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10.1038/s41467-021-23751-3 http://scihub22266oqcxt.onion/10.1038/s41467-021-23751-3 34131140!8206078!34131140     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=34131140&cmd=llinks): Failed to open stream: HTTP request failed! 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Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease |pdf=|usr=}}{{34131140}} gab.com Text Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease JO: Nat Commun http://www.kidney.de/pget.php?&tw=1&pmid=34131140 #FOAvip The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL(pro)) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL(pro). Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CL(pro)s, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands. Twit Text FOAVip Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease ????Nat Commun http://www.kidney.de/pget.php?&tw=1&pmid=34131140 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=34131140 #FOAvip English Wikipedia <ref>{{Cite pmid|34131140}}</ref> Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease #MMPMID34131140 Su H; Yao S; Zhao W; Zhang Y; Liu J; Shao Q; Wang Q; Li M; Xie H; Shang W; Ke C; Feng L; Jiang X; Shen J; Xiao G; Jiang H; Zhang L; Ye Y; Xu Y Nat Commun 2021[Jun]; 12 (1): 3623 PMID34131140show ga The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL(pro)) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL(pro). Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CL(pro)s, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands. |Antiviral Agents/chemistry/pharmacology[MESH] |COVID-19 Drug Treatment[MESH] |Coronavirus 3C Proteases/*drug effects[MESH] |Coronavirus Papain-Like Proteases[MESH] |Drug Design[MESH] |Flavonoids[MESH] |HEK293 Cells[MESH] |Humans[MESH] |Kinetics[MESH] |Ligands[MESH] |Molecular Dynamics Simulation[MESH] |Protease Inhibitors/chemistry/pharmacology[MESH] |Pyrogallol/*chemistry/*isolation & purification/*pharmacology[MESH] |SARS-CoV-2/*drug effects[MESH]Identification of pyrogallol as a warhead in design of covalent inhibi(epmc).pdf DeepDyve Pubget Overpricing