既知の化合物がCOVID-19耐性株に有効な可能性を発見(Old Molecules Show Promise for Fighting Resistant Strains of COVID-19 Virus)

2025-12-08 カリフォルニア大学サンディエゴ校 (UCSD)

Colorized scanning electron micrograph of a cell (blue) infected with SARS-CoV-2 virus particles (pink), isolated from a patient sample. Credit: National Institute of Allergy and Infectious Diseases (NIAID)

<関連情報>

• https://today.ucsd.edu/story/old-molecules-show-promise-for-fighting-resistant-strains-of-covid-19-virus
• https://www.tandfonline.com/doi/full/10.1080/14756366.2025.2585619

システインプロテアーゼ阻害剤の既存コレクションから、コロナウイルスMpro 酵素のベンジルカルバメート阻害剤を発見 Discovery of benzyl carbamate inhibitors of coronavirus Mpro enzymes from a legacy collection of cysteine protease inhibitors

Mateus Sá Magalhães Serafim,Thales Kronenberger,Karol R. Francisco,Erik Vinicius de Sousa Reis,Ellen Gonçalves de Oliveira,Fernanda Kelly Marcelino e Oliveira, …
Journal of Enzyme Inhibition and Medicinal Chemistry  Published:17 Nov 2025
DOI:https://doi.org/10.1080/14756366.2025.2585619

Abstract

The constant emergence of SARS-CoV-2 resistance drives the search for new antivirals. We screened the SARS-CoV-2 cysteine proteases, the main protease (M^pro) and papain-like protease (PL^pro), with 141 peptidyl and peptidomimetic inhibitors designed to target a trypanosome cysteine protease. Five compounds (1a–5a) inhibited M^pro (IC₅₀ of 0.1601–16.42 µM), whereas none inhibited PL^pro. Compounds 1a–4a inhibited human cathepsin L (hCatL; 0.184–10.74 µM), which is important for viral entry into human cells. Compounds 1a and 5a, and its synthesised (R,S) enantiomer, 5b, which share a benzyl carbamate moiety, inhibited the M^pro of SARS-CoV/MERS-CoV (0.0732–0.8295 µM). The three compounds were biochemically characterised as covalent reversible inhibitors. Compounds 5a and 5b, which contain vinyl ketone warheads, were specific for M^pro, and this behaviour was supported by covalent and noncovalent computational simulations. This study highlights the importance of revisiting legacy assets to identify starting points for new antiviral drugs.