Substrate Interaction Inhibits γ-secretase Production of Amyloid-β Peptides

Overview

Journal Chem Commun (Camb)

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2020 Feb 5

PMID 32016207

Citations 3

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production.

Suzuki R, Takahashi H, Yoshida C, Hidaka M, Ogawa T, Futai E Int J Mol Sci. 2023; 24(4).

PMID: 36835396 PMC: 9959964. DOI: 10.3390/ijms24043970.

Covalent fragment inhibits intramembrane proteolysis.

Eden A, Zhao J, Xiao Y, Gibson J, Wang C Front Mol Biosci. 2022; 9:958399.

PMID: 36158579 PMC: 9490316. DOI: 10.3389/fmolb.2022.958399.

Targeting Amyloidogenic Processing of APP in Alzheimer's Disease.

Zhao J, Liu X, Xia W, Zhang Y, Wang C Front Mol Neurosci. 2020; 13:137.

PMID: 32848600 PMC: 7418514. DOI: 10.3389/fnmol.2020.00137.

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