PXD056098-1

PXD056098 is an original dataset announced via ProteomeXchange.

Title	Expedited SARS-CoV-2 MPro inhibitor discovery through a modular, 'direct-to-biology' approach
Description	Reactive fragment (RF) screening has emerged as an efficient method for ligand discovery across the proteome, irrespective of a target’s perceived tractability. To date, however, the efficiency of subsequent optimisation campaigns has largely been low-throughput, constrained by the need for synthesis and purification of target compounds. We report a high-throughput platform for ‘direct-to-biology’ (D2B) screening of cysteine-targeting chloroacetamide RFs, wherein synthesis is performed in 384-well plates allowing direct assessment in downstream biological assays without purification. Here, the developed platform was used to optimise inhibitors of SARS-CoV-2 main protease (MPro), an established drug target for the treatment of COVID-19. An initial RF hit was developed into a series of potent inhibitors, and further exploration using D2B screening enabled a ‘switch’ to a reversible inhibitor series. This example of ligand discovery for MPro illustrates the acceleration that D2B chemistry can offer for optimising RFs towards covalent inhibitor candidates, as well as providing future impetus to explore the evolution of RFs into non-covalent ligands.
HostingRepository	PRIDE
AnnounceDate	2024-12-20
AnnouncementXML	Submission_2024-12-20_06:52:42.569.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Harry Wilders
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	biotinylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-23 08:40:08	ID requested
⏵ 1	2024-12-20 06:52:42	announced

10.1002/ANIE.202418314;

submitter keyword: Covalent Drug Discovery, Chemoproteomics,SARS-CoV-2 MPro

Jacob Theodore Bush
contact affiliation	Chemical Biology, GSK, UK
contact email	jacob.x.bush@gsk.com
lab head
Harry Wilders
contact affiliation	GSK The Francis Crick Institute
contact email	harry.x.wilders@gsk.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/12/PXD056098

PRIDE project URI

• PRIDE
  1. PXD056098
     1. Label: PRIDE project
     2. Name: Expedited SARS-CoV-2 MPro inhibitor discovery through a modular, 'direct-to-biology' approach