Assistant Professor Structural and Chemical Biology
Mount Sinai School of Medicine
Towards Novel Therapeutics for Alzheimers Disease Using a Structure Guided High-Throughput Screening Approach
Alzheimers disease (AD) is the most common cause of dementia in people 65 years of age and older. Currently there is no cure for AD and its treatment constitutes an enormous public health burden, with annual costs in the US alone approaching 100 billion dollars. A hallmark of AD is the presence of senile plaques composed of dystrophic neurites surrounding extracellular aggregates of 40 and 42 amino acid long amyloid beta-peptides (Abeta40 and Abeta42). These peptides result from the degradation of amyloid precursor proteins into a C-terminal fragment (betaCTF), which is further cleaved within its putative transmembrane domain (TMD) by gamma-secretase. Increased production of the aggregation-prone Abeta42 constitutes an important risk factor in AD. Considerable evidence indicates that betaCTF dimerization correlates with Abeta42 production and that dimer dissociation can reduce Abeta42 levels. Our goal is to develop novel small-molecule AD therapeutics that inhibit Abeta42 production by targeting betaCTF dimerization. To achieve this goal, we will use a structure-guided, high-throughput screening approach that will be implemented by a highly synergistic intramural team with strong expertise in biochemistry, chemistry, and computational structural biology. Specifically, our aims are: 1) Large-scale screen of small chemical compounds at the intramural Translational Chemical Biology Center for their ability to disrupt betaCTF dimerization and to inhibit Abeta42 production using a validated fluorescence resonance energy transfer (FRET)-based betaCTF dimerization assay, and an in vitro gamma-secretase activity assay, respectively; 2) Binding epitope detection at the betaCTF-TMD dimer interface from advanced free energy calculations and in silico docking experiments of those compounds that modulate dimerization and have an effect on Abeta42 production. Our combined experimental and computational approach will provide structure-activity relationship information on the target betaCTF that is expected to facilitate identification of lead compounds for further development as novel AD therapeutics.