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Disrupting the Conserved Salt Bridge in the Trimerization of Influenza A Nucleoprotein

Disrupting the Conserved Salt Bridge in the Trimerization of Influenza A Nucleoprotein

J Med Chem. 2020 Jan 9;63(1):205-215. Epub 2019 Dec 17.
doi: 10.1021/acs.jmedchem.9b01244

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摘要

Antiviral drug resistance in influenza infections has been a major threat to public health. In order to develop a broad-spectrum inhibitor of influenza to combat the problem of drug resistance, we previously identified the highly conserved E339…R416 salt bridge of the nucleoprotein trimer as a target, and compound 1 as an inhibitor disrupting the salt bridge with an EC50 = 2.7 µM against influenza A (A/WSN/1933). We have further modified this compound via a structure-based approach and performed an antiviral activity screen to identify compounds 29 and 30 with EC50 values of 110 and 120 nM respectively and without measurable host cell cytotoxicity. Compared to the clinically used neuraminidase inhibitors, these two compounds showed better activity profiles against drug-resistant influenza A strains, as well as influenza B, and improved survival of influenza-infected mice.