| Autor: |
Moore, C. L., Leatherwood, D. D., Diehl, T. S., Selkoe, D. J., Wolfe, M. S. |
| Zdroj: |
Journal of Medicinal Chemistry; September 7, 2000, Vol. 43 Issue: 18 p3434-3442, 9p |
| Abstrakt: |
The final step in the generation of the amyloid-β protein (Aβ), implicated in the etiology of Alzheimer's disease, is proteolysis within the transmembrane region of the amyloid precursor protein (APP) by γ-secretase. Although considered an important target for therapeutic design, γ-secretase has been neither well-characterized nor definitively identified. Previous studies in our laboratory using substrate-based difluoro ketone and difluoro alcohol transition-state analogue inhibitors suggest that γ-secretase is an aspartyl protease with loose sequence specificity. To further characterize the active site of γ-secretase, we prepared a series of difluoro ketone peptide analogues with varying steric bulkiness in the P1 position and tested the ability of these compounds to inhibit Aβ production in APP-transfected cells. Incorporation of bulky, aliphatic P1 side chains, such as sec-butyl or cyclohexylmethyl, led to increased γ-secretase inhibitory potency, suggesting a large S1 pocket to accommodate these substituents and providing further evidence for loose sequence specificity. The cyclohexylmethyl P1 substituent allowed N-terminal truncation to a low-molecular-weight compound (<600 Da) that effectively blocked Aβ production (IC50 ~ 5 μM). This finding suggests that optimal S1 binding may allow the development of potent inhibitors with ideal pharmaceutical properties. Moreover, a difluoro alcohol analogue with a cyclohexylmethyl P1 substituent was equipotent with its difluoro ketone counterpart, providing strong evidence that γ-secretase is an aspartyl protease. All new analogues inhibited total Aβ and Aβ42 production with the same rank order of potency and increased Aβ42 production at low concentrations, providing further evidence for distinct γ-secretases that are nevertheless closely similar with respect to active site topology and mechanism. |
| Databáze: |
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