Exploring the Binding Potency and Specificity of Small Molecules Against the Transmembrane Amyloid Precursor Protein Fragment, C99

Abstract

The Amyloid Precursor Protein (APP) is a ubiquitously expressed single-pass transmembrane receptor that is involved in a variety of roles ranging from neurological development to synaptic plasticity and homeostasis. Despite several biological functions, APP is most famous for being the precursor of Amyloid-β (Aβ) peptides, a hypothesized cause of Alzheimer's disease (AD; Amyloid Cascade Hypothesis). 30 years of research on APP have passed yet there are no reported chemical probes that can bind APP in a potent and specific way. The 3D structure of the βAPP-CTF (C99; the C-terminal 99-residue protein product of APP cleavage by β-secretase) revealed a hydrophobic, transmembrane pseudo-pocket that binds cholesterol, motivating the concept that C99 may be able to bind other hydrophobic small-molecules. Here I describe the results of NMR-based high-throughput screening (HTS) of small-molecules for compounds that bind avidly and specifically to C99 in model membranes.