About: α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment

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About: α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment
Creator	Liu, Hong Hilgenfeld, Rolf Ma, Qingjun Neyts, Johan Kusov, Yuri Leyssen, Pieter Lin, Daizong Snijder, Eric Wang, Jiang De Wilde, Adriaan Von Brunn, Albrecht Lanko, Kristina Nian, Yong Zhang, Linlin
source	Medline; PMC; WHO
abstract	[Image: see text] The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease–inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC(50) values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.
has issue date	2020-02-11(xsd:dateTime)
bibo:doi	10.1021/acs.jmedchem.9b01828
bibo:pmid	32045235
has license	no-cc
sha1sum (hex)	00e945f3938efdc9d46139eedea6284cce579f35
schema:url	https://doi.org/10.1021/acs.jmedchem.9b01828
resource representing a document's title	α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment
has PubMed Central identifier	PMC7098070
has PubMed identifier	32045235
schema:publication	J Med Chem
resource representing a document's body	covid:00e945f3938efdc9d46139eedea6284cce579f35#body_text
is schema:about of	named entity 'SPECTRUM' named entity 'proteases' named entity 'Middle East Respiratory Syndrome coronavirus' named entity 'proteases' named entity 'active-site' named entity 'inhibitors' named entity 'unique' named entity 'viral' named entity 'Synthesis' named entity 'Inhibitors' named entity 'DESIGN' named entity 'ENTEROVIRUSES' named entity '3C PROTEASES' named entity 'TARGETS' named entity 'SUBSTRATE' named entity 'SYNTHESIZED' named entity 'ANTIVIRAL DRUGS' named entity 'ANTIVIRALS' named entity 'PROTEASES' named entity 'PROTEASE' named entity 'VALUES' named entity 'ORDER' named entity 'ENTEROVIRUS' named entity 'STRUCTURES' named entity 'UNIQUE' named entity 'OPTIMIZATION' named entity 'SHARE' named entity 'INHIBITORS' named entity 'BASED' named entity 'EXHIBITS' named entity 'ASSESSMENT' named entity 'ACTIVITY' named entity 'REPLICATION' named entity 'SYNTHESIS' named entity 'STRUCTURE' named entity 'VIRUS-INFECTED CELL' named entity 'TESTED' named entity 'PART OF' named entity 'DESIGN' named entity 'DISPLAY' named entity 'ACTIVITY' named entity 'HUH7' named entity 'SUITABLE' named entity 'DEVELOPMENT' named entity 'AS INHIBITORS' named entity 'BASED' named entity 'OBTAIN' named entity 'CELLS' named entity 'THEIR' named entity 'MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS' named entity 'THESE' named entity 'MAIN' named entity 'PEPTIDOMIMETIC' named entity 'BROAD' named entity 'SPECIFICITY' named entity 'BETACORONAVIRUSES' named entity 'STRUCTURE' named entity 'MOST OF' named entity 'CORONAVIRUS' named entity 'CORONAVIRUSES' named entity 'GLUTAMINE' named entity 'VIRUS' named entity 'INHIBITORS' named entity 'BEST' named entity 'REQUIREMENT' named entity 'COMPLEXES' named entity 'NEAR' named entity 'ARCHITECTURE'

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