Memapsin 2 (Beta-Secretase) Inhibitors: Drug Development

E-ISSN： 1875-5828|5|2|121-131

ISSN： 1567-2050

Source： Current Alzheimer Research, Vol.5, Iss.2, 2008-04, pp. : 121-131

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Abstract

Memapsin 2 (&bgr;-secretase, BACE 1) processing of &bgr;-amyloid precursor protein is the first step in the pathway leading to the production of amyloid-&bgr;, thus, it is a major target for the development of inhibitor drug for the treatment of Alzheimers's Disease. Although there are distinctive advantages of this protease as a drug target, the development of drug-like memapsin 2 inhibitors has been somewhat slow since the cloning of the protease seven years ago. Here we review the progress of memapsin 2 inhibitor development using crystal structure-based design cycles. Recent progress has evolved the inhibitors into sizes sufficiently small to penetrate cell membranes and the blood-brain barrier yet retain potency for the inhibition of A&bgr; production in cultured cells and experimental animals. Such progress lends optimism that clinically useful memapsin 2 inhibitors will eventually be developed.