Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer's disease

Amyloid-beta (A beta), a neurotoxic peptide, is linked to the onset of Alzheimer's disease (AD). Increased A beta content within neuronal cell mitochondria is a pathological feature in both human and mouse models with AD. This accumulation of A beta within the mitochondrial landscape perpetuates increased free radical production and activation of the apoptotic pathway. Human Presequence Protease (hPreP) is responsible for the degradation of mitochondrial amyloid-beta peptide in human neuronal cells, and is thus an attractive target to increase the proteolysis of A beta. Therefore, it offers a potential target for Alzheimer's drug design, by identifying potential activators of hPreP. We applied structure-based drug design, combined with experimental methodologies to investigate the ability of various compounds to enhance hPreP proteolytic activity. Compounds 3c & 24c enhanced hPreP-mediated proteolysis of A beta (1-42), pF(1)beta (2-54) and fluorogenic-substrate V. These results suggest that activation of hPreP by small benzimidazole derivatives provide a promising avenue for AD treatment. Published by Elsevier Masson SAS.