Structures of two coronavirus main proteases: Implications for substrate binding and antiviral drug design
Structures of two coronavirus main proteases: Implications for substrate binding and antiviral drug design
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两种冠状病毒主要蛋白酶的结构：对底物结合和抗病毒药物设计的影响
DOI：
10.1128/jvi.02114-07
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发表时间：
2008-03-01
影响因子：
5.4
通讯作者：
Rao, Zihe
中科院分区：
文献类型：
--
作者：
Xue, Xiaoyu;Yu, Hongwei;Rao, Zihe
冠状病毒（CoV）可以感染人类和多种动物，引起多种疾病。冠状病毒主要蛋白酶（M-Pro）通过复制酶多蛋白的蛋白水解加工在病毒基因表达和复制中发挥关键作用，是抗冠状病毒药物设计的一个有吸引力的目标。在本研究中，分别测定了传染性支气管炎病毒 (IBV) M-Pro 和严重急性呼吸综合征冠状病毒 (SARS-CoV) M-Pro 突变体 (H41A) 与 N 端自动裂解底物复合物的晶体结构，以阐明 M-Pro 的结构灵活性和底物结合。首次在 COV M-Pro 结构中鉴定出 IBV M-Pro 的单体形式。将这两种结构与其他可用的 M-Pro 结构进行比较，为设计针对 CoV M-Pro 的基于底物的抑制剂提供了新的见解。此外，迈克尔受体抑制剂（称为 N3）与 IBV M-Pro 共结晶，并被发现在体外证明 IBV M-Pro 失活并对鸡胚胎中的 IBV 具有有效的抗病毒活性。这为设计针对冠状病毒相关疾病的广谱抑制剂提供了可行的动物模型。 N3 基于结构的优化产生了两种更有效的先导化合物 N27 和 H16，对 SARS-CoV M-Pro 具有有效的抑制作用。
Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M-Pro), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) M-Pro and a severe acute respiratory syndrome CoV (SARS-CoV) M-Pro mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M-Pro. A monomeric form of IBV M-Pro was identified for the first time in COV M-Pro, structures. A comparison of these two structures to other available M-Pro structures provides new insights for the design of substrate-based inhibitors targeting CoV M-Pro. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M-Pro and was found to demonstrate in vitro inactivation of IBV M-Pro and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M-Pro.