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| | <table><tr><td colspan='2'>[[8fy6]] 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=8FY6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FY6 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[8fy6]] 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=8FY6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FY6 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]] 2Å</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]] 2Å</td></tr> |
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OW1:Nirmatrelvir+(reacted+form)'>OW1</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YVZ:(1R,2S,5S)-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-N-{(2R)-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide'>YVZ</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=8fy6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fy6 OCA], [https://pdbe.org/8fy6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fy6 RCSB], [https://www.ebi.ac.uk/pdbsum/8fy6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fy6 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=8fy6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fy6 OCA], [https://pdbe.org/8fy6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fy6 RCSB], [https://www.ebi.ac.uk/pdbsum/8fy6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fy6 ProSAT]</span></td></tr> |
| | </table> | | </table> |
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| | There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease M(pro) plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of M(pro). By comparing the efficacy of a panel of warheads installed on a common scaffold against M(pro), we discovered that the terminal alkyne could covalently modify M(pro) as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of M(pro). Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond. | | There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease M(pro) plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of M(pro). By comparing the efficacy of a panel of warheads installed on a common scaffold against M(pro), we discovered that the terminal alkyne could covalently modify M(pro) as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of M(pro). Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond. |
| | | | |
| - | Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.,Ngo C, Fried W, Aliyari S, Feng J, Qin C, Zhang S, Yang H, Shanaa J, Feng P, Cheng G, Chen XS, Zhang C J Med Chem. 2023 Aug 18. doi: 10.1021/acs.jmedchem.3c00810. PMID:37595260<ref>PMID:37595260</ref> | + | Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.,Ngo C, Fried W, Aliyari S, Feng J, Qin C, Zhang S, Yang H, Shanaa J, Feng P, Cheng G, Chen XS, Zhang C J Med Chem. 2023 Sep 14;66(17):12237-12248. doi: 10.1021/acs.jmedchem.3c00810. , Epub 2023 Aug 18. PMID:37595260<ref>PMID:37595260</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| Structural highlights
Function
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][1] 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
There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease M(pro) plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of M(pro). By comparing the efficacy of a panel of warheads installed on a common scaffold against M(pro), we discovered that the terminal alkyne could covalently modify M(pro) as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of M(pro). Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond.
Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.,Ngo C, Fried W, Aliyari S, Feng J, Qin C, Zhang S, Yang H, Shanaa J, Feng P, Cheng G, Chen XS, Zhang C J Med Chem. 2023 Sep 14;66(17):12237-12248. doi: 10.1021/acs.jmedchem.3c00810. , Epub 2023 Aug 18. PMID:37595260[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors. Science. 2020 Mar 20. pii: science.abb3405. doi: 10.1126/science.abb3405. PMID:32198291 doi:http://dx.doi.org/10.1126/science.abb3405
- ↑ Ngo C, Fried W, Aliyari S, Feng J, Qin C, Zhang S, Yang H, Shanaa J, Feng P, Cheng G, Chen XS, Zhang C. Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease. J Med Chem. 2023 Aug 18. PMID:37595260 doi:10.1021/acs.jmedchem.3c00810
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