Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir
Xiaoxin Chen, Xiaodong Huang, Qinhai Ma, Petr Kuzmič, Biao Zhou, Sai Zhang, Jizheng Chen, Jinxin Xu, Bin Liu, Haiming Jiang, Wenjie Zhang, Chunguang Yang, Shiguan Wu, Jianzhou Huang, Haijun Li, Chaofeng Long, Xin Zhao, Hongrui Xu, Yanan Sheng, Yaoting Guo, Chuanying Niu, Xue Lu, Yong Xu, Jinsong Liu, Tianyu Zhang, James Spencer, Zhenzhen Zhu, Wenbin Deng, Xinwen Chen, Shuhui Chen, Nanshan Zhong, Xiaoli Xiong, Zifeng Yang
Abstract
Abstract Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (M pro ), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from M pro compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 M pro :RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named ‘leritrelvir’ for COVID-19 treatment in China.