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dc.contributor.authorLoring, Heather S.
dc.contributor.authorParelkar, Sangram
dc.contributor.authorMondal, Santanu
dc.contributor.authorThompson, Paul R
dc.date2022-08-11T08:08:25.000
dc.date.accessioned2022-08-23T15:54:29Z
dc.date.available2022-08-23T15:54:29Z
dc.date.issued2020-09-15
dc.date.submitted2020-09-11
dc.identifier.citation<p>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. <a href="https://doi.org/10.1016/j.bmc.2020.115644">Link to article on publisher's site</a></p>
dc.identifier.issn0968-0896 (Linking)
dc.identifier.doi10.1016/j.bmc.2020.115644
dc.identifier.pmid32828421
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29563
dc.description.abstractSterile 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32828421&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1016/j.bmc.2020.115644
dc.subjectHydrolase
dc.subjectNAD
dc.subjectNeurodegeneration
dc.subjectNicotinamide
dc.subjectSARM1
dc.subjectTIR domain
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry
dc.subjectBiological Factors
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectNervous System Diseases
dc.titleIdentification of the first noncompetitive SARM1 inhibitors
dc.typeJournal Article
dc.source.journaltitleBioorganic and medicinal chemistry
dc.source.volume28
dc.source.issue18
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1784
dc.identifier.contextkey19345858
html.description.abstract<p>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.</p>
dc.identifier.submissionpathfaculty_pubs/1784
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentThompson Lab
dc.contributor.departmentProgram in Chemical Biology
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages115644


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