Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer

Area of Science:

• Biochemistry
• Neuroscience
• Pharmacology

Background:

• Apolipoprotein E (apoE) is a crucial lipid carrier protein with three main isoforms: apoE2, apoE3, and apoE4.
• The apoE4 isoform is a significant genetic risk factor for late-onset Alzheimer's disease (LOAD).

Purpose of the Study:

• To identify small molecule stabilizers of apoE4 function for potential Alzheimer's disease therapy.
• To explore therapeutic strategies targeting apoE4 in Alzheimer's disease.

Main Methods:

• NMR-based fragment screening of the N-terminal domain of apoE4.
• Characterization of fragment binding using biophysical techniques.
• Obtaining a crystal structure of the bound core and subsequent core elaboration.

Main Results:

• Identified a benzyl amidine-based fragment binder for apoE4.
• A refined compound demonstrated activity in an IL-6 and IL-8 cytokine release assay.
• Biophysical and structural data confirmed fragment binding to apoE4.

Conclusions:

• A novel small molecule targeting apoE4 was developed through fragment-based drug discovery.
• The identified compound shows potential for therapeutic intervention in Alzheimer's disease by modulating apoE4 function.
• Further development of this compound could lead to new treatments for LOAD.