tetano
Editor, Senior Moderator
Eur J Med Chem
. 2023 Feb 6;250:115186.
doi: 10.1016/j.ejmech.2023.115186. Online ahead of print.
Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses
Lucile Brier[SUP] 1 [/SUP], Haitham Hassan[SUP] 1 [/SUP], Xavier Hanoulle[SUP] 2 [/SUP], Valerie Landry[SUP] 3 [/SUP], Danai Moschidi[SUP] 2 [/SUP], Lowiese Desmarets[SUP] 4 [/SUP], Yves Rouillé[SUP] 4 [/SUP], Julie Dumont[SUP] 3 [/SUP], Adrien Herledan[SUP] 3 [/SUP], Sandrine Warenghem[SUP] 3 [/SUP], Catherine Piveteau[SUP] 1 [/SUP], Paul Carré[SUP] 3 [/SUP], Sarah Ikherbane[SUP] 3 [/SUP], François-Xavier Cantrelle[SUP] 2 [/SUP], Elian Dupré[SUP] 2 [/SUP], Jean Dubuisson[SUP] 4 [/SUP], Sandrine Belouzard[SUP] 4 [/SUP], Florence Leroux[SUP] 5 [/SUP], Benoit Deprez[SUP] 6 [/SUP], Julie Charton[SUP] 7 [/SUP]
Affiliations
Abstract
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[SUP]pro[/SUP]) 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[SUP]pro[/SUP] 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[SUP]pro[/SUP]. 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.
Keywords: 3CL protease Inhibitors; Antiviral; Coronavirus; SARS-CoV-2.
. 2023 Feb 6;250:115186.
doi: 10.1016/j.ejmech.2023.115186. Online ahead of print.
Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses
Lucile Brier[SUP] 1 [/SUP], Haitham Hassan[SUP] 1 [/SUP], Xavier Hanoulle[SUP] 2 [/SUP], Valerie Landry[SUP] 3 [/SUP], Danai Moschidi[SUP] 2 [/SUP], Lowiese Desmarets[SUP] 4 [/SUP], Yves Rouillé[SUP] 4 [/SUP], Julie Dumont[SUP] 3 [/SUP], Adrien Herledan[SUP] 3 [/SUP], Sandrine Warenghem[SUP] 3 [/SUP], Catherine Piveteau[SUP] 1 [/SUP], Paul Carré[SUP] 3 [/SUP], Sarah Ikherbane[SUP] 3 [/SUP], François-Xavier Cantrelle[SUP] 2 [/SUP], Elian Dupré[SUP] 2 [/SUP], Jean Dubuisson[SUP] 4 [/SUP], Sandrine Belouzard[SUP] 4 [/SUP], Florence Leroux[SUP] 5 [/SUP], Benoit Deprez[SUP] 6 [/SUP], Julie Charton[SUP] 7 [/SUP]
Affiliations
- PMID: 36796300
- DOI: 10.1016/j.ejmech.2023.115186
Abstract
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[SUP]pro[/SUP]) 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[SUP]pro[/SUP] 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[SUP]pro[/SUP]. 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.
Keywords: 3CL protease Inhibitors; Antiviral; Coronavirus; SARS-CoV-2.