Peptide-based, irreversible inhibitors of γ-secretase activity

The characterization of the enzymes responsible for amyloid β-peptide (Aβ) production is considered to be a primary goal towards the development of future therapeutics for the treatment of Alzheimer’s disease. Inhibitors of γ-secretase activity were critical in demonstrating that the presenilins (PSs) likely comprised at least part of the active site of the γ-secretase enzyme complex, with two highly conserved membrane aspartates presumably acting as catalytic residues. However, whether or not these aspartates are actually the catalytic residues of the enzyme complex or are merely essential for normal PS function and/or maturation is still unknown. In this paper, we report the development of reactive inhibitors of γ-secretase activity that are functionally irreversible. Since such inhibitors have been shown to bind catalytic residues in other aspartyl proteases (e.g., HIV protease), they might be used to determine if the transmembrane aspartates of PSs are involved directly in substrate cleavage.