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Abstract The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a class of base-exchange inhibitors (BEXi) targeting human SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS.
1. Introduction Neurodegenerative disorders represent many currently incurable diseases that are rapidly rising in prevalence, in part due to an increasing elderly population. Consequently, effective pharmacotherapies and the development of new treatment approaches are desperately needed. For several years, our laboratory has been interested in investigating the biological properties of the hexapeptide angiotensin IV (Ang IV).
Protein-based assays are essential tools for many laboratories in both industrial and academic settings. Protein targets of interest are often found at low abundance and can be complex in nature, making their analysis intractable. One of the considerable challenges when developing assays is that small sample sizes can limit the amount of relevant information that can be extracted.
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