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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Inhibition of BACE, a Promising Approach to Alzheimers Disease Therapy

Author(s): Silvio Roggo

Volume 2, Issue 4, 2002

Page: [359 - 370] Pages: 12

DOI: 10.2174/1568026024607490

Price: $65

Abstract

The first proteolytic step in the processing of amyloid precursor protein (APP) to amyloid-beta (Aβ) in the brain is performed by β-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 Alzheimers disease therapy. The first potent inhibitors are based on the sequence of APP around the β-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


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