TAILIEUCHUNG - Báo cáo khoa học: Cell biology, regulation and inhibition of b-secretase (BACE-1)

Since the discovery of the b-secretase responsible for initiating the Alzheimer’s amyloid cascade as a novel membrane-bound aspartic protein-ase, termed ‘b-site amyloid precursor protein cleaving enzyme’, ‘aspartyl protease-2’ or ‘membrane-anchored aspartic proteinase of the pepsin family-2’, huge efforts have been devoted to an understanding of its biol-ogy and structure in the subsequent decade. | ỊFEBS Journal REVIEW ARTICLE Cell biology regulation and inhibition of b-secretase BACE-1 Clare E. Hunt and Anthony J. Turner Proteolysis Research Group Institute of Molecular and Cellular Biology Faculty of BiologicalSciences University of Leeds UK Keywords Alzheimer s disease amyloid amyloid precursor protein aspartic proteinase BACE inhibitors memapsin neurodegeneration protease secretase Correspondence A. J. Turner Institute of Molecular and Cellular Biology Faculty of Biological Sciences University of Leeds Leeds LS2 9JT UK Fax 44 113 343 3157 Tel 44 113 343 3131 E-mail Received 1 December 2008 revised 16 January 2009 accepted 23 January 2009 doi Since the discovery of the b-secretase responsible for initiating the Alzheimer s amyloid cascade as a novel membrane-bound aspartic proteinase termed b-site amyloid precursor protein cleaving enzyme aspartyl protease-2 or membrane-anchored aspartic proteinase of the pepsin family-2 huge efforts have been devoted to an understanding of its biology and structure in the subsequent decade. This has paid off in many respects as it has been cloned its structure solved novel physiological substrates of the enzyme discovered and numerous inhibitors of its activity developed in a relatively short space of time. The inhibition of b-secretase activity in vivo remains one of the most viable strategies for the treatment of Alzheimer s disease although progress in getting inhibitors to the clinic has been slow partly as a consequence of its aspartic proteinase character which poses considerable problems for the production of potent selective and brain-accessible compounds. This review reflects on the development of b-secretase biology and chemistry to date highlighting the diverse and innovative strategies applied to the modulation of its activity at the molecular and cellular levels. The proteinase originally termed b-secretase catalyses the initial step in the amyloidogenic

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