Substrate interaction inhibits γ-secretase production of amyloid-β peptides

Jing Zhao; Yuanyuan Xiao; Xinyue Liu; Soohyun Kim; Xianzhong Wu; Marilia Barros; Ran Zhuang; Xuben Hou; Yingkai Zhang; Nikolaos K. Robakis; Yue-Ming Li; Jonathan S. Dordick; Iban Ubarretxena-Belandia; Chunyu Wang

doi:10.1039/C9CC09170J

Substrate interaction inhibits γ-secretase production of amyloid-β peptides†

Jing Zhao,

^a Yuanyuan Xiao,^a Xinyue Liu,^a Soohyun Kim,^b Xianzhong Wu,^c Marilia Barros,^c Ran Zhuang,^a Xuben Hou,^d Yingkai Zhang,^e Nikolaos K. Robakis,^b Yue-Ming Li,^c Jonathan S. Dordick,^afg Iban Ubarretxena-Belandia^hij and Chunyu Wang

*^afk

Author affiliations

* Corresponding authors

^a Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
E-mail: wangc5@rpi.edu

^b Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

^c Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

^d Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China

^e Department of Chemistry, New York University, New York, NY 10003, USA

^f Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA

^g Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA

^h Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

ⁱ Instituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, Leioa, Spain

^j Ikerbasque, Basque Foundation for Science, Bilbao, Spain

^k Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA

Abstract

Combining NMR, mass spectrometry, AlphaLISA and cell assays, we discovered a compound C1 that binds C-terminal juxtamembrane lysines at the transmembrane domain of the amyloid precursor protein (APPTM) and inhibits γ-secretase production of amyloid-β with μM IC₅₀. Our work suggests that targeting APPTM is a novel and viable strategy in AD drug discovery.

Chemical Communications

Substrate interaction inhibits γ-secretase production of amyloid-β peptides†

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Substrate interaction inhibits γ-secretase production of amyloid-β peptides

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