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High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.

ABSTRACT: The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.

SUBMITTER: Zang Y

PROVIDER: S-EPMC9871955 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.

Zang Yi Y Su Mingbo M Wang Qingxing Q Cheng Xi X Zhang Wenru W Zhao Yao Y Chen Tong T Jiang Yingyan Y Shen Qiang Q Du Juan J Tan Qiuxiang Q Wang Peipei P Gao Lixin L Jin Zhenming Z Zhang Mengmeng M Li Cong C Zhu Ya Y Feng Bo B Tang Bixi B Xie Han H Wang Ming-Wei MW Zheng Mingyue M Pan Xiaoyan X Yang Haitao H Xu Yechun Y Wu Beili B Zhang Leike L Rao Zihe Z Yang Xiuna X Jiang Hualiang H Xiao Gengfu G Zhao Qiang Q Li Jia J

Protein & cell 20220928 1

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l ...[more]

PMID: 36726755

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Project description:BackgroundThe unavoidable propagation of the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has underscored the urgent requirement for efficacious therapeutic agents. The dried fruit of Terminalia chebula Retz., namely Chebulae Fructus, is widely used for treating bacterial and viral infectious diseases, which was witnessed to perform anti-SARS-CoV-2 activity in recommended Chinese patent medicine.AimSARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) present essential effects on SARS-CoV-2 replication and transcription, considering as the attractive targets for therapeutic intervention. In this study, we focused on the dual-target to obtain broad-spectrum antiviral candidates from Chebulae Fructus.MethodsThe identified compounds from Chebulae Fructus were used to build a library in a previous study, which were evaluated by molecular docking to screen potential antiviral agents. The SARS-CoV-2 Mpro and PLpro were expressed in E. coli cells and purified. Fluorescence resonance energy transfer (FRET) and surface plasmon resonance (SPR) were utilized to verify the affinity with dual targets. SARS-CoV-2 wild-type, Omicron BA.5 and Omicron EG.5 variants were employed to validate their antiviral activities in vitro. Molecular dynamics simulation was conducted via Gromacs 2022 software in 500 ns to unveil the conformation stability.ResultsTargeting on Mpro and PLpro, eight compounds were screened as the potential dual-target inhibitors in molecular docking. In FRET and SPR assays, 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) and 1,2,3,6-tetra-O-galloyl-β-D-glucose (TGG) showed good inhibitory activities with IC50 values ranging from 1.33 to 27.37 μM, and affinity with KD values ranging from 0.442 to 0.776 μM. Satisfactorily, both PGG and TGG display antiviral activity in vitro with EC50 values ranging from 3.20 to 37.29 μM, suggesting as the promising candidates against SARS-CoV-2. In molecular dynamics simulation study, the complexes of Mpro-PGG, Mpro-TGG, PLpro-PGG, and PLpro-TGG exhibited stability over 500 ns period, unveiling the potential interactions.ConclusionPGG and TGG are the promising dual-target inhibitors of SARS-CoV-2, which may avoid drug resistance and have a good development prospect. The outcomes of this study provide an effective strategy to systematically explore the antiviral bioactive compounds from Chebulae Fructus.

Dataset Information

High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.

Publications

High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.

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