Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus

Jizhou Wang, Chunlong Ma, Jun Wang, Hyunil Jo, Belgin Canturk, Giacomo Fiorin, Lawrence H. Pinto, Robert A. Lamb, Michael L. Klein, William F. DeGrado

Research output: Contribution to journalArticle

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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 the S31N mutant. However, the 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 (44) 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.

Original languageEnglish (US)
Pages (from-to)2804-2812
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number7
DOIs
StatePublished - Apr 11 2013
Externally publishedYes

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Amantadine
Influenza A virus
Human Influenza
Protons
Rimantadine
Pharmaceutical Preparations
Pharmaceutical Chemistry
Pandemics
Drug Discovery
Benzene
Drug Resistance
Infection

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus. / Wang, Jizhou; Ma, Chunlong; Wang, Jun; Jo, Hyunil; Canturk, Belgin; Fiorin, Giacomo; Pinto, Lawrence H.; Lamb, Robert A.; Klein, Michael L.; DeGrado, William F.

In: Journal of Medicinal Chemistry, Vol. 56, No. 7, 11.04.2013, p. 2804-2812.

Research output: Contribution to journalArticle

Wang, Jizhou ; Ma, Chunlong ; Wang, Jun ; Jo, Hyunil ; Canturk, Belgin ; Fiorin, Giacomo ; Pinto, Lawrence H. ; Lamb, Robert A. ; Klein, Michael L. ; DeGrado, William F. / Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 7. pp. 2804-2812.
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