Structure-based design:: Potent inhibitors of human brain memapsin 2 (β-secretase)

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 (A beta) 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.