Toward β-Secretase-1 Inhibitors with Improved Isoform Selectivity

Area of Science:

• Biochemistry
• Neuroscience
• Drug Discovery

Background:

• Beta-secretase 1 (BACE1) initiates amyloid precursor protein (APP) proteolysis, producing toxic amyloid-beta (Aβ) peptides implicated in Alzheimer's disease pathogenesis.
• The related BACE2 isoform processes melanocyte proteins, raising concerns about pigmentation side effects with non-selective inhibitors.

Purpose of the Study:

• To investigate the development of isoform-selective BACE1 inhibitors to mitigate Alzheimer's disease while avoiding pigmentation issues.
• To identify structural features of selective BACE1 inhibitors for rational drug design.

Main Methods:

• Cocrystallographic analysis of 47 compounds to understand selectivity profiles.
• Clustering of compounds based on selectivity data.
• Structure-based design and synthesis of novel BACE1 inhibitors.
• Functional assays in human melanocytes to assess PMEL processing inhibition.

Main Results:

• Selective BACE1 inhibitors displayed distinct conformational features near the flap and S3 subpocket.
• Lead molecule 28, combining a pyrimidinyl C-ring and methylcyclohexyl group, achieved approximately 50-fold BACE1 selectivity.
• Molecule 28 demonstrated significantly reduced inhibition of PMEL processing in human melanocytes compared to non-selective inhibitors.

Conclusions:

• Developing isoform-selective BACE1 inhibitors is achievable.
• The identified structural features can guide the design of potent and selective BACE1 inhibitors.
• Lead molecule 28 represents a functionally selective inhibitor with potential therapeutic applications for Alzheimer's disease without pigmentation risks.