Novel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1

作者：Wu Fang; Schweizer Claude; Rudinskiy Nikita; Taylor David M; Kazantsev Aleksey; Luthi Carter Ruth; Fraering Patrick C^*

来源：The FASEB Journal, 2010, 24(7): 2464-2474.

DOI：10.1096/fj.09-148031

• Alzheimer's disease
• amyloid-beta peptides
• presenilin-1
• off-target effect
• substrate-binding sites

gamma-Secretase is an intramembrane-cleaving protease responsible for the final proteolytic event in the production of the amyloid-beta peptides (A beta) implicated in Alzheimer's disease ( AD). Inhibition of gamma-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 gamma-secretase inhibitors. Here we show that 2-hydroxy naphthyl derivatives, a previously identified subclass of NAD( ) analog inhibitors of sirtuin 2 (SIRT2), are direct gamma-secretase inhibitors. Subsequent structure-activity relationship studies further showed that 2-hydroxy-1-naphthaldehyde is the minimal pharmacophore for gamma-secretase inhibition. In evaluating target protein determinants of inhibition, we identified a common GXG signature nucleotide-binding site (NBS) shared by the gamma-secretase subunit presenilin-1 C-terminal fragment (PS1-CTF), SIRT2, and Janus kinase 3 (JAK3). Because a detailed 3-dimensional structure of gamma-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 gamma-secretase substrates.-Wu, F., Schweizer, C., Rudinskiy, N., Taylor, D. M., Kazantsev, A., Luthi-Carter, R., Fraering, P.C. Novel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1. FASEB J. 24, 2464-2474 (2010). www.fasebj.org

• 出版日期2010-7