View source for 8okl


==Crystal structure of F2F-2020185-01X bound to the main protease (3CLpro/Mpro) of SARS-CoV-2.==
<StructureSection load='8okl' size='340' side='right'caption='[[8okl]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8okl]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OKL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OKL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=83N:~{tert}-butyl+~{N}-[(2~{S})-1-[(2~{S},4~{S})-4-methoxy-2-[[(2~{S})-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxidanylidene-butan-2-yl]carbamate'>83N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8okl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8okl OCA], [https://pdbe.org/8okl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8okl RCSB], [https://www.ebi.ac.uk/pdbsum/8okl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8okl ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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(pro)) 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 beta-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CL(pro) 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 muM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CL(pro) validating our design. Altogether, these results foster future work toward broad-spectrum 3CL(pro) 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 I, Corona A, Cerchia C, Cassese E, Improta S, Costanzi E, Pelliccia S, Morasso S, Esposito F, Paulis A, Scognamiglio S, Di Leva FS, Storici P, Brindisi M, Tramontano E, Cannalire R, Summa V Eur J Med Chem. 2023 May 5;253:115311. doi: 10.1016/j.ejmech.2023.115311. Epub , 2023 Mar 31. PMID:37043904<ref>PMID:37043904</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8okl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Costanzi E]]
[[Category: Demitri N]]
[[Category: Storici P]]