Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors |
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| Authors: | Dr. Shuwen Wu Jing Huang Dr. Sabrina Gazzarrini Si He Lihua Chen Dr. Jun Li Dr. Li Xing Dr. Chufang Li Prof. Ling Chen Dr. Constantinos G. Neochoritis George P. Liao Prof. Haibing Zhou Prof. Alexander Dömling Prof. Anna Moroni Prof. Wei Wang |
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| Affiliation: | 1. Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, P.R.?China;2. State Key Laboratory of Virology of China, Wuhan University, Wuhan, P.R.?China;3. Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Milan, Italy;4. Worldwide Research & Development, Pfizer Inc., Cambridge, MA, USA;5. Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangzhou, Guangdong, P.R.?China;6. Department of Drug Design, University of Groningen, Groningen, The Netherlands |
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| Abstract: | Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The ?NH2 to ?N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane ( 27 ), with an EC50 value of 0.487 μm against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains. |
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| Keywords: | amantadines antiviral agents influenza inhibitors isocyanides M2 channels |
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