SARS-CoV-2 M<sup>pro</sup> inhibitors with antiviral activity in a transgenic mouse model

doi:10.1126/science.abf1611

GSTDTAP > 气候变化

DOI	10.1126/science.abf1611
	SARS-CoV-2 M^pro 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
	2021-03-26
发表期刊	Science
出版年	2021
英文摘要	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][1] 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. [1]: /lookup/doi/10.1126/science.abf1611
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/321102
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Jingxin Qiao,Yue-Shan Li,Rui Zeng,et al. SARS-CoV-2 M^pro inhibitors with antiviral activity in a transgenic mouse model[J]. Science,2021.
APA	Jingxin Qiao.,Yue-Shan Li.,Rui Zeng.,Feng-Liang Liu.,Rong-Hua Luo.,...&Shengyong Yang.(2021).SARS-CoV-2 M^pro inhibitors with antiviral activity in a transgenic mouse model.Science.
MLA	Jingxin Qiao,et al."SARS-CoV-2 M^pro inhibitors with antiviral activity in a transgenic mouse model".Science (2021).