View source for 9vs1


==Crystal structure of SARS-CoV-2 3CL protease in complex with compound 15==
<StructureSection load='9vs1' size='340' side='right'caption='[[9vs1]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9vs1]] 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=9VS1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9VS1 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]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1MA2:4-chloranyl-3-[6-methyl-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-2,4,5-tris(oxidanylidene)-1-[[3,4,5-tris(fluoranyl)phenyl]methyl]pyrido[4,3-d]pyrimidin-7-yl]benzenecarbonitrile'>A1MA2</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=9vs1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9vs1 OCA], [https://pdbe.org/9vs1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9vs1 RCSB], [https://www.ebi.ac.uk/pdbsum/9vs1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9vs1 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 ==
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has spread around the world since 2020, affecting many people and placing a heavy burden on medical facilities and the economy. The 3C-like protease (3CL(pro)) of SARS-CoV-2 is an essential enzyme for viral replication, and has been therefore attracting attention as a drug target. With the aim of creating novel non-covalent 3CL(pro) inhibitors, we planned a scaffold hopping transformation starting with ensitrelvir, which was discovered by Shionogi. Optimization of the substituents at the 5- and 7-positions of the newly designed quinazolinedione scaffold led to the discovery of compound 16, which exceeds ensitrelvir in enzyme inhibitory and antiviral activities. We solved the X-ray co-crystal structure of our synthesized inhibitor and 3CL(pro), and clarified the interaction that contributes to its high activity. The newly discovered compound has shown good results in terms of metabolic stability and oral absorption in rat PK studies. It is expected to be a good lead compound for finding superior 3CL(pro) inhibitors.

Design, synthesis and biological evaluation of novel quinazolinedione derivatives as non-covalent SARS-CoV-2 3CL protease inhibitors.,Taoda Y, Hori A, Tadano G, Sugiyama S, Masakado S, Tanaka S, Ogasahara R, Nakahara K, Maeno S, Unoh Y, Tachibana Y, Uehara S, Sako Y, Yamamoto S, Kawashima S, Nobori H, Kato T Bioorg Med Chem Lett. 2025 Dec 15;129:130400. doi: 10.1016/j.bmcl.2025.130400. , Epub 2025 Sep 10. PMID:40939708<ref>PMID:40939708</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9vs1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Taoda Y]]
[[Category: Yamamoto S]]