Memapsin 2 (beta-secretase) inhibitors: drug development

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.