SARS-CoV-2 Mpro inhibitor identification using a cellular gain-of-signal assay for high-throughput screening

SLAS DISCOVERY, Год журнала: 2024, Номер 29(6), С. 100181 - 100181

Опубликована: Авг. 23, 2024

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2, SARS2) is responsible for the COVID-19 pandemic and infections that continue to affect lives of millions people worldwide, especially those who are older and/or immunocompromised. The SARS2 main protease enzyme, Mpro (also called 3C-like protease, 3CLpro), a bona fide drug target as evidenced by potent inhibition with nirmatrelvir ensitrelvir, active components drugs Paxlovid Xocova, respectively. However, existence ensitrelvir-resistant isolates underscores need develop next-generation different resistance profiles distinct mechanisms action. Here, we report results high-throughput screen 649,568 compounds using cellular gain-of-signal assay. In this assay, inhibits expression luciferase reporter, 8,777 small molecules were considered hits causing gain in activity 3x SD above sample field (6.8% relative 100 µM GC376). Single concentration dose-response experiments confirmed 3,522/8,762 candidate inhibitors. parallel, all initial screening tested peptide cleavage assay purified only 39/8,762 showed inhibition. Importantly, 19/39 (49%) re-tested positive both assays, including two previously reported inhibitors, demonstrating efficacy overall strategy. This approach led rediscovery known inhibitors such calpain inhibitor II, well discovery novel provide chemical information future development efforts.

Язык: Английский

ACVPICPred: inhibitory activity prediction of anti-coronavirus peptides based on artificial neural network

Computational and Structural Biotechnology Journal, Год журнала: 2024, Номер 23, С. 3625 - 3633

Опубликована: Окт. 2, 2024

Язык: Английский