Beta-secretase as a therapeutic target for inhibitor drugs.
Recent identification of beta-scretasse being a membrane-associated aspartic protease has stimulated strong interest on this enzyme as a therapeutic target for Alzheimer s disease. Here we review the current understanding in the structure-function relationship as well as the status in the design of its inhibitors of this protease, memapsin 2 (BACE, ASP-2). The development in the basic tools, such as the preparation of recombinant memapsin 2, the assay method for kinetic measurements of inhibition, the determination of the subsite specificity and the crystal structure of memapsin 2 complexed to a tight-binding inhibitor, has made the structural based inhibitor design possible. More recent inhibitors, having Ki values in the nanomolar range and molecular size in low 700 Da, show some promise that clinically useful inhibitors of beta-scretasse may be attainable.
Ghosh
Arun K
AK
Department of Chemistry, University of Illinois at Chicago, USA.
Hong
Lin
L
Tang
Jordan
J
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015195:Drug Design; D010450:Endopeptidases; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013379:Substrate Specificity
D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse