title: Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer's disease.
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.
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Ave., Lawrence, KS 66047, USA.
authors.forename: Jhansi Rani
authors.initials: JR
authors.lastname: Vangavaragu
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Ave., Lawrence, KS 66047, USA.
authors.forename: Koteswara Rao
authors.initials: KR
authors.lastname: Valasani
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Ave., Lawrence, KS 66047, USA.
authors.forename: Xueqi
authors.initials: X
authors.lastname: Gan
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Ave., Lawrence, KS 66047, USA. Electronic address: shidu@ku.edu.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015195:Drug Design; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010447:Peptide Hydrolases / Q000187:drug effects*; D059748:Proteolysis; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D016229:Amyloid beta-Peptides; D020536:Enzyme Activators; D018696:Neuroprotective Agents; D010447:Peptide Hydrolases
keywords: Alzheimer's disease; Amyloid beta; Benzimidazole derivatives; Enzyme activators; hPreP