Deciphering and Targeting Arginase-1 Oligomerization: A New Strategy for Enzyme Inhibition
(2026)
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- Abstract
- (en) Arginase-1 (ARG-1) is a homotrimeric enzyme implicated in numerous pathological conditions, including cancer, cardiovascular diseases, and neurovascular disorders. To date, despite promising preclinical results, catalytic-site inhibitors have shown limited clinical efficacy and structural diversity. This thesis explores the targeting of ARG-1 oligomerization as an alternative strategy to achieve enzyme inhibition. Through the development of biophysical and biochemical tools, this work first investigated the structural and functional determinants of ARG-1 oligomerization, demonstrating that trimerization is essential for catalytic activity and protein stability, and identifying an allosteric site involved in stabilizing the trimeric assembly. Different strategies to disrupt this assembly were then explored using peptides, covalent inhibitors, and small molecules identified through screening, leading to the first compounds capable of inhibiting ARG-1 through oligomeric disruption.
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Citations
Dechenne, J. (2026). Deciphering and Targeting Arginase-1 Oligomerization: A New Strategy for Enzyme Inhibition. https://hdl.handle.net/2078.5/280286