The generation of the 40/42-residue amyloid β (Aβ) peptide in human brain by proteolysis of the membrane anchored β-amyloid precursor protein (APP) is a key event in the progression of Alzheimer's disease. 1 Proteases involved in the production of Aβ peptide are known as γand β-secretases. β-Secretase, which catalyzes the rate-limiting step in Aβ Supporting Information Available: Experimental procedures for the synthesis of Leu-Ala dipeptide isostere and solid-phase synthesis of OM99-1 and OM99-2 (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
Memapsin 2 (beta-secretase) is one of two proteases that cleave the beta-amyloid precursor protein (APP) to produce the 40-42 residue amyloid-beta peptide (Abeta) in the human brain, a key event in the progression of Alzheimer's disease. On the basis of the X-ray crystal structure of our lead inhibitor (2, OM99-2 with eight residues) bound to memapsin, we have reduced the molecular weight and designed potent memapsin inhibitors. Structure-based design and preliminary structure-activity studies have been presented.
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