The “misfolding” and assembly of proteins into ordered and amorphous aggregates is implicated in a wide range of detrimental and beneficial biological functions. Although much less is known about protein misfolding than protein folding, it appears that the molecular interactions governing these two processes are very different. To further illuminate the molecular determinants of protein aggregation, we have sought to understand the underlying protein-protein interactions. Recently we have demonstrated that peptide microarrays can be used to identify small sequence elements within several amyloid-forming proteins that govern their aggregation behavior (Tessier & Lindquist, Nature, 2007). In this presentation we will discuss our recent work using peptide microarrays to understand the interactions governing aggregation of closely related prions and how these interactions regulate species barriers. Moreover, we will discuss analysis of the peptide interactions driving Aß aggregation associated with Alzheimer's disease, mechanisms of small molecule inhibition of Aß aggregation and novel synthesis approaches for generating small molecule regulators of Aß aggregation.

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