Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir.
Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir.
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DOI：
10.1021/acsptsci.1c00099
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发表时间：
2021-08-13
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Xia Z;Sacco M;Hu Y;Ma C;Meng X;Zhang F;Szeto T;Xiang Y;Chen Y;Wang J
SARS-CoV-2主蛋白酶（Mpro）是一种介导病毒多蛋白裂解的半胱氨酸蛋白酶，是一种经过验证的抗病毒药物靶点。Mpro在所有7种人类冠状病毒中高度保守，某些Mpro抑制剂具有广谱抗病毒活性。本研究基于SARS-CoV-2 Mpro与GC-376、telaprevir和boceprevir的x射线叠加晶体结构，设计了两种杂化抑制剂UAWJ9-36-1和UAWJ9-36-3。UAWJ9-36-1和UAWJ9-36-3对SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-OC43、HCoV-NL63、HCoV-229E和HCoV-HKU1的Mpro具有较强的结合和酶促抑制作用。基于细胞的Flip-GFP Mpro检测结果显示，UAWJ9-36-1和UAWJ9-36-3抑制了SARS-CoV-2 Mpro细胞内蛋白酶活性。此外，UAWJ9-36-1和UAWJ9-36-3对SARS-CoV-2、HCoV-OC43、HCoV-NL63和HCoV-229E具有较强的抗病毒活性，其中UAWJ9-36-3对SARS-CoV-2的抑制作用强于GC-376。选择性分析结果显示，UAWJ9-36-1和UAWJ9-36-3对宿主半胱氨酸蛋白酶calpain I和cathepsin L的选择性指数高于GC-376，而对cathepsin k的选择性指数则低于GC-376。使用UAWJ9-36-1和UAWJ9-36-3的SARS-CoV-2 Mpro的x射线晶体结构在1.9 Å处都得到了解析，验证了我们的设计假设。综上所述，混合抑制剂UAWJ9-36-1和UAWJ9-36-3作为新型冠状病毒广谱抗病毒药物有进一步开发的潜力。
SARS-CoV-2 main protease (Mpro) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. Mpro is highly conserved among all seven human coronaviruses, with certain Mpro inhibitors having broad-spectrum antiviral activity. In this study, we designed two hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 based on the superimposed X-ray crystal structures of SARS-CoV-2 Mpro with GC-376, telaprevir, and boceprevir. Both UAWJ9-36-1 and UAWJ9-36-3 showed potent binding and enzymatic inhibition against the Mpro’s from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP Mpro assay results show that UAWJ9-36-1 and UAWJ9-36-3 inhibited the intracellular protease activity of SARS-CoV-2 Mpro. In addition, UAWJ9-36-1 and UAWJ9-36-3 had potent antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, with UAWJ9-36-3 being more potent than GC-376 in inhibiting SARS-CoV-2. Selectivity profiling revealed that UAWJ9-36-1 and UAWJ9-36-3 had an improved selectivity index over that of GC-376 against host cysteine proteases calpain I and cathepsin L, but not cathepsin K. The X-ray crystal structures of SARS-CoV-2 Mpro with UAWJ9-36-1 and UAWJ9-36-3 were both solved at 1.9 Å, which validated our design hypothesis. Overall, hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 are promising candidates to be further developed as broad-spectrum coronavirus antivirals.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.3
作者：
Hu, Yanmei;Ma, Chunlong;Wang, Jun
通讯作者：
Wang, Jun
影响因子：
5.4
作者：
Froggatt HM;Heaton BE;Heaton NS
通讯作者：
Heaton NS
影响因子：
13.6
作者：
Sacco MD;Ma C;Lagarias P;Gao A;Townsend JA;Meng X;Dube P;Zhang X;Hu Y;Kitamura N;Hurst B;Tarbet B;Marty MT;Kolocouris A;Xiang Y;Chen Y;Wang J
通讯作者：
Wang J
影响因子：
17.1
作者：
Rathnayake AD;Zheng J;Kim Y;Perera KD;Mackin S;Meyerholz DK;Kashipathy MM;Battaile KP;Lovell S;Perlman S;Groutas WC;Chang KO
通讯作者：
Chang KO