(1099-B) Targeting SARM1 for treating axon degeneration

Abstract: SARM1 has been identified as a critical driver of Wallerian degeneration, that is, the programmed axon degeneration in response to chemical and mechanical damage. SARM1 is therefore considered a potential target of interest for neurological disorders, such that inhibition of activity could slow disease progression. The multi-domain full-length SARM1 protein organises into a ring-shaped octamer, where each protomer resides N-terminal ARM domains that allosterically regulate the activity of the C-terminal TIR domain and with oligomerization organized by bridging SAM domains. The enzymatic activity is allosterically regulated by levels of NMN and NAD+, intracellular metabolites that act reciprocally to activate and inhibit the enzyme, respectively. This presents two potential binding sites for small molecule inhibitors of SARM1 activity. Here, we identified and characterised a class of base-exchange inhibitors that act at the catalytic TIR domain through the sequential use of a biochemical and a cellular assay, where a constitutively active form of SARM1 without the regulatory ARM domains is expressed. This assay works well for characterization of base-exchange inhibitors, while it shows no activity for recently published covalent allosteric blockers, in line with their expected mode of action.