Intra-or intercomplex binding to the γ-secretase enzyme: a model to differentiate inhibitor classes

Abstract:

γ-Secretase is one of the critical enzymes required for the generation of amyloid-β peptides from the β-amyloid precursor protein. Because amyloid-β peptides are generally accepted to play a key role in Alzheimer disease, γ-secretase inhibition holds the promise for a disease-modifying therapy for this neurodegenerative condition. Although recent progress has enhanced the understanding of the biology and composition of the γ-secretase enzyme complex, less information is available on the actual interaction of various inhibitor classes with the enzyme. Here we show that the two principal classes of inhibitor described in the scientific and patent literature, aspartyl protease transition state analogue and small molecule non-transition state inhibitors, display fundamental differences in the way they interact with the enzyme. Taking advantage of a γ-secretase enzyme overexpressing cellular system and different …

Año de publicación:

2006

Keywords:

Fuente:

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