β-secretase as a target for the treatment of Alzheimer's disease

Finding inhibitors of the first step of the amyloid cascade, Abeta(42) generation, is a major goal of Alzheimer's disease drug development. Two target protease activities, beta-and gamma-secretase, were detected more than 10 years ago but progress in this area has been slow because the enzymes were not identified. Using an expression cloning strategy we have identified a novel membrane bound aspartic protease, BACE1, as beta-secretase. The enzyme has been characterized in detail. The X-ray crystal structure, which is critical for rational inhibitor design, has been solved and shown to be similar to that of other pepsin family members. Our recent knockout studies show that BACE1 is critical for Abeta generation, but the knockout mice show an otherwise normal phenotype, raising the possibility that therapeutic BACE1 inhibition could be accomplished without major mechanism based toxicity. Target-mediated toxicity of beta-secretase inhibition cannot be ruled out, however, as long as the major substrates of this enzyme are unknown. Although various peptidic beta-secretase inhibitors have been published, the key challenge now is the generation of more drug-like compounds that could be developed for therapeutic purposes. The focus of this review is progress in the beta-secretase field from the identification of the enzyme in 1999 to the most recent publications. (C) 2002 Wiley-Liss, Inc.