TY - JOUR TI - SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model AU - Qiao, Jingxin AU - Li, Yue-Shan AU - Zeng, Rui AU - Liu, Feng-Liang AU - Luo, Rong-Hua AU - Huang, Chong AU - Wang, Yi-Fei AU - Zhang, Jie AU - Quan, Baoxue AU - Shen, Chenjian AU - Mao, Xin AU - Liu, Xinlei AU - Sun, Weining AU - Yang, Wei AU - Ni, Xincheng AU - Wang, Kai AU - Xu, Ling AU - Duan, Zi-Lei AU - Zou, Qing-Cui AU - Zhang, Hai-Lin AU - Qu, Wang AU - Long, Yang-Hao-Peng AU - Li, Ming-Hua AU - Yang, Rui-Cheng AU - Liu, Xiaolong AU - You, Jing AU - Zhou, Yangli AU - Yao, Rui AU - Li, Wen-Pei AU - Liu, Jing-Ming AU - Chen, Pei AU - Liu, Yang AU - Lin, Gui-Feng AU - Yang, Xin AU - Zou, Jun AU - Li, Linli AU - Hu, Yiguo AU - Lu, Guang-Wen AU - Li, Wei-Min AU - Wei, Yu-Quan AU - Zheng, Yong-Tang AU - Lei, Jian AU - Yang, Shengyong T2 - Science AB - Targeting the SARS-CoV-2 main protease Vaccines are an important tool in the fight against COVID-19, but developing antiviral drugs is also a high priority, especially with the rise of variants that may partially evade vaccines. The viral protein main protease is required for cleaving precursor polyproteins into functional viral proteins. This essential function makes it a key drug target. Qiao et al. designed 32 inhibitors based on either boceprevir or telaprevir, both of which are protease inhibitors approved to treat hepatitis C virus. Six compounds protected cells from viral infection with high potency, and two of these were selected for in vivo studies based on pharmokinetic experiments. Both showed strong antiviral activity in a mouse model. Science, this issue p. 1374 The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 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 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal 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 transgenic mouse model of SARS-CoV-2 infection, 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. Designed SARS-CoV-2 Mpro (main protease) inhibitors display excellent antiviral activity both in vitro and in a transgenic mouse model. Designed SARS-CoV-2 Mpro (main protease) inhibitors display excellent antiviral activity both in vitro and in a transgenic mouse model. DA - 2021/03/26/ PY - 2021 DO - 10.1126/science.abf1611 DP - science.sciencemag.org VL - 371 IS - 6536 SP - 1374 EP - 1378 LA - en SN - 0036-8075, 1095-9203 UR - https://science.sciencemag.org/content/371/6536/1374 Y2 - 2021/03/31/05:47:42 ER -