JINGXIN QIAO, YUE-SHAN LI, RUI ZENG, FENG-LIANG LIU, RONG-HUA LUO, CHONG HUANG, YI-FEI WANG, JIE ZHANG, BAOXUE QUAN, CHENJIAN SHEN, XIN MAO, XINLEI LIU, WEINING SUN, WEI YANG, XINCHENG NI, KAI WANG, LING XU, ZI-LEI DUAN, QING-CUI ZOU, HAI-LIN ZHANG, WANG QU, YANG-HAO-PENG LONG, MING-HUA LI, RUI-CHENG YANG, XIAOLONG LIU, JING YOU, YANGLI ZHOU, RUI YAO, WEN-PEI LI, JING-MING LIU, PEI CHEN, YANG LIU, GUI-FENG LIN, XIN YANG, JUN ZOU, LINLI LI, YIGUO HU, GUANG-WEN LU, WEI-MIN LI, YU-QUAN WEI, YONG-TANG ZHENG, JIAN LEI, SHENGYONG YANG
Science, 2021, eabf1611
The COVID-19 pandemic caused by the SARS-CoV-2 virus continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either Boceprevir or Telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro with IC50 values ranging from 7.6 to 748.5 nM. The co-crystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a SARS-CoV-2 infection transgenic mouse model, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.