γ-Secretase Modulation and its Promise for Alzheimer's Disease: a Rationale for Drug Discovery

The genetics of Alzheimer's disease (AD) implies that restoring non-pathological levels or ratios of different amyloid-β (Aβ) peptide species in the brain could prevent the onset or delay the progression of this neurodegenerative disease. In particular, a selective reduction of the longer Aβ(1-42) peptide which is widely believed to be causative of AD is currently seen as an attractive approach for a disease-modifying therapy. Based on the knowledge that Aβ(1-42) and various shorter Aβ peptides are generated by the same γ-secretase enzyme, the concept of allosteric modulation of the cleavage specificity of this aspartic protease has been introduced to the field of protease drug discovery and fuelled novel medicinal chemistry efforts. γ-Secretase modulation holds the promise that chemical entities can be synthesized which restore non-pathological enzyme activity by shifting the actual substrate cleavage towards the generation of shorter Aβ peptides. It can be assumed that this approach has gained considerable attraction for pharmaceutical drug discovery since the development of non-selective protease inhibitors for γ-secretase has been proven to be difficult due to inherent mechanism-based liabilities.