The amyloid β-protein (Aβ), implicated in the pathogenesis of Alzheimer's disease (AD), is a proteolytic metabolite generated by the sequential action of β- and γ-secretases on the amyloid precursor protein (APP). The two main forms of Aβ are 40- and 42-amino acid C-terminal variants, Aβ40 and Aβ42. We recently described a difluoro ketone peptidomimetic (1) that blocks Aβ production at the γ-secretase level [Wolfe, M. S., et al. (1998) J. Med. Chem. 41, 6-9]. Although designed to inhibit Aβ42 production, 1 also effectively blocked Aβ40 formation. Various amino acid changes in 1 still resulted in inhibition of Aβ4'0 and Aβ42 production, suggesting relatively loose sequence specificity by γ- secretase. The alcohol counterparts of selected difluoro ketones also lowered Aβ levels, indicating that the ketone carbonyl is not essential for activity and suggesting that these compounds inhibit an aspartyl protease. Selected compounds inhibited the aspartyl protease cathepsin D but not the cysteine protease calpain, corroborating previous suggestions that γ-secretase is an aspartyl protease with some properties similar to those of cathepsin D. Also, since the γ-secretase cleavage sites on APP are within the transmembrane region, we consider the hypothesis that this region binds to γ-secretase as an α-helix and discuss the implications of this model for the mechanism of certain forms of hereditary AD.
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