Targeting SARM1: from inhibition for neuroprotection to activation for neuroablation.

Sterile alpha and TIR motif-containing protein 1 (SARM1),is a central enzyme that drives programmed axon degeneration and has gathered significant interest as a therapeutic target. Despite preclinical development of inhibitory therapeutic approaches, clear evidence of the role of SARM1 in human neurodegeneration had been missing until recently. New discoveries demonstrate SARM1 involvement in widespread human neurodegenerative processes. Advances in understanding the mechanism of action of SARM1 have revealed key properties for developing the next generation of SARM1 inhibitors for neuroprotection. Unexpectedly, recent discoveries of pyridine-derived specific SARM1 activators have expanded the therapeutic possibilities for SARM1 beyond neuroprotection to include neuroablation. In this review, we discuss evidence linking SARM1 to human disease and the current challenges to developing safe and effective inhibitors. We also review the emerging field of SARM1 activators and their potential for the development of highly selective neuroablative therapeutics.