Memapsin 2 (beta-secretase) inhibitors: drug development
Arun K Ghosh1, Nagaswamy Kumaragurubaran, Ling Hong
1Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
Abstract:
Memapsin 2 (beta-secretase, BACE 1) processing of beta-amyloid precursor protein is the first step in the pathway leading to the production of amyloid-beta, 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 Abeta production in cultured cells and experimental animals. Such progress lends optimism that clinically useful memapsin 2 inhibitors will eventually be developed.
Insights
Developing inhibitors for Memapsin 2 (beta-secretase, BACE 1) is crucial for Alzheimer's Disease treatment. Recent advancements have yielded small, potent inhibitors capable of crossing the blood-brain barrier, offering hope for clinical use.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Memapsin 2 (beta-secretase, BACE 1) initiates amyloid-beta production, a key factor in Alzheimer's Disease.
- BACE 1 is a significant therapeutic target for Alzheimer's treatment.
- Developing effective BACE 1 inhibitors has faced challenges since the enzyme's cloning.
Purpose of the Study:
- To review the progress in developing Memapsin 2 inhibitors.
- To highlight advancements in crystal structure-based drug design for BACE 1 inhibitors.
- To assess the potential of current inhibitors for Alzheimer's therapy.
Main Methods:
- Crystal structure-based design cycles were employed.
- Inhibitor development focused on achieving small molecular size.
- Potency was evaluated in cellular and animal models.
Main Results:
- Inhibitors have been refined to be small enough for cell membrane and blood-brain barrier penetration.
- Developed inhibitors maintain potency in inhibiting Abeta production.
- Successful inhibition was observed in both cultured cells and experimental animals.
Conclusions:
- Significant progress has been made in developing Memapsin 2 inhibitors.
- The development of clinically useful Memapsin 2 inhibitors for Alzheimer's Disease is optimistic.
- Structure-based design has been effective in creating promising BACE 1 inhibitors.
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