: Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the β-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low μM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics.

Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination / Stefanelli, Irina; Corona, Angela; Cerchia, Carmen; Cassese, Emilia; Improta, Salvatore; Costanzi, Elisa; Pelliccia, Sveva; Morasso, Stefano; Esposito, Francesca; Paulis, Annalaura; Scognamiglio, Sante; Di Leva, Francesco Saverio; Storici, Paola; Brindisi, Margherita; Tramontano, Enzo; Cannalire, Rolando; Summa, Vincenzo. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1768-3254. - 253:(2023), p. 115311. [10.1016/j.ejmech.2023.115311]

Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination

Stefanelli, Irina;Cerchia, Carmen;Cassese, Emilia;Improta, Salvatore;Pelliccia, Sveva;Di Leva, Francesco Saverio;Brindisi, Margherita;Cannalire, Rolando
;
Summa, Vincenzo
2023

Abstract

: Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the β-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low μM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics.
2023
Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination / Stefanelli, Irina; Corona, Angela; Cerchia, Carmen; Cassese, Emilia; Improta, Salvatore; Costanzi, Elisa; Pelliccia, Sveva; Morasso, Stefano; Esposito, Francesca; Paulis, Annalaura; Scognamiglio, Sante; Di Leva, Francesco Saverio; Storici, Paola; Brindisi, Margherita; Tramontano, Enzo; Cannalire, Rolando; Summa, Vincenzo. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1768-3254. - 253:(2023), p. 115311. [10.1016/j.ejmech.2023.115311]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/919824
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