Development of an Activity-Based Probe for SARM1, an NAD Hydrolase Involved in Neuronal Degeneration

Tommasi, Sebastian

Student Work

Development of an Activity-Based Probe for SARM1, an NAD Hydrolase Involved in Neuronal Degeneration

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SARM1, sterile alpha and toll/interleukin receptor motif containing protein 1, is a protein involved in the degeneration of neurons. The protein functions as an NAD+ glycohydrolase and its activity increases in response to stress or damage. Many neurodegenerative diseases share the key characteristic of axon degeneration, which is caused by SARM1 activation. Preliminary studies show that SARM1 knockout mice are protected from axon degeneration (Henninger, 2016). As such, there has been intense interest in developing inhibitors for this enzyme. The primary focus of this research is to develop an activity-based probe through the characterization of previously identified SARM1 inhibitors. The characterization of these isothiazole-derived inhibitors is reported herein. Using kinetic assays, we have been able to begin modeling an activity-based probe with this isothiazole warhead. Development of an assay-based probe will improve the understanding around SARM1 function and regulation.

This report represents the work of one or more WPI undergraduate students submitted to the faculty as evidence of completion of a degree requirement. WPI routinely publishes these reports on its website without editorial or peer review.

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