Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro,ACS Central Science

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Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro
ACS Central Science ( IF 12.7 ) Pub Date : 2023-01-25 , DOI: 10.1021/acscentsci.2c01359
Ningke Hou ₁ , Lei Shuai _{2,

3} , Lijing Zhang _{4,

5} , Xuping Xie ₆ , Kaiming Tang ₇ , Yunkai Zhu ₈ , Yin Yu ₈ , Wenyi Zhang ₄ , Qiaozhu Tan ₄ , Gongxun Zhong _{2,

3} , Zhiyuan Wen _{2,

3} , Chong Wang _{2,

3} , Xijun He _{2,

3} , Hong Huo ₂ , Haishan Gao ₄ , You Xu ₄ , Jing Xue ₄ , Chen Peng ₄ , Jing Zou ₆ , Craig Schindewolf ₉ , Vineet Menachery ₉ , Wenji Su ₁₀ , Youlang Yuan ₁₀ , Zuyuan Shen ₁₀ , Rong Zhang ₈ , Shuofeng Yuan ₇ , Hongtao Yu ₄ , Pei-Yong Shi ₆ , Zhigao Bu _{2,

3} , Jing Huang ₄ , Qi Hu ₄

Affiliation

Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China.
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No.678 Haping Road, Xiangfang District, Harbin 150069, China.
National High Containment Laboratory for Animal Diseases Control and Prevention, Harbin 150069, China.
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Institute of Biology, Westlake Institute for Advanced Study, Westlake University, No.18 Shilongshan Road Cloud Town, Xihu District, Hangzhou 310024, Zhejiang China.
Zhejiang University, 866 Yuhangtang Rd, Hangzhou 310058, Zhejiang, China.
Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, Texas 77555, United States.
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Biosafety Level 3 Laboratory, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
WuXi AppTec (Shanghai) Co., Ltd. 288 Middle Fu Te Road, Shanghai 200131, China.

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC₅₀ values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.

中文翻译：

SARS-CoV-2 3CLpro 高效非共价抑制剂的开发

3C 样蛋白酶 (3CLpro) 是 SARS-CoV-2 和其他冠状病毒复制的必需酶，因此是冠状病毒药物发现的目标。目前报道的冠状病毒3CLpro抑制剂几乎都是共价抑制剂。在这里，我们报告了 3CLpro 的特异性非共价抑制剂的开发。最有效的 WU-04 有效阻断 SARS-CoV-2 在人体细胞中的复制，EC ₅₀值在 10-nM 范围内。WU-04 还高效抑制 SARS-CoV 和 MERS-CoV 的 3CLpro，表明它是冠状病毒 3CLpro 的泛抑制剂。当口服相同剂量时，WU-04 在 K18-hACE2 小鼠中显示出与 PF-07321332 (Nirmatrelvir) 相似的抗 SARS-CoV-2 活性。因此，WU-04 是一种很有前途的冠状病毒治疗候选药物。

更新日期：2023-01-25

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