The rise and fall of SARM1 base-exchange inhibitors - PubMed
2 hours ago
- #SARM1 inhibitors
- #axonal degeneration
- #drug discovery
- The SARM1 enzyme is a key driver of axonal degeneration and a target for treating chemotherapy-induced peripheral neuropathy and other nervous system diseases.
- Researchers identified and optimized a class of base-exchange inhibitors (BEXi) targeting human SARM1, studying their molecular interactions with cryo-EM, HDX-MS, and SAXS.
- BEXi showed robust inhibition in biochemical and cellular assays, but sub-inhibitory concentrations paradoxically activated SARM1 and accelerated neurite degeneration in neuronal assays.
- Even at high concentrations, BEXi only delayed, rather than prevented, neurite degeneration in primary neuronal cells.
- Due to these findings, the development of BEXi was discontinued in favor of alternative strategies, highlighting SARM1's complexity as a therapeutic target.