posted on 2019-04-01, 00:00authored byAndrew M. Petros, Alla Korepanova, Clarissa G. Jakob, Wei Qiu, Sanjay C. Panchal, Jie Wang, Justin D. Dietrich, Jason T. Brewer, Frauke Pohlki, Andreas Kling, Kyle Wilcox, Viktor Lakics, Lamiaa Bahnassawy, Peter Reinhardt, Sarathy Karunan Partha, Pierre M. Bodelle, Marc Lake, Erik I. Charych, Vincent S. Stoll, Chaohong Sun, Eric G. Mohler
Apolipoprotein E is a 299-residue
lipid carrier protein produced
in both the liver and the brain. The protein has three major isoforms
denoted apoE2, apoE3, and apoE4 which differ at positions 112 and
158 and which occur at different frequencies in the human population.
Genome-wide association studies indicate that the possession of two
apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer’s
disease (LOAD). In an attempt to identify a small molecule stabilizer
of apoE4 function that may have utility as a therapy for Alzheimer’s
disease, we carried out an NMR-based fragment screen on the N-terminal
domain of apoE4 and identified a benzyl amidine based fragment binder.
In addition to NMR, binding was characterized using various other
biophysical techniques, and a crystal structure of the bound core
was obtained. Core elaboration ultimately yielded a compound that
showed activity in an IL-6 and IL-8 cytokine release assay.