Isocyanides as Influenza A Virus Subtype H5N1 Wild-Type M2 Channel Inhibitors.
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.
Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P.R. China.|State Key Laboratory of Virology of China, Wuhan University, Wuhan, 430071, P.R. China.
Shuwen
S
Wu
Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P.R. China.
Jing
J
Huang
Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Via Celoria 26, 20133, Milan, Italy.
Sabrina
S
Gazzarrini
Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P.R. China.
Si
S
He
Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P.R. China.
Lihua
L
Chen
Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P.R. China.
Jun
J
Li
Worldwide Research & Development, Pfizer Inc., 200 Cambridge Park Drive, Cambridge, MA, 02421, USA.
Li
L
Xing
Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangzhou, Guangdong, 510530, P.R. China.
Chufang
C
Li
Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, Guangzhou, Guangdong, 510530, P.R. China.
Ling
L
Chen
Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Constantinos G
CG
Neochoritis
Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
George P
GP
Liao
Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P.R. China.
Haibing
H
Zhou
Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Alexander
A
Dömling
Department of Biosciences, University of Milan and, Institute of Biophysics (IBF) Milan, National Research Council (CNR), Via Celoria 26, 20133, Milan, Italy.
Anna
A
Moroni
Key Laboratory of Combinatorial Biosynthesis & Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P.R. China. waw6@whu.edu.cn.
Wei
W
Wang
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003486:Cyanides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000086082:Viroporin Proteins
D000998:Antiviral Agents; D003486:Cyanides; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
M2 channels; amantadines; antiviral agents; influenza; inhibitors; isocyanides