Substrate interaction inhibits γ-secretase production of amyloid-β peptides.
Jing ZhaoYuanyuan XiaoXinyue LiuSoohyun KimXianzhong WuMarilia BarrosRan ZhuangXuben HouYingkai ZhangNikolaos K RobakisYue-Ming LiJonathan S DordickIban Ubarretxena-BelandiaChunyu WangPublished in: Chemical communications (Cambridge, England) (2020)
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.