Structure-Based Design:  Potent Inhibitors of Human Brain Memapsin 2 (β-Secretase)

Memapsin 2 (β-secretase) is one of two proteases that cleave the β-amyloid precursor protein (APP) to produce the 40−42 residue amyloid-β peptide (Aβ) 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.