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Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CL^pro.

ABSTRACT: The emerging SARS-CoV-2 infection is the cause of the global COVID-19 pandemic. To date, there are limited therapeutic options available to fight this disease. Here we examined the inhibitory abilities of two broad-spectrum antiviral natural products chebulagic acid (CHLA) and punicalagin (PUG) against SARS-CoV-2 viral replication. Both CHLA and PUG reduced virus-induced plaque formation in Vero-E6 monolayer at noncytotoxic concentrations, by targeting the enzymatic activity of viral 3-chymotrypsin-like cysteine protease (3CL^pro) as allosteric regulators. Our study demonstrates the potential use of CHLA and PUG as novel COVID-19 therapies.

SUBMITTER: Du R

PROVIDER: S-EPMC8052511 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CL<sup>pro</sup>.

Du Ruikun R Cooper Laura L Chen Zinuo Z Lee Hyun H Rong Lijun L Cui Qinghua Q

Antiviral research 20210417

The emerging SARS-CoV-2 infection is the cause of the global COVID-19 pandemic. To date, there are limited therapeutic options available to fight this disease. Here we examined the inhibitory abilities of two broad-spectrum antiviral natural products chebulagic acid (CHLA) and punicalagin (PUG) against SARS-CoV-2 viral replication. Both CHLA and PUG reduced virus-induced plaque formation in Vero-E6 monolayer at noncytotoxic concentrations, by targeting the enzymatic activity of viral 3-chymotryp ...[more]

PMID: 33872675

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Project description:BackgroundThe 3C-like proteases (3CLpros) are cysteine-rich homodimeric proteins and can be covalently modified by numerous natural and synthetic compounds, which in turn, block the proteolytic activity or the formation of enzymatically active dimeric forms. Although herbal medicines have been widely used to treat COVID-19, identification of the key herbal constituents that can covalently modify the 3CLpros in β-coronaviruses (CoVs) remains a big challenge.AimsTo construct a comprehensive approach for efficient discovering the covalent SARS-CoV-2 3CLpro inhibitors from herbal medicines. To decipher the key anti-SARS-CoV-2 3CLpro constituents in Ginkgo biloba extract 50 (GBE50) and to study their anti-SARS-CoV-2 3CLpro mechanisms.MethodsSARS-CoV-2 3CLpro inhibition assay including time-dependent inhibition assays and inactivation kinetic analyses were conducted using a fluorescence-based biochemical assay. The constituents in GBE50 were analyzed by UHPLC-Q-Exactive Orbitrap HRMS. The peptides modified by herbal constituents were characterized by using nanoLC-MS/MS.ResultsFollowing testing the anti-SARS-CoV-2 3CLpro effects of 104 herbal medicines, it was found that Ginkgo biloba extract 50 (GBE50) potently inhibited SARS-CoV-2 3CLpro in dose- and time-dependent manners. A total of 38 constituents were identified from GBE50 by UHPLC-Q-Exactive Orbitrap HRMS, while 26 peptides modified by 18 constituents were identified by chemoproteomic profiling. The anti-SARS-CoV-2 3CLpro effects of 18 identified covalent inhibitors were then validated by performing time-dependent inhibition assays. The results clearly demonstrated that most tested constituents showed time-dependent inhibition on SARS-CoV-2 3CLpro, while gallocatechin and sciadopitysin displayed the most potent anti-SARS-CoV-2 3CLpro effects.ConclusionCollectively, GBE50 and some constituents in this herbal product could strongly inhibit SARS-CoV-2 3CLpro in dose- and time-dependent manner. Gallocatechin and sciadopitysin were identified as potent SARS-CoV-2 3CLpro inhibitors, which offers promising lead compounds for the development of novel anti-SARS-CoV-2 drugs.

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Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CL^pro.

Publications

Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CL<sup>pro</sup>.

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Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro.

Publications

Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CL<sup>pro</sup>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CL^pro.