Novel 7‐secretase inhibitors uncover a common nucleotide‐binding site in JAK3, SIRT2, and PS1

Abstract

γ-Secretase is an intramembrane-cleaving protease responsible for the final proteolytic event in the production of the amyloid-β peptides (Aβ) implicated in Alzheimer's disease (AD). Inhibition of γ-secretase activity is thus an attractive therapeutic strategy to slow down the pathogenesis of AD. Drugs often target more than one biomolecule because of conserved 3-dimensional structures in prospective protein binding sites. We have capitalized on this phenomenon of nature to identify new γ-secretase inhibitors. Here we show that 2-hydroxy naphthyl derivatives, a previously identified subclass of NAD+ analog inhibitors of sirtuin 2 (SIRT2), are direct γ-secretase inhibitors. Subsequent structure-activity relationship studies further showed that 2-hydroxy-1- naphthaldehyde is the minimal pharmacophore for γ-secretase inhibition. In evaluating target protein determinants of inhibition, we identified a common GXG signature nucleotide-binding site (NBS) shared by the γ-secretase subunit presenilin-1 C-terminal fragment (PS1-CTF), SIRT2, and Janus kinase 3 (JAK3). Because a detailed 3-dimensional structure of γ-secretase is beyond our knowledge, we took advantage of the known crystal structure of human JAK3 to model the NBS of the PS1-CTF, which includes the catalytic residue D385. Our results suggest that the flexible PS1-CTF 381LGLG384 loop comprises a substrate-docking site capable of recognizing specifically different γ-secretase substrates. © FASEB.