PXD035400-2

PXD035400 is an original dataset announced via ProteomeXchange.

Title	Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain
Description	The NAD hydrolase (NADase) SARM1 acts as a central executioner of programmed axon death and is a possible therapeutic target for neurodegenerative disorders. While orthosteric inhibitors of SARM1 have been described, this multi-domain enzyme is also subject to intricate forms of autoregulation, suggesting the potential for allosteric modes of inhibition. Previous studies have identified multiple cysteine residues that support SARM1 activation and catalysis, but which of these cysteines, if any, might be selectively targetable by electrophilic small molecules remains unknown. Here we describe the chemical proteomic discovery of a series of tryptoline acrylamides that site-specifically and stereoselectively modify cysteine-311 (C311) in the non-catalytic, autoregulatory armadillo repeat (ARM) domain of SARM1. These covalent compounds inhibit the NADase activity of WT-SARM1, but not C311A or C311S SARM1 mutants, show a high degree of proteome-wide selectivity for SARM1_C311, and stereoselectively block vincristine- and vacor-induced neurite degeneration in primary rodent dorsal root ganglion neurons. Our findings describe selective, covalent inhibitors of SARM1 targeting an allosteric cysteine, pointing to a potentially attractive therapeutic strategy for axon degeneration-dependent forms of neurological disease.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:57:09.613.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hannah Feldman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-20 00:13:18	ID requested
1	2022-08-22 14:36:29	announced
⏵ 2	2023-11-14 08:57:09	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: Covalent, chemical proteomics, allosteric inhibition, axonopathy, neurodegeneration

Benjamin F. Cravatt
contact affiliation	Department of Chemistry, Scripps Research
contact email	cravatt@scripps.edu
lab head
Hannah Feldman
contact affiliation	Postdoctoral Fellow
contact email	hfeldman@scripps.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035400
     1. Label: PRIDE project
     2. Name: Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain