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Drug Repurposing for the SARS-CoV-2 Papain-Like Protease.

ABSTRACT: As the pathogen of COVID-19, SARS-CoV-2 encodes two essential cysteine proteases that process the pathogen's two large polypeptide products pp1a and pp1ab in the human cell host to form 15 functionally important, mature nonstructural proteins. One of the two enzymes is papain-like protease or PL^Pro . It possesses deubiquitination and deISGylation activities that suppress host innate immune responses toward SARS-CoV-2 infection. To repurpose drugs for PL^Pro , we experimentally screened libraries of 33 deubiquitinase and 37 cysteine protease inhibitors on their inhibition of PL^Pro . Our results showed that 15 deubiquitinase and 1 cysteine protease inhibitors exhibit strong inhibition of PL^Pro at 200 μM. More comprehensive characterizations revealed seven inhibitors GRL0617, SJB2-043, TCID, DUB-IN-1, DUB-IN-3, PR-619, and S130 with an IC₅₀ value below 40 μM and four inhibitors GRL0617, SJB2-043, TCID, and PR-619 with an IC₅₀ value below 10 μM. Among four inhibitors with an IC₅₀ value below 10 μM, SJB2-043 is the most unique in that it does not fully inhibit PL^Pro but has a noteworthy IC₅₀ value of 0.56 μM. SJB2-043 likely binds to an allosteric site of PL^Pro to convene its inhibition effect, which needs to be further investigated. As a pilot study, the current work indicates that COVID-19 drug repurposing by targeting PL^Pro holds promise, but in-depth analysis of repurposed drugs is necessary to avoid omitting critical allosteric inhibitors.

SUBMITTER: Cho CC

PROVIDER: S-EPMC8653067 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Repurposing clinically approved drugs for COVID-19 treatment targeting SARS-CoV-2 papain-like protease.

Project description:COVID-19 is a disease caused by SARS-CoV-2, which has led to more than 4 million deaths worldwide. As a result, there is a worldwide effort to develop specific drugs for targeting COVID-19. Papain-like protease (PLpro) is an attractive drug target because it has multiple essential functions involved in processing viral proteins, including viral genome replication and removal of post-translational ubiquitination modifications. Here, we established two assays for screening PLpro inhibitors according to protease and anti-ISGylation activities, respectively. Application of the two screening techniques to the library of clinically approved drugs led to the discovery of tanshinone IIA sulfonate sodium and chloroxine with their IC50 values of lower than 10 μM. These two compounds were found to directly interact with PLpro and their molecular mechanisms of binding were illustrated by docking and molecular dynamics simulations. The results highlight the usefulness of the two developed screening techniques for locating PLpro inhibitors.

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| S-EPMC8652770 | biostudies-literature

Targeting SARS-CoV-2 Main Protease: A Computational Drug Repurposing Study.

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Repurposing Known Drugs as Covalent and Non-covalent Inhibitors of the SARS-CoV-2 Papain-Like Protease.

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| S-SCDT-EMBOJ-2020-106275 | biostudies-other

Repurposing of FDA-approved antivirals, antibiotics, anthelmintics, antioxidants, and cell protectives against SARS-CoV-2 papain-like protease.

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| S-EPMC7332862 | biostudies-literature

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Computational drug repurposing for the identification of SARS-CoV-2 main protease inhibitors.

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| S-EPMC9538446 | biostudies-literature

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