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
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- 作者：Jizhou Wang ; Chunlong Ma ; Jun Wang ; Hyunil Jo ; Belgin Canturk ; Giacomo Fiorin ; Lawrence H. Pinto ; Robert A. Lamb ; Michael L. Klein ; William F. DeGrado
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：April 11, 2013
- 年：2013
- 卷：56
- 期：7
- 页码：2804-2812
- 全文大小：484K
- 年卷期：v.56,no.7(April 11, 2013)
- ISSN：1520-4804
文摘
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.