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科学家发现在转基因小鼠模型中具有抗病毒活性的SARS-CoV-2抑制剂
作者:小柯机器人 发布时间:2021/2/20 14:11:19

四川大学杨胜勇等研究人员合作发现在转基因小鼠模型中具有抗病毒活性的SARS-CoV-2 Mpro抑制剂。该项研究成果于2021年2月18日在线发表在《科学》杂志上。

由SARS-CoV-2病毒引起的COVID-19大流行不断对全球公共健康构成严重威胁。SARS-CoV-2的Mpro在病毒复制中起着核心作用。 研究人员设计和合成了32种新的含双环脯氨酸的主要蛋白酶(Mpro)抑制剂,它们均来自Boceprevir或Telaprevir,且均被批准为抗病毒药。所有化合物均在体外抑制SARS-CoV-2 Mpro活性,IC50值为7.6至748.5 nM。Mpro与最有效的化合物之一MI-23的共晶体结构揭示了其相互作用模式。

两种化合物(MI-09和MI-30)在基于细胞的测定中均显示出出色的抗病毒活性。在SARS-CoV-2感染转基因小鼠模型中,用MI-09或MI-30口服或腹膜内治疗可显著降低肺部病毒载量和肺部病变。两者在大鼠中也显示出良好的药代动力学性质和安全性。 

附:英文原文

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

Author: 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

Issue&Volume: 2021/02/18

Abstract: 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.

DOI: 10.1126/science.abf1611

Source: https://science.sciencemag.org/content/early/2021/02/17/science.abf1611

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037