tetano
Editor, Senior Moderator
J Med Chem. 2016 Jan 15. [Epub ahead of print]
[h=1]Discovery of highly potent inhibitors targeting the predominant drug-resistant S31N mutant of the influenza A virus M2 proton channel.[/h] Li F, Ma C, DeGrado WF, Wang J.
[h=3]Abstract[/h] With the emergence of highly pathogenic avian influenza (HPAI) H7N9 and H5N1 strains, there is a pressing need to develop direct-acting antivirals (DAAs) to combat such deadly viruses. The M2-S31N proton channel of the influenza A virus (A/M2) is one of the validated and most conserved proteins encoded by the current circulating influenza A viruses, thus it represents a high-profile drug target for therapeutic intervention. We recently discovered a series of S31N inhibitors with the general structure of adamantyl-1-NH2+CH2-aryl, but they generally had poor physical properties and some showed toxicity in vitro. In this study, we sought to optimize both the adamantyl as well as the aryl/heteroaryl group. Several compounds from this study exhibited submicromolar EC50 ??values against S31N-containing A/WSN/33 influenza viruses in antiviral plaque reduction assays with a selectivity index greater than 100, indicating that these compounds are promising candidates for in depth preclinical pharmacology.
PMID: 26771709 [PubMed - as supplied by publisher]
[h=1]Discovery of highly potent inhibitors targeting the predominant drug-resistant S31N mutant of the influenza A virus M2 proton channel.[/h] Li F, Ma C, DeGrado WF, Wang J.
[h=3]Abstract[/h] With the emergence of highly pathogenic avian influenza (HPAI) H7N9 and H5N1 strains, there is a pressing need to develop direct-acting antivirals (DAAs) to combat such deadly viruses. The M2-S31N proton channel of the influenza A virus (A/M2) is one of the validated and most conserved proteins encoded by the current circulating influenza A viruses, thus it represents a high-profile drug target for therapeutic intervention. We recently discovered a series of S31N inhibitors with the general structure of adamantyl-1-NH2+CH2-aryl, but they generally had poor physical properties and some showed toxicity in vitro. In this study, we sought to optimize both the adamantyl as well as the aryl/heteroaryl group. Several compounds from this study exhibited submicromolar EC50 ??values against S31N-containing A/WSN/33 influenza viruses in antiviral plaque reduction assays with a selectivity index greater than 100, indicating that these compounds are promising candidates for in depth preclinical pharmacology.
PMID: 26771709 [PubMed - as supplied by publisher]