期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 8, 页码 4056-4073出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00091
关键词
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资金
- National Natural Science Foundation of China [81811530340, 81773567, 81622042, 81573277, 31770309]
- Tsinghua University-Peking University Joint Center for Life Sciences
- China Postdoctoral Science Foundation [2017M620806]
Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit to lead, a novel potent small molecule (RYL-634) was identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue virus, Zika virus, chikungunya virus, enterovirus 71, human immunodeficiency virus, respiratory syncytial virus, and others. The mechanism of action and potential targets of RYL-634 were further explored by the combination of activity-based protein profiling and other techniques. Finally, human dihydroorotate dehydrogenase was validated as the major target of RYL-634. We did not observe any mutant resistance under our pressure selections with RYL-634, and it had a strong synergistic effect with some Food and Drug Administration-approved drugs. Hence, there is great potential for developing new broad-spectrum antivirals based on RYL-634.
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