Modulation of gamma-secretase specificity using small molecule allosteric inhibitors

Area of Science:

• Biochemistry
• Neuroscience
• Pharmacology

Background:

• Gamma-secretase cleaves amyloid precursor protein and Notch receptors, implicated in Alzheimer disease and cancer.
• Regulation of gamma-secretase specificity remains poorly understood despite its importance.

Purpose of the Study:

• To discover selective gamma-secretase inhibitors for drug development.
• To investigate the mechanisms regulating gamma-secretase specificity.

Main Methods:

• Screening of chemical libraries to identify novel inhibitors.
• Development of a di-coumarin family of inhibitors.
• Utilizing a multiple photo-affinity probe approach to study inhibitor-enzyme interactions.

Main Results:

• Identified di-coumarin inhibitors that preferentially inhibit Abeta42 production over other gamma-secretase activities.
• Demonstrated that these inhibitors bind to an allosteric site, inducing conformational changes in the active site.
• Showed selective inhibition of Abeta42 production due to allosteric binding.

Conclusions:

• Revealed a mechanism for gamma-secretase specificity regulation via allosteric inhibition.
• Provided insights into how familial presenilin mutations affect gamma-secretase active site and specificity.
• Established a basis for developing new therapeutic agents for Alzheimer disease.