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,ACS Pharmacology & Translational Science

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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
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-06-09 , DOI: 10.1021/acsptsci.1c00099
Zilei Xia ₁ , Michael Sacco ₂ , Yanmei Hu ₁ , Chunlong Ma ₁ , Xiangzhi Meng ₃ , Fushun Zhang ₃ , Tommy Szeto ₁ , Yan Xiang ₃ , Yu Chen ₂ , Jun Wang ₁

Affiliation

SARS-CoV-2 main protease (M^pro) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. M^pro is highly conserved among all seven human coronaviruses, with certain M^pro 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 M^pro with GC-376, telaprevir, and boceprevir. Both UAWJ9-36-1 and UAWJ9-36-3 showed potent binding and enzymatic inhibition against the M^pro’s from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP M^pro assay results show that UAWJ9-36-1 and UAWJ9-36-3 inhibited the intracellular protease activity of SARS-CoV-2 M^pro. 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 M^pro 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.

中文翻译：

以肽模拟抑制剂 GC-376、Telaprevir 和 Boceprevir 的叠加共晶结构为指导合理设计混合型 SARS-CoV-2 主要蛋白酶抑制剂

SARS-CoV-2 主要蛋白酶 (M ^pro ) 是一种半胱氨酸蛋白酶，可介导病毒多蛋白的裂解，是经过验证的抗病毒药物靶点。M ^pro在所有七种人类冠状病毒中高度保守，某些 M ^pro抑制剂具有广谱抗病毒活性。在本研究中，我们基于 SARS-CoV-2 M ^pro与 GC-376、特拉匹韦和博普瑞韦的叠加 X 射线晶体结构，设计了两种混合抑制剂UAWJ9-36-1和UAWJ9-36-3 。UAWJ9-36-1和UAWJ9-36-3均对来自 SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-OC43、HCoV-NL63、HCoV-229E 的M ^pro表现出有效的结合和酶抑制作用和 HCoV-HKU1。基于细胞的 Flip-GFP M ^pro检测结果表明，UAWJ9-36-1和UAWJ9-36-3抑制 SARS-CoV-2 M ^pro的细胞内蛋白酶活性。此外，UAWJ9-36-1和UAWJ9-36-3对SARS-CoV-2、HCoV-OC43、HCoV-NL63和HCoV-229E具有有效的抗病毒活性，其中UAWJ9-36-3比GC-更有效。 376 抑制 SARS-CoV-2。选择性分析显示，UAWJ9-36-1和UAWJ9-36-3对宿主半胱氨酸蛋白酶钙蛋白酶 I 和组织蛋白酶 L 的选择性指数比 GC-376 有所提高，但对组织蛋白酶 K 的选择性指数没有改善。SARS-的 X 射线晶体结构具有UAWJ9-36-1和UAWJ9-36-3的CoV-2 M ^pro均在 1.9 Å 处得到解析，这验证了我们的设计假设。总体而言，混合抑制剂UAWJ9-36-1和UAWJ9-36-3是有希望进一步开发为广谱冠状病毒抗病毒药物的候选药物。

更新日期：2021-08-13

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