About: Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against M(pro) and cathepsin L

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About: Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against M(pro) and cathepsin L Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against M(pro) and cathepsin L
Creator	Chen, Yu Wang, Jun Ma, Chunlong Zhang, Xiujun Tarbet, Bart Hurst, Brett Meng, Xiangzhi Xiang, Yan Hu, Yanmei Marty, Michael Sacco, Michael Townsend, Julia Dube, Peter Gao, Ang Kitamura, Naoya Kolocouris, Antonios Lagarias, Panagiotis
Source	BioRxiv; Medline; PMC
abstract	The main protease (M(pro)) of SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic, is a key antiviral drug target. While most SARS-CoV-2 M(pro) inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently discovered several M(pro) inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II/XII, which are also active against human cathepsin L, a host-protease that is important for viral entry. To determine the binding mode of these calpain inhibitors and establish a structure-activity relationship, we solved X-ray crystal structures of M(pro) in complex with calpain inhibitors II and XII, and three analogues of GC-376, one of the most potent M(pro) inhibitors in vitro. The structure of M(pro) with calpain inhibitor II confirmed the S1 pocket of M(pro) can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. Interestingly, the structure of calpain inhibitor XII revealed an unexpected, inverted binding pose where the P1’ pyridine inserts in the S1 pocket and the P1 norvaline is positioned in the S1’ pocket. The overall conformation is semi-helical, wrapping around the catalytic core, in contrast to the extended conformation of other peptidomimetic inhibitors. Additionally, the structures of three GC-376 analogues UAWJ246, UAWJ247, and UAWJ248 provide insight to the sidechain preference of the S1’, S2, S3 and S4 pockets, and the superior cell-based activity of the aldehyde warhead compared with the α-ketoamide. Taken together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of M(pro) inhibitors as SARS-CoV-2 antivirals.
has issue date	2020-07-27(xsd:dateTime)
bibo:doi	10.1101/2020.07.27.223727
bibo:pmid	32766590
has license	cc-by-nc
sha1sum (hex)	b16d6bf1200f59e47816941d773bbac14abddc28
schema:url	https://doi.org/10.1101/2020.07.27.223727
resource representing a document's title	Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against M(pro) and cathepsin L
has PubMed Central identifier	PMC7402059
has PubMed identifier	32766590
schema:publication	bioRxiv
resource representing a document's body	covid:b16d6bf1200f59e47816941d773bbac14abddc28#body_text
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