View source for 8wti


==Crystal structure of the SARS-CoV-2 main protease in complex with 20j==
<StructureSection load='8wti' size='340' side='right'caption='[[8wti]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8wti]] 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=8WTI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8WTI 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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8wti FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8wti OCA], [https://pdbe.org/8wti PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8wti RCSB], [https://www.ebi.ac.uk/pdbsum/8wti PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8wti ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/R1A_SARS2 R1A_SARS2] Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7]  Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.[UniProtKB:P0C6X7]  May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[UniProtKB:P0C6X7]  Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7]  Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7]  Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7]  Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7]  Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7]  Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7]  May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7]  Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[UniProtKB:P0C6X7]
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== Publication Abstract from PubMed ==
Although the SARS-CoV-2 pandemic has ended, multiple sporadic cases still exist, posing a request for more antivirals. The main protease (M(pro)) of SARS-CoV-2, a key enzyme for viral replication, is an attractive target for drug development. Here, we report the discovery of a new potent alpha-ketoamide-containing M(pro) inhibitor, N-((R)-1-cyclohexyl-2-(((R)-3-methoxy-1-oxo-1-((1-(2-oxo-2-((thiazol-2-ylmethyl)amino)acetyl)cyclobutyl)amino)propan-2-yl)amino)-2-oxoethyl)-4,4-difluorocyclohexane-1-carboxamide (20j). This compound presented promising enzymatic inhibitory activity against SARS-CoV-2 M(pro) with an IC(50) value of 19.0 nM, and an excellent antiviral activity in cell-based assay with an EC(50) value of 138.1 nM. This novel covalent inhibitor may be used as a lead compound for subsequent drug discovery against SARS-CoV-2.

Discovery of alpha-Ketoamide inhibitors of SARS-CoV-2 main protease derived from quaternized P1 groups.,Huang Q, Quan B, Chen Y, Zhao X, Zhou Y, Huang C, Qiao J, Wang Y, Li Y, Yang S, Lei J, Li L Bioorg Chem. 2024 Feb;143:107001. doi: 10.1016/j.bioorg.2023.107001. Epub 2023 , Dec 6. PMID:38101266<ref>PMID:38101266</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Lei J]]
[[Category: Yang SY]]
[[Category: Zeng R]]
[[Category: Zhao X]]