Year: 2026
Type: article
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. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades. The sterile alpha and TIR motif containing 1 (SARM1) is a crucial enzyme in axonal degeneration, making it a potential target for treating nervous system diseases. Here, the authors identify and optimize base-exchange inhibitors (BEXi) targeting SARM1, revealing their limitations and highlighting the complexity of SARM1 as a therapeutic target.
Source: Communications Chemistry
Authors: Thomas Lundbäck, Vijay Chandrasekar, Chendi Gu, Hyoungseok Ju, Robyn McAdam, Maria Palomero, Kasim Sader, Bradley Peter, Lisa Wissler, Philip Nevin, Edmund Foster, Tanguy Jamier, Pravallika Manjappa, Carina Johansson, Jenny Sandmark, Mei Ding, Anette Persson-Kry, Sanhita Mitra, Tugce Munise Satir, Bilada Bilican, Mirko Messa, Graham Fraser, John Linley, Helen Plant, Rachel Moore, Tina Seifert, Michael Lerche, Carina Raynochek, Ewa Nilsson, Nour Majbour, Richard Lucey, Taiana Maia de Oliveira, Qi Wang, Iain Chessell, Perla Breccia, Rebecca Jarvis
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,690
Funders: AstraZeneca Mölndal, AstraZeneca
OpenAlex ID: W4416302578