Wednesday, February 24, 2021

SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model

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

DOI: 10.1126/science.abf1611

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.




Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...