tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2015 Jul 13. pii: AAC.00781-15. [Epub ahead of print]
[h=1]A Novel Ranking System for Identifying Efficacious Anti-Influenza PB2 Inhibitors.[/h] Tsai AW[SUP]1[/SUP], McNeil CF[SUP]2[/SUP], Leeman JR[SUP]2[/SUP], Bennett HB[SUP]2[/SUP], Nti-Addae K[SUP]3[/SUP], Huang C[SUP]4[/SUP], Germann UA[SUP]5[/SUP], Byrn RA[SUP]2[/SUP], Berlioz-Seux F[SUP]4[/SUP], Rijnbrand R[SUP]2[/SUP], Clark MP[SUP]6[/SUP], Charifson PS[SUP]6[/SUP], Jones SM[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Through antigenic drift and shift, influenza (flu) viral infections continue to be an annual cause of morbidity in healthy populations and mortality among the elderly and at risk patients. The emergence of highly pathogenic avian influenza viruses like H5N1 and H7N9 and the rapid spread of the swine origin H1N1 influenza virus in 2009 demonstrate the continued need for effective influenza therapeutics. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited start-to-treat window and resistant variants have shown up in the population. In addition, an older class of influenza antiviral drugs, the adamantanes, are no longer recommended for treatment due to widespread resistance.There remains a need for new influenza therapeutics with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein that demonstrate excellent in vitro and in vivo properties have been identified. To evaluate the vivo efficacy of these PB2 inhibitors, we have utilized a mouse influenza A virus infection model. In addition to the traditional endpoints: mortality, morbidity, and body weight (BW) loss, we also measured lung function using whole body plethysmography (WBP) and used these to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more effective treatments for influenza in patients.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26169418 [PubMed - as supplied by publisher]
[h=1]A Novel Ranking System for Identifying Efficacious Anti-Influenza PB2 Inhibitors.[/h] Tsai AW[SUP]1[/SUP], McNeil CF[SUP]2[/SUP], Leeman JR[SUP]2[/SUP], Bennett HB[SUP]2[/SUP], Nti-Addae K[SUP]3[/SUP], Huang C[SUP]4[/SUP], Germann UA[SUP]5[/SUP], Byrn RA[SUP]2[/SUP], Berlioz-Seux F[SUP]4[/SUP], Rijnbrand R[SUP]2[/SUP], Clark MP[SUP]6[/SUP], Charifson PS[SUP]6[/SUP], Jones SM[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Through antigenic drift and shift, influenza (flu) viral infections continue to be an annual cause of morbidity in healthy populations and mortality among the elderly and at risk patients. The emergence of highly pathogenic avian influenza viruses like H5N1 and H7N9 and the rapid spread of the swine origin H1N1 influenza virus in 2009 demonstrate the continued need for effective influenza therapeutics. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited start-to-treat window and resistant variants have shown up in the population. In addition, an older class of influenza antiviral drugs, the adamantanes, are no longer recommended for treatment due to widespread resistance.There remains a need for new influenza therapeutics with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein that demonstrate excellent in vitro and in vivo properties have been identified. To evaluate the vivo efficacy of these PB2 inhibitors, we have utilized a mouse influenza A virus infection model. In addition to the traditional endpoints: mortality, morbidity, and body weight (BW) loss, we also measured lung function using whole body plethysmography (WBP) and used these to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more effective treatments for influenza in patients.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26169418 [PubMed - as supplied by publisher]