Disrupting the Conserved Salt Bridge in the Trimerization of Influenza A Nucleoprotein
| Autor: | Jim-Min Fang, Ying-Ta Wu, Shao-Hung Lu, Jhih-Bin Chen, Chi-Huey Wong, Chiu-Chun Chou, Yi-Chou Huang, Jennifer L. Woodring, Yu-Hou Chen, Ming-Daw Tsai, Shih-Chi Wang, Ting-Jen R. Cheng, Larissa B. Krasnova |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.drug_class
Static Electricity Drug resistance Plasma protein binding 01 natural sciences Antiviral Agents 03 medical and health sciences Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Animals Cytotoxicity 030304 developmental biology 0303 health sciences Mice Inbred BALB C Aniline Compounds Binding Sites biology Molecular Structure Chemistry Viral Core Proteins RNA-Binding Proteins Nucleocapsid Proteins Virology 0104 chemical sciences Nucleoprotein Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Thiazoles Influenza A virus biology.protein Molecular Medicine Female Salt bridge Antiviral drug Protein Multimerization Neuraminidase Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 63(1) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|