Poster abstracts
Poster number 10 submitted by Claire Hoffman
Targeting cross-β-sheet surfaces with small molecule imaging agents
Claire Hoffman (Department of Biological Chemistry and Pharmacology), Jeff Kuret (Department of Biological Chemistry and Pharmacology)
Abstract:
Positron emission tomography (PET) is poised to revolutionize preclinical assessment of high-prevalence neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Although many candidate radiotracers have been developed, the mechanisms that mediate their high affinity binding (i.e., low nM) to the surfaces presented by α-synuclein, β-amyloid, or tau cross-β-sheet aggregates are not fully understood. This is in part because radiotracers tend to be flat heterocycles with limited three-dimensional character, and because their high-density binding partners are composed of shallow channels located along aggregate surfaces. To address this problem, we developed a family of small molecule probes and characterized their interaction with α-synuclein, β-amyloid, and tau aggregates using a thioflavin dye displacement assay. Probes with relative selectivity for individual aggregate compositions were identified. To further characterize the mechanism of probe binding, a library of synthetic binding sites constructed from the PHF6 site of tau protein (VQ2IV4YK) was prepared. The peptide library was engineered to generate aggregates with a common hydrophobic core but with external surfaces that differed with respect to hydrophobicity, polarizability, channel width, aromatic side chain availability, and net charge. Results showed that the peptide library members formed filamentous aggregates that bound thioflavin dye. Probe affinity for individual peptide aggregates was then determined by thioflavin displacement assay. The results point toward molecular descriptors important for engagement with cross-β-sheet surfaces of varying side chain composition.
Keywords: neurodegenerative disease, radiotracer, PHF6