, Volume 5, Issue 3, pp 399–408

β-Secretase as a therapeutic target for Alzheimer’s disease

Review Article


β-Secretase (memapsin 2, BACE1) is an attractive target for the development of inhibitor drugs to treat Alzheimer’s disease (AD). Not only does this protease function at the first step in the pathway leading to the production of amyloid-β (Aβ), its gene deletion produces only mild phenotypes. In addition, β-secretase is an aspartic protease whose mechanism and inhibition are well known. The development of β-secretase inhibitors, actively pursued over the last seven years, has been slow, due to the difficulty in combining the required properties in a single inhibitor molecule. Steady progress in this field, however, has brought about inhibitors that contain many targeted characteristics. In this review, we describe the strategy of structure-based inhibitor evolution in the development of β-secretase inhibitor drug. The current status of the field offers grounds for some optimism, in that β-secretase inhibitors have been shown to reduce brain Aβ and to rescue the cognitive decline in transgenic AD mice, and an orally available β-secretase inhibitor drug candidate is in clinical trial. With this knowledge base, it seems reasonable to expect that more drug candidates will be tested in human, and then successful disease-modifying drugs may ultimately emerge from this target.

Key Words

β-secretase amyloid precursor protein secretase inhibitor drug Alzheimer’s disease 

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2008

Authors and Affiliations

  1. 1.Departments of Chemistry and Medicinal ChemistryPurdue UniversityWest Lafayette
  2. 2.Oklahoma Medical Research FoundationUniversity of Oklahoma Health Science CenterOklahoma City
  3. 3.Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Science CenterOklahoma City
  4. 4.Protein Studies Research Program, MS 28Oklahoma Medical Research FoundationOklahoma City

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