Inhibition of BACE, a Promising Approach to Alzheimer's Disease Therapy

Author: Roggo, S.

Source: Current Topics in Medicinal Chemistry, Volume 2, Number 4, 1 April 2002 , pp. 359-370(12)

Publisher: Bentham Science Publishers

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Abstract:

The first proteolytic step in the processing of amyloid precursor protein (APP) to amyloid-beta (A bgr

) in the brain is performed by bgr

-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 bgr

-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.

Keywords: bace; aspartic protease; inhibition; app; amyliod; pepstatin; protease; indinavir; amprenavir; tipranavir; aliskiren