUP]GTP cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a K[SUB]D[/SUB] of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC[SUB]50[/SUB] for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC[SUB]50[/SUB] in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A 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 delayed start-to-treat experiments, with 100% survival up to 96 h post infection and partial survival in groups where the initiation of therapy was delayed up to 120 h post infection. At different doses, VX-787 showed a 1- to >5-log reduction in lung 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 ? 2014, American Society for Microbiology. All Rights Reserved.
PMID: 25547360 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25547360