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Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses

Since end of 2019, the global and unprecedented outbreak caused by the coronavirus SARS-CoV-2 led to dramatic numbers of infections and deaths worldwide. SARS-CoV-2 produces two large viral polyproteins which are cleaved by two cysteine proteases encoded by the virus, the 3CL protease (3CL(pro)) and...

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Detalles Bibliográficos
Autores principales: Brier, Lucile, Hassan, Haitham, Hanoulle, Xavier, Landry, Valerie, Moschidi, Danai, Desmarets, Lowiese, Rouillé, Yves, Dumont, Julie, Herledan, Adrien, Warenghem, Sandrine, Piveteau, Catherine, Carré, Paul, Ikherbane, Sarah, Cantrelle, François-Xavier, Dupré, Elian, Dubuisson, Jean, Belouzard, Sandrine, Leroux, Florence, Deprez, Benoit, Charton, Julie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Masson SAS. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901219/
https://www.ncbi.nlm.nih.gov/pubmed/36796300
http://dx.doi.org/10.1016/j.ejmech.2023.115186
Descripción
Sumario:Since end of 2019, the global and unprecedented outbreak caused by the coronavirus SARS-CoV-2 led to dramatic numbers of infections and deaths worldwide. SARS-CoV-2 produces two large viral polyproteins which are cleaved by two cysteine proteases encoded by the virus, the 3CL protease (3CL(pro)) and the papain-like protease, to generate non-structural proteins essential for the virus life cycle. Both proteases are recognized as promising drug targets for the development of anti-coronavirus chemotherapy. Aiming at identifying broad spectrum agents for the treatment of COVID-19 but also to fight emergent coronaviruses, we focused on 3CL(pro) that is well conserved within this viral family. Here we present a high-throughput screening of more than 89,000 small molecules that led to the identification of a new chemotype, potent inhibitor of the SARS-CoV-2 3CL(pro). The mechanism of inhibition, the interaction with the protease using NMR and X-Ray, the specificity against host cysteine proteases and promising antiviral properties in cells are reported.