A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants
Chong Huang, Huiping Shuai, Jingxin Qiao, Yuxin Hou, Rui Zeng, Anjie Xia, Lingwan Xie, Zhen Fang, Yueyue Li, Chaemin Yoon, Qiao Huang, Bingjie Hu, Jing You, Baoxue Quan, Xiu Zhao, Nihong Guo, Shiyu Zhang, Ronggang Ma, Jiahao Zhang, Yifei Wang, Ruicheng Yang, Shanshan Zhang, Jinshan Nan, Haixing Xu, Falu Wang, Jian Lei, Hin Chu, Shengyong Yang
Signal Transduction and Targeted Therapy, doi:10.1038/s41392-023-01392-w
Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (M pro ). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance M pro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.
AUTHOR CONTRIBUTIONS S.Y., H.C., and J.L. conceived research; and C.H. performed the drug design; C.H., A.X., and Z.F. with the assistance of Q.H., J.Y., B.Q., N.G., S.Z., R.M., J.Z., S.Z., J.N., H.X., and F.W. performed the chemical synthesis; R.Z., L.X., J.Q., and X.Z. performed gene expression, protein purification and crystallization experiments; R.Z., L.X., and J.L. determined the crystal structures; J.Q. and Y.L. performed high-throughput screening, enzymatic activity and inhibition assays, IC 50 measurements, DSF assays, cytotoxicity assays and in vivo toxicity assays; H.S., Y.H., C.Y., and B.H. performed in vitro and in vivo antiviral assays; S.Y., J.L., and H.C. with the assistance of C.H., H.S., J.Q., and R.Z. wrote and revised the manuscript. All authors have read and approved the article.
ADDITIONAL INFORMATION Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41392-023-01392-w. Competing interests: All authors declared no competing interests. S.Y. is the member of editorial board, he has not been involved in the process of the manuscript handling.
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