tetano
Editor, Senior Moderator
J Med Chem. 2013 Feb 25. [Epub ahead of print]
Discovery of Novel Dual Inhibitors of Wild-type and the Most Prevalent Drug-Resistant Mutant, S31N, of M2 Proton Channel from Influenza A Virus.
Wang J, Ma C, Wang J, Jo H, Canturk B, Fiorin G, Pinto LH, Lamb RA, Klein ML, Degrado WF.
Abstract
Abstract: Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting S31N mutant. However, S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections.
PMID:
23437766
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23437766
Discovery of Novel Dual Inhibitors of Wild-type and the Most Prevalent Drug-Resistant Mutant, S31N, of M2 Proton Channel from Influenza A Virus.
Wang J, Ma C, Wang J, Jo H, Canturk B, Fiorin G, Pinto LH, Lamb RA, Klein ML, Degrado WF.
Abstract
Abstract: Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting S31N mutant. However, S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections.
PMID:
23437766
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23437766