tetano
Editor, Senior Moderator
Eur J Med Chem
. 2025 Oct 28;302(Pt 1):118277.
doi: 10.1016/j.ejmech.2025.118277. Online ahead of print. A new chemotype that opens the S2∗ pocket of the 3CL protease exhibits antiviral activity against SARS-CoV-2
Laura Mourot[SUP] 1 [/SUP], Fatima-Zahra Chaibi[SUP] 1 [/SUP], Nour Bou-Karroum[SUP] 1 [/SUP], Paul Carré[SUP] 1 [/SUP], Alberto Abengozar Munoz[SUP] 1 [/SUP], Valérie Landry[SUP] 2 [/SUP], Audrey Tarricone[SUP] 3 [/SUP], Alexandre Biela[SUP] 1 [/SUP], Catherine Piveteau[SUP] 1 [/SUP], Gleb Novikov[SUP] 1 [/SUP], Elian Dupré[SUP] 4 [/SUP], Jean Dubuisson[SUP] 5 [/SUP], Sandrine Belouzard[SUP] 3 [/SUP], Florence Leroux[SUP] 6 [/SUP], Benoit Deprez[SUP] 7 [/SUP], Xavier Hanoulle[SUP] 4 [/SUP], Julie Charton[SUP] 8 [/SUP]
Affiliations
Coronaviruses have caused 3 pandemics in the past 2 decades. The SARS-CoV-2, the causative agent of the COVID-19 already led to more than 7 million deaths worldwide. The 3CL protease (3CL[SUP]pro[/SUP], M[SUP]pro[/SUP]) plays a key role in the replication of the SARS-CoV-2 and has been validated as promising therapeutic target as evidenced by the recent clinical use of anti-coronavirus drugs inhibitors of this protease. In addition, its high conservation among coronaviruses gives an opportunity to identify broad-spectrum anti-coronavirus compounds to combat not only SARS-CoV-2 but also emerging coronaviruses. Here we report our efforts to optimize a small non-covalent inhibitor (F01) identified by an NMR-based screening, which resulted in a 40-fold potency improvement in 3CL[SUP]pro[/SUP] inhibition with the low micromolar inhibitor 55. This compound displayed a promising antiviral activity in cells without cytotoxicity. In addition, it was shown to inhibit the 3CL[SUP]pro[/SUP] of SARS-CoV-1 and displayed high selectivity towards host cysteine proteases such as cathepsins L and K and calpain. The binding mode of a closed analog (57) was elucidated by X-ray structure with the protease and revealed the compound opens and fills a new pocket (S2∗) untargeted by others inhibitors. This original structural feature along with the promising preliminary results obtained for this new chemotype deserve future optimization to further improve potency and pharmacokinetics properties of this series.
Keywords: 3CL(pro); Non-covalent inhibitors; SARS-CoV-2.
. 2025 Oct 28;302(Pt 1):118277.
doi: 10.1016/j.ejmech.2025.118277. Online ahead of print. A new chemotype that opens the S2∗ pocket of the 3CL protease exhibits antiviral activity against SARS-CoV-2
Laura Mourot[SUP] 1 [/SUP], Fatima-Zahra Chaibi[SUP] 1 [/SUP], Nour Bou-Karroum[SUP] 1 [/SUP], Paul Carré[SUP] 1 [/SUP], Alberto Abengozar Munoz[SUP] 1 [/SUP], Valérie Landry[SUP] 2 [/SUP], Audrey Tarricone[SUP] 3 [/SUP], Alexandre Biela[SUP] 1 [/SUP], Catherine Piveteau[SUP] 1 [/SUP], Gleb Novikov[SUP] 1 [/SUP], Elian Dupré[SUP] 4 [/SUP], Jean Dubuisson[SUP] 5 [/SUP], Sandrine Belouzard[SUP] 3 [/SUP], Florence Leroux[SUP] 6 [/SUP], Benoit Deprez[SUP] 7 [/SUP], Xavier Hanoulle[SUP] 4 [/SUP], Julie Charton[SUP] 8 [/SUP]
Affiliations
- PMID: 41166766
- DOI: 10.1016/j.ejmech.2025.118277
Coronaviruses have caused 3 pandemics in the past 2 decades. The SARS-CoV-2, the causative agent of the COVID-19 already led to more than 7 million deaths worldwide. The 3CL protease (3CL[SUP]pro[/SUP], M[SUP]pro[/SUP]) plays a key role in the replication of the SARS-CoV-2 and has been validated as promising therapeutic target as evidenced by the recent clinical use of anti-coronavirus drugs inhibitors of this protease. In addition, its high conservation among coronaviruses gives an opportunity to identify broad-spectrum anti-coronavirus compounds to combat not only SARS-CoV-2 but also emerging coronaviruses. Here we report our efforts to optimize a small non-covalent inhibitor (F01) identified by an NMR-based screening, which resulted in a 40-fold potency improvement in 3CL[SUP]pro[/SUP] inhibition with the low micromolar inhibitor 55. This compound displayed a promising antiviral activity in cells without cytotoxicity. In addition, it was shown to inhibit the 3CL[SUP]pro[/SUP] of SARS-CoV-1 and displayed high selectivity towards host cysteine proteases such as cathepsins L and K and calpain. The binding mode of a closed analog (57) was elucidated by X-ray structure with the protease and revealed the compound opens and fills a new pocket (S2∗) untargeted by others inhibitors. This original structural feature along with the promising preliminary results obtained for this new chemotype deserve future optimization to further improve potency and pharmacokinetics properties of this series.
Keywords: 3CL(pro); Non-covalent inhibitors; SARS-CoV-2.