Study of memapsin 2 (beta-secretase) and strategy of inhibitor design.
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.
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015394:Molecular Structure
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human