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| | <table><tr><td colspan='2'>[[7sh7]] is a 1 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=7SH7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SH7 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[7sh7]] is a 1 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=7SH7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SH7 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]] 1.85Å</td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> |
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9GI:benzyl+[(2S,3R)-3-tert-butoxy-1-{[(2S)-3-cyclohexyl-1-oxo-1-(2-{[(3S)-2-oxopyrrolidin-3-yl]methyl}-2-propanoylhydrazinyl)propan-2-yl]amino}-1-oxobutan-2-yl]carbamate+(non-preferred+name)'>9GI</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9GI:(phenylmethyl)+~{N}-[(2~{S},3~{R})-1-[[(2~{S})-3-cyclohexyl-1-oxidanylidene-1-[2-[[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]methyl]-2-propanoyl-hydrazinyl]propan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxidanylidene-butan-2-yl]carbamate'>9GI</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</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=7sh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sh7 OCA], [https://pdbe.org/7sh7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sh7 RCSB], [https://www.ebi.ac.uk/pdbsum/7sh7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sh7 ProSAT]</span></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=7sh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sh7 OCA], [https://pdbe.org/7sh7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sh7 RCSB], [https://www.ebi.ac.uk/pdbsum/7sh7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sh7 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Function == | + | <div style="background-color:#fffaf0;"> |
| - | [https://www.uniprot.org/uniprot/R1AB_SARS2 R1AB_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] (PubMed:32198291). Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7]<ref>PMID:32198291</ref> 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] Responsible for replication and transcription of the viral RNA genome.[UniProtKB:P0C6X7] Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.[UniProtKB:P0C6X7] Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens.[UniProtKB:P0C6X7] Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.[UniProtKB:P0C6X7] Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system.[UniProtKB:P0C6X7]
| + | == Publication Abstract from PubMed == |
| | + | Main protease (M (Pro) ) of SARS-CoV-2, the viral pathogen of COVID-19, is a crucial nonstructural protein that plays a vital role in the replication and pathogenesis of the virus. Its protease function relies on three active site pockets to recognize P1, P2, and P4 amino acid residues in a substrate and a catalytic cysteine residue for catalysis. By converting the P1 Calpha atom in an M (Pro) substrate to nitrogen, we showed that a large variety of azapeptide inhibitors with covalent warheads targeting the M (Pro) catalytic cysteine could be easily synthesized. Through the characterization of these inhibitors, we identified several highly potent M (Pro) inhibitors. Specifically, one inhibitor, MPI89 that contained an aza-2,2-dichloroacetyl warhead, displayed a 10 nM EC (50) value in inhibiting SARS-CoV-2 from infecting ACE2 (+) A549 cells and a selectivity index of 875. The crystallography analyses of M (Pro) bound with 6 inhibitors, including MPI89, revealed that inhibitors used their covalent warheads to covalently engage the catalytic cysteine and the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 represents one of the most potent M (Pro) inhibitors developed so far, suggesting that further exploration of the azapeptide platform and the aza-2,2-dichloroacetyl warhead is needed for the development of potent inhibitors for the SARS-CoV-2 M (Pro) as therapeutics for COVID-19. |
| | + | |
| | + | An Azapeptide Platform in Conjunction with Covalent Warheads to Uncover High-Potency Inhibitors for SARS-CoV-2 Main Protease.,Khatua K, Alugubelli YR, Yang KS, Vulupala VR, Blankenship LR, Coleman DD, Atla S, Chaki SP, Geng ZZ, Ma XR, Xiao J, Chen PC, Cho CD, Vatansever EC, Ma Y, Yu G, Neuman BW, Xu S, Liu WR bioRxiv [Preprint]. 2023 Apr 12:2023.04.11.536467. doi: , 10.1101/2023.04.11.536467. PMID:37090597<ref>PMID:37090597</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 7sh7" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Structural highlights
Publication Abstract from PubMed
Main protease (M (Pro) ) of SARS-CoV-2, the viral pathogen of COVID-19, is a crucial nonstructural protein that plays a vital role in the replication and pathogenesis of the virus. Its protease function relies on three active site pockets to recognize P1, P2, and P4 amino acid residues in a substrate and a catalytic cysteine residue for catalysis. By converting the P1 Calpha atom in an M (Pro) substrate to nitrogen, we showed that a large variety of azapeptide inhibitors with covalent warheads targeting the M (Pro) catalytic cysteine could be easily synthesized. Through the characterization of these inhibitors, we identified several highly potent M (Pro) inhibitors. Specifically, one inhibitor, MPI89 that contained an aza-2,2-dichloroacetyl warhead, displayed a 10 nM EC (50) value in inhibiting SARS-CoV-2 from infecting ACE2 (+) A549 cells and a selectivity index of 875. The crystallography analyses of M (Pro) bound with 6 inhibitors, including MPI89, revealed that inhibitors used their covalent warheads to covalently engage the catalytic cysteine and the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 represents one of the most potent M (Pro) inhibitors developed so far, suggesting that further exploration of the azapeptide platform and the aza-2,2-dichloroacetyl warhead is needed for the development of potent inhibitors for the SARS-CoV-2 M (Pro) as therapeutics for COVID-19.
An Azapeptide Platform in Conjunction with Covalent Warheads to Uncover High-Potency Inhibitors for SARS-CoV-2 Main Protease.,Khatua K, Alugubelli YR, Yang KS, Vulupala VR, Blankenship LR, Coleman DD, Atla S, Chaki SP, Geng ZZ, Ma XR, Xiao J, Chen PC, Cho CD, Vatansever EC, Ma Y, Yu G, Neuman BW, Xu S, Liu WR bioRxiv [Preprint]. 2023 Apr 12:2023.04.11.536467. doi: , 10.1101/2023.04.11.536467. PMID:37090597[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Khatua K, Alugubelli YR, Yang KS, Vulupala VR, Blankenship LR, Coleman DD, Atla S, Chaki SP, Geng ZZ, Ma XR, Xiao J, Chen PC, Cho CD, Vatansever EC, Ma Y, Yu G, Neuman BW, Xu S, Liu WR. An Azapeptide Platform in Conjunction with Covalent Warheads to Uncover High-Potency Inhibitors for SARS-CoV-2 Main Protease. bioRxiv [Preprint]. 2023 Apr 12:2023.04.11.536467. PMID:37090597 doi:10.1101/2023.04.11.536467
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