文摘
It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein, we report structure鈥揳ctivity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogues of brequinar.
Keywords:
High-throughput screening; structure鈭抋ctivity relationship; antiviral; human DHODH inhibitor