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

• Published in: Journal of medicinal chemistry Vol. 63; no. 1; pp. 205 - 215
• Main Authors: Woodring, Jennifer L, Lu, Shao-Hung, Krasnova, Larissa, Wang, Shih-Chi, Chen, Jhih-Bin, Chou, Chiu-Chun, Huang, Yi-Chou, Cheng, Ting-Jen Rachel, Wu, Ying-Ta, Chen, Yu-Hou, Fang, Jim-Min, Tsai, Ming-Daw, Wong, Chi-Huey
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.01.2020; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; TARGET; DRUG; H5N1 NUCLEOPROTEIN; AMINO-ACIDS; INHIBITORS; VIRUS NUCLEOPROTEIN; IDENTIFICATION; OLIGOMERIZATION; MUTATIONAL ANALYSIS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01244

Antiviral drug resistance in influenza infections has been a major threat to public health. 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 antiviral activity screening 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.