8d0d
Human SARM1 TIR domain bound to an NB-7-ADPR adduct
Structural highlights
FunctionSARM1_HUMAN Negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway which plays a pivotal role in activating axonal degeneration following injury. Promotes Wallerian degeneration an injury-induced axonal death pathway which involves degeneration of an axon distal to the injury site. Can activate neuronal death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response. Inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.[1] [2] [3] [4] Publication Abstract from PubMedAxon degeneration is an early pathological event in many neurological diseases. The identification of the nicotinamide adenine dinucleotide (NAD) hydrolase SARM1 as a central metabolic sensor and axon executioner presents an exciting opportunity to develop novel neuroprotective therapies that can prevent or halt the degenerative process, yet limited progress has been made on advancing efficacious inhibitors. We describe a class of NAD-dependent active-site SARM1 inhibitors that function by intercepting NAD hydrolysis and undergoing covalent conjugation with the reaction product adenosine diphosphate ribose (ADPR). The resulting small-molecule ADPR adducts are highly potent and confer compelling neuroprotection in preclinical models of neurological injury and disease, validating this mode of inhibition as a viable therapeutic strategy. Additionally, we show that the most potent inhibitor of CD38, a related NAD hydrolase, also functions by the same mechanism, further underscoring the broader applicability of this mechanism in developing therapies against this class of enzymes. Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease.,Bratkowski M, Burdett TC, Danao J, Wang X, Mathur P, Gu W, Beckstead JA, Talreja S, Yang YS, Danko G, Park JH, Walton M, Brown SP, Tegley CM, Joseph PRB, Reynolds CH, Sambashivan S Neuron. 2022 Sep 7. pii: S0896-6273(22)00749-8. doi:, 10.1016/j.neuron.2022.08.017. PMID:36087583[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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