期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 11, 页码 2139-2145出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00215
关键词
Alphavirus; covalent inhibitors; cysteine protease; nsP2; dihydroquinoline
资金
- US National Institutes of Health [SC3GM122629, G12MD007581]
- NIH-RISE [5R25GM067122]
- Office of Naval Research [N0017315RMV04]
- Joint Science and Technology Office for Chemical and Biological Defense (JSTO-CBD) of the Defense Threat Reduction Agency (DTRA) [CB10217]
Emerging infectious diseases like those caused by arboviruses such as Venezuelan equine encephalitis virus (VEEV) pose a serious threat to public health systems. Development of medical countermeasures against emerging infectious diseases are of utmost importance. In this work, an acrylate and vinyl sulfone-based chemical series was investigated as promising starting scaffolds against VEEV and as inhibitors of the cysteine protease domain of VEEVs nonstructural protein 2 (nsP2). Primary screen and dose response studies were performed to evaluate the potency and cytotoxicity of the compounds. The results provide structural insights into a new class of potent nonpeptidic covalent inhibitors of nsP2 cysteine protease represented by compound 11 (VEEV TrD, EC50 = 2.4 mu M (HeLa), 1.6 mu M (Vero E6)). These results may facilitate the evolution of the compounds into selective and broad-spectrum anti-alphaviral drug leads.
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