Structure-Based Design of Covalent SARS-CoV-2 Papain-like Protease Inhibitors

IF 5.3 2区材料科学 Q2 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Nano Materials Pub Date : 2024-11-05 DOI:10.1021/acs.jmedchem.4c01872

Bin Tan, Xueying Liang, Ahmadullah Ansari, Prakash Jadhav, Haozhou Tan, Kan Li, Francesc Xavier Ruiz, Eddy Arnold, Xufang Deng, Jun Wang

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Abstract

The COVID-19 pandemic is caused by SARS-CoV-2, a highly transmissible and pathogenic RNA betacoronavirus. Like other RNA viruses, SARS-CoV-2 continues to evolve with or without drug selection pressure, and many variants have emerged since the beginning of the pandemic. The papain-like protease, PL^pro, is a cysteine protease that cleaves viral polyproteins as well as ubiquitin and ISG15 modifications from host proteins. Leveraging our recently discovered Val70^Ub binding site in PL^pro, we designed covalent PL^pro inhibitors by connecting cysteine reactive warheads to the biarylphenyl PL^pro inhibitors via flexible linkers. Several leads displayed potent enzymatic inhibition (IC₅₀ = 0.1–0.3 μM) and antiviral activity (EC₅₀ = 0.09–0.96 μM). Fumaramide inhibitors Jun13567 (15), Jun13728 (16), and Jun13714 (18) showed favorable in vivo pharmacokinetic properties with intraperitoneal injection. The X-ray crystal structure of PL^pro with Jun13567 (15) validated our design strategy, revealing covalent conjugation between the catalytic Cys111 and the fumaramide warhead. The results suggest these covalent PL^pro inhibitors are promising SARS-CoV-2 antiviral drug candidates.

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基于结构设计的共价 SARS-CoV-2 Papain 类蛋白酶抑制剂

COVID-19 大流行是由 SARS-CoV-2 引起的，SARS-CoV-2 是一种高传播性和致病性的 RNA betacoronavirus。与其他 RNA 病毒一样，SARS-CoV-2 也在药物选择压力或无药物选择压力的情况下不断进化，自大流行开始以来已出现了许多变种。类似木瓜蛋白酶的 PLpro 是一种半胱氨酸蛋白酶，能裂解病毒多聚蛋白以及宿主蛋白中的泛素和 ISG15 修饰物。利用最近在 PLpro 中发现的 Val70Ub 结合位点，我们设计了共价 PLpro 抑制剂，通过灵活的连接体将半胱氨酸反应弹头连接到双芳基苯基 PLpro 抑制剂上。几种先导化合物显示了强效的酶抑制作用（IC50 = 0.1-0.3 μM）和抗病毒活性（EC50 = 0.09-0.96 μM）。富马酰胺抑制剂 Jun13567 (15)、Jun13728 (16) 和 Jun13714 (18) 通过腹腔注射显示出良好的体内药代动力学特性。PLpro与Jun13567（15）的X射线晶体结构验证了我们的设计策略，揭示了催化Cys111与富马酰胺弹头之间的共价连接。结果表明，这些共价 PLpro 抑制剂是很有前途的 SARS-CoV-2 抗病毒候选药物。

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来源期刊

ACS Applied Nano Materials Multiple-

CiteScore

8.30

自引率

3.40%

发文量

1601

期刊介绍： ACS Applied Nano Materials is an interdisciplinary journal publishing original research covering all aspects of engineering, chemistry, physics and biology relevant to applications of nanomaterials. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important applications of nanomaterials.