Unfolded peptides originating from the endoproteolysis of large proteins are known to assemble into amyloid fibrils in several diseases like Familial Amyloidosis, Finnish Type (FAF). Small organic molecules will be used to prevent a misfolding event that leads to proteolysis. The goal of this research is to synthesize and screen a library of lysophosphatidic acid (LPA) analogs that are capable of binding to gelsolin or both. The best binders will be tested for amyloid inhibition. Biophysical studies will be performed in order to determine the mechanism of action of the lead compounds. Specifically, we are interested in whether the best binders improve folding kinetics or change the thermodynamics of gelsolin. We will try to cocrystallize gelsolin or a S1-S2 domain construct with active small molecules in order to gain structural information regarding the PIP2- binding region of gelsolin. Such studies will most likely lead to improved small molecules that may be used in studies in cell cultures.
