Current Medicinal Chemistry - Volume 9, Issue 11, 2002

A considerable body of evidence has accumulated in recent years implicating the ß-amyloid protein (Aß) in the etiology of Alzheimer's disease (AD). The highly hydrophobic Aß can nucleate and form neurotoxic fibrils that are the principal components of the cerebral plaques characteristic of AD. Aß is formed from the amyloid-ßprecursor protein (APP) through two protease activities. First, ß-secretase cleaves APP at the Aß N-term Read More

In the nonamyloidogenic processing pathway the Alzheimer's amyloid precursor protein (APP) is proteolytically cleaved by α-secretase. As this cleavage occurs at the Lys16-Leu17 bond within the amyloid β domain, it prevents deposition of intact amyloidogenic peptide. In addition, the large ectodomain (sAPPα) released by the action of α-secretase has several neuroprotective properties. Studies with a range of hydroxamic a Read More

The discovery of small molecules that inhibit β-peptide and other amyloid fibril formation has been impeded by featureless structure-activity-relationships, low apparent efficacy of inhibition, and by the perception that protein-protein interactions are too diffuse to be proper medicinal chemistry targets. Atomic resolution structural information on the critical target species are lacking. Despite these difficulties, substoichi Read More

Recent identification of β-scretasse being a membrane-associated aspartic protease has stimulated strong interest on this enzyme as a therapeutic target for Alzheimer's disease. Here we review the current understanding in the structure-function relationship as well as the status in the design of its inhibitors of this protease, memapsin 2 (BACE, ASP-2). The development in the basic tools, such as the preparation of recombinant m Read More