The genetics of
Alzheimer's disease (AD) implies that restoring non-pathological levels or ratios of different
amyloid-beta (Abeta)
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
Abeta(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
Abeta(1-42) and various shorter Abeta
peptides are generated by the same
gamma 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.
Gamma-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 Abeta
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
gamma-secretase has been proven to be difficult due to inherent mechanism-based liabilities.