Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors

  • J Med Chem. 2019 Apr 25;62(8):4056-4073. doi: 10.1021/acs.jmedchem.9b00091.
Yiqing Yang  1 ,  Lin Cao  2 ,  Hongying Gao  1 ,  Yue Wu ,  Yaxin Wang  3 ,  Fang Fang ,  Tianlong Lan ,  Zhiyong Lou ,  Yu Rao
Affiliations
  • 1. Tsinghua University-Peking University Joint Center for Life Sciences , Beijing 100084 , P. R. China.
  • 2. College of Life Sciences , Nankai University , Tianjin 300071 , P. R. China.
  • 3. College of Life Sciences , Hebei Normal University , Shijiazhuang , Hebei 050024 , P. R. China.
PMID: 30938999 DOI: 10.1021/acs.jmedchem.9b00091
Abstract

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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