Synthesis and Biophysical Analysis of Small Molecule Antagonists of Toxic Protein Aggregation

Protein aggregation is the seminal event in several neurodegenerative disorders and the primary degradation mechanism for protein therapeutics. We seek to identify molecules that antagonize protein aggregation and elucidate the mechanism by which they exert their anti-aggregation activity. In this presentation we will discuss our use of enzymatic oxidation to synthesize oligophenolic compounds that inhibit and reverse toxic Aß aggregation associated with Alzheimer's disease. Moreover, we will discuss our mechanistic analysis of how these molecules modify Aß self-interactions and aggregation behavior. In addition, we will discuss our development of a high-throughput peptide microarray approach for identifying small molecules with anti-aggregation activity and for understanding how these molecules exert their activity. We expect that these novel synthesis and screening methods will yield important molecular insights into preventing and reversing toxic protein aggregation.