Inhibition of BACE, a promising approach to Alzheimer's disease therapy.

The first proteolytic step in the processing of amyloid precursor protein (APP) to amyloid-beta (Abeta) in the brain is performed by beta-site APP cleaving enzyme (BACE1). This enzyme is a membrane bound aspartic protease with high homology of the catalytic domain to renin and pepsin and of yet unknown physiologic function. It is a primary drug discovery target for Alzheimer s disease therapy. The first potent inhibitors are based on the sequence of APP around the beta-secretase cleavage site EVNL/DAEF, with the scissile Leu-Asp amide bond being replaced by a hydroxyethylene transition state analogue isostere. In addition, lipophilic sidechains have been incorporated and a crystal structure of such an octapeptidic inhibitor bound in the active site is already available. Recent progress in the field of BACE inhibition is reviewed.