8OKL

Crystal structure of F2F-2020185-01X bound to the main protease (3CLpro/Mpro) of SARS-CoV-2.

Summary for 8OKL

• Entry DOI: 10.2210/pdb8okl/pdb
• Descriptor: 3C-like proteinase nsp5, tert-butyl-N-[(2S)-1-[(2S,4S)-4-methoxy-2-[[(2S)-1-oxidanyl-3-[(3S)-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxidanylidene-butan-2-yl]carbamate, 1,2-ETHANEDIOL, ... (8 entities in total)
• Functional Keywords: sars-cov-2, mpro, 3clpro, exscalate4cov, drug discovery, elettra, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 69009.44

Authors

Costanzi, E.,Demitri, N.,Storici, P. (deposition date: 2023-03-28, release date: 2023-05-03, Last modification date: 2024-10-09)

Primary citation

Stefanelli, I.,Corona, A.,Cerchia, C.,Cassese, E.,Improta, S.,Costanzi, E.,Pelliccia, S.,Morasso, S.,Esposito, F.,Paulis, A.,Scognamiglio, S.,Di Leva, F.S.,Storici, P.,Brindisi, M.,Tramontano, E.,Cannalire, R.,Summa, V.
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.
Eur.J.Med.Chem., 253:115311-115311, 2023

PubMed 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 (3CL) 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 3CL 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 3CL validating our design. Altogether, these results foster future work toward broad-spectrum 3CL inhibitors to challenge CoVs related pandemics.

PubMed: 37043904
DOI: 10.1016/j.ejmech.2023.115311

Experimental method

X-RAY DIFFRACTION (1.5 Å)