L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secretase Activity

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Abstract
Progressive cerebral amyloid β-protein (Aβ) deposition is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Elevated levels of Aβ(42) peptide formation have been linked to early-onset familial AD-causing gene mutations in the amyloid β-protein precursor (AβPP) and the presenilins. Sequential cleavage of AβPP by the β- and γ-secretases generates the N- and C-termini of the Aβ peptide, making both the β- and γ-secretase enzymes potential therapeutic targets for AD. The identity of the AβPP γ-secretase and the mechanism by which the C-termini of Aβ are formed remain uncertain, although it has been suggested that the presenilins themselves are novel intramembrane-cleaving γ-secretases of the aspartyl protease class [Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., and Selkoe, D. J. (1999) Nature 398, 513−517]. In this study we report the identification of L-685,458 as a structurally novel inhibitor of AβPP γ-secretase activity, with a similar potency for inhibition of Aβ(42) and Aβ(40) peptides. This compound contains an hydroxyethylene dipeptide isostere which suggests that it could function as a transition state analogue mimic of an aspartyl protease. The preferred stereochemistry of the hydroxyethylene dipeptide isostere was found to be the opposite to that required for inhibition of the HIV-1 aspartyl protease, a factor which may contribute to the observed specificity of this compound. Specific and potent inhibitors of AβPP γ-secretase activity such as L-685,458 will enable important advances toward the identification and elucidation of the mechanism of action of this enigmatic protease.