Amyloidogenic proteins self-assemble to form ordered fibrillar structures associated with neurodegenerative disease.  Therapeutics for these protein-linked diseases do not currently address the formation of cytotoxic fibrillar formations.   Current research in this direction focuses on the identification of small molecules which act to inhibit the aggregation process. We use insulin as a model protein and probe the kinetics associated with protein aggregation in the presence of small molecules chosen to stabilize the protein.  The kinetics of aggregation of bovine and porcine insulin denatured at 65-75�C over the course of about an hour have been studied by rheology and small angle x-ray scattering (SAXS) and are compared to aggregation in the presence of inhibiting molecules including metacresol and rifampicin The protein is observed by SAXS to move from dimer conformation (~14�) to fibrils on the order of 500� with some evidence of mediation of aggregation by the presence of inhibiting molecules.

Amyloid fibril inhibition by small molecules

244th National Meeting (2012)

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