γ-Secretase: A Catalyst of Alzheimer Disease and Signal Transduction

L-685,458 is an apartyl protease transition-state analog that reacts with the presenilins.

Photoreactive groups (shown as pruple star-like geometries) incorportated into L-685,458 result in covalent labeling of PS1, schematized as yellow (N-terminal–derived fragment) and red (C-terminal–derived fragment) subunits. Depending on placement of the photoreactive function, either of the two PS1 subunits can be covalently modified by the inhibitor. The hydroxyethylene isostere of L-685,458 is highlighted (see Figure 5).