Loading...
Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer’s disease
Vangavaragu, Jhansi Rani Koteswara Rao, Valasani Gan, Xueqi Yan, Shirley ShiDu
Vangavaragu, Jhansi Rani
Koteswara Rao, Valasani
Gan, Xueqi
Yan, Shirley ShiDu
Citations
Altmetric:
Abstract
Amyloid-β (Aβ), a neurotoxic peptide, is linked to the onset of Alzheimer’s disease (AD). Increased Aβ content within neuronal cell mitochondria is a pathological feature in both human and mouse models with AD. This accumulation of Aβ 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-β peptide in human neuronal cells, and is thus an attractive target to increase the proteolysis of Aβ. 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 & 4c enhanced hPreP-mediated proteolysis of Aβ (1–42), pF1β (2–54) and fluorogenic-substrate V. These results suggest that activation of hPreP by small benzimidazole derivatives provide a promising avenue for AD treatment.
Description
Date
2014-04-09
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Collections
Files
Loading...
Vangavaragu_2014.pdf
Adobe PDF, 1.35 MB
Research Projects
Organizational Units
Journal Issue
Keywords
Amyloid beta, Alzheimer’s disease, Enzyme activators, Benzimidazole derivatives, hPreP
Citation
Vangavaragu, J. R., Valasani, K. R., Gan, X., & Yan, S. S. (2014). Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer’s disease. European Journal of Medicinal Chemistry, 76, 506–516. http://doi.org/10.1016/j.ejmech.2014.02.046