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UMass Chan Affiliations
Graduate School of Biomedical SciencesThompson Lab
Program in Chemical Biology
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2020-09-15Keywords
HydrolaseNAD
Neurodegeneration
Nicotinamide
SARM1
TIR domain
Amino Acids, Peptides, and Proteins
Biochemistry
Biological Factors
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Nervous System Diseases
Metadata
Show full item recordAbstract
Sterile Alpha and Toll Interleukin Receptor Motif-containing protein 1 (SARM1) is a key therapeutic target for diseases that exhibit Wallerian-like degeneration; Wallerian degeneration is characterized by degeneration of the axon distal to the site of injury. These diseases include traumatic brain injury, peripheral neuropathy, and neurodegenerative diseases. SARM1 promotes neurodegeneration by catalyzing the hydrolysis of NAD(+) to form a mixture of ADPR and cADPR. Notably, SARM1 knockdown prevents degeneration, indicating that SARM1 inhibitors will likely be efficacious in treating these diseases. Consistent with this hypothesis is the observation that NAD(+) supplementation is axoprotective. To identify compounds that block the NAD(+) hydrolase activity of SARM1, we developed and performed a high-throughput screen (HTS). This HTS assay exploits an NAD(+) analog, etheno-NAD(+) (ENAD) that fluoresces upon cleavage of the nicotinamide moiety. From this screen, we identified berberine chloride and zinc chloride as the first noncompetitive inhibitors of SARM1. Though modest in potency, the noncompetitive mode of inhibition, suggests the presence of an allosteric binding pocket on SARM1 that can be targeted for future therapeutic development. Additionally, zinc inhibition and site-directed mutagenesis reveals that cysteines 629 and 635 are critical for SARM1 catalysis, highlighting these sites for the design of inhibitors targeting SARM1.Source
Loring HS, Parelkar SS, Mondal S, Thompson PR. Identification of the first noncompetitive SARM1 inhibitors. Bioorg Med Chem. 2020 Sep 15;28(18):115644. doi: 10.1016/j.bmc.2020.115644. Epub 2020 Jul 17. PMID: 32828421; PMCID: PMC7443514. Link to article on publisher's site
DOI
10.1016/j.bmc.2020.115644Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29563PubMed ID
32828421Related Resources
ae974a485f413a2113503eed53cd6c53
10.1016/j.bmc.2020.115644