银杏酸和漆树酸是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）半胱氨酸蛋白酶的特异性共价抑制剂。

Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases.

作者信息

Chen Zinuo, Cui Qinghua, Cooper Laura, Zhang Pin, Lee Hyun, Chen Zhaoyu, Wang Yanyan, Liu Xiaoyun, Rong Lijun, Du Ruikun

机构信息

College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.

Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.

出版信息

Cell Biosci. 2021 Feb 28;11(1):45. doi: 10.1186/s13578-021-00564-x.

BACKGROUND

In the urgent campaign to develop therapeutics against SARS-CoV-2, natural products have been an important source of new lead compounds.

RESULTS

We herein identified two natural products, ginkgolic acid and anacardic acid, as inhibitors using a high-throughput screen targeting the SARS-CoV-2 papain-like protease (PL). Moreover, our study demonstrated that the two hit compounds are dual inhibitors targeting the SARS-CoV-2 3-chymotrypsin-like protease (3CL) in addition to PL. A mechanism of action study using enzyme kinetics further characterized the two compounds as irreversible inhibitors against both 3CL and PL. Significantly, both identified compounds inhibit SARS-CoV-2 replication in vitro at nontoxic concentrations.

CONCLUSIONS

Our finding provides two novel natural products as promising SARS-CoV-2 antivirals.

背景

在开发针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）治疗方法的紧急行动中，天然产物一直是新先导化合物的重要来源。

结果

我们在此通过针对SARS-CoV-2木瓜样蛋白酶（PL）的高通量筛选，鉴定出两种天然产物——银杏酸和腰果酚酸为抑制剂。此外，我们的研究表明，这两种命中化合物除了靶向PL外，还是靶向SARS-CoV-2 3-糜蛋白酶样蛋白酶（3CL）的双重抑制剂。利用酶动力学进行的作用机制研究进一步将这两种化合物表征为针对3CL和PL的不可逆抑制剂。值得注意的是，两种鉴定出的化合物在无毒浓度下均可抑制SARS-CoV-2在体外的复制。