Study of memapsin 2 (beta-secretase) and strategy of inhibitor design

• Published in: Journal of molecular neuroscience 2003-01, Vol.20 (3), p.299-304
• Main Authors: Tang, Jordan, Ghosh, Arun K, Hong, Lin, Koelsch, Gerald, Turner, 3rd, Robert T, Chang, Wanpin
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Protein Precursor - drug effects; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; Aspartic endopeptidase; Blood-brain barrier; Catalytic Domain - drug effects; Catalytic Domain - physiology; Design; Drug Design; Drug development; Endopeptidases; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Enzymology; Humans; Inhibitor drugs; Inhibitors; Molecular Structure; Neurodegenerative diseases; Secretase; Transgenic mice
• ISSN: 0895-8696; 0895-8696; 1559-1166
• DOI: 10.1385/JMN:20:3:299

The discovery that beta-secretase is a membrane-anchored aspartic protease memapsin 2 has stimulated much interest in the design and testing of its inhibitors for the treatment of Alzheimer's disease. This article discusses the strategy for the development of such inhibitor drugs. Enzymology and structural determination tools have permitted the design of memapsin 2 inhibitors with high potency and in a size range possible for penetration of the blood-brain barrier. Transgenic Alzheimer's mice have been used to show that when memapsin 2 inhibitors are transported to the brain, they effectively reduce the production of amyloid beta. Although development of a clinical candidate of memapsin 2 inhibitor drug remains a very challenging undertaking, the progress so far lends some optimism for future prospects.