About: Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease

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About: Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
Creator	Chen, Yu Wang, Jun Ma, Chunlong Zhang, Xiujun Tarbet, Bart Hurst, Brett Hu, Yanmei Marty, Michael Sacco, Michael Szeto, Tommy Townsend, Julia
Source	Medline; PMC
abstract	A new coronavirus SARS-CoV-2, also called novel coronavirus 2019 (2019-nCoV), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.35% as of May 26, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (M(pro)). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC(50) values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC(50) values ranging from 0.49 to 3.37 µM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known substrate-based peptidomimetic M(pro) inhibitors. A complex crystal structure of SARS-CoV-2 M(pro) with GC-376, determined at 2.15 Å resolution with three protomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by M(pro). Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.
has issue date	2020-06-15(xsd:dateTime)
bibo:doi	10.1038/s41422-020-0356-z
bibo:pmid	32541865
has license	no-cc
sha1sum (hex)	84f4ba9567dc9b3d8e9bec5d9918da1826c5424e
schema:url	https://doi.org/10.1038/s41422-020-0356-z
resource representing a document's title	Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
has PubMed Central identifier	PMC7294525
has PubMed identifier	32541865
schema:publication	Cell Res
resource representing a document's body	covid:84f4ba9567dc9b3d8e9bec5d9918da1826c5424e#body_text
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