Dynameomics: From Simulation of All Protein Folds to the Design of Amyloid Inhibitors and Diagnostics

Synopsis

We have been involved in the development and use of realistic computer simulations of proteins to characterize the conformational changes associated with amyloid formation. In so doing we discovered a novel structure adopted by amyloidogenic proteins, but not 'normal' proteins, and we proposed that it defines the toxic soluble oligomers formed en route to the nontoxic mature fibrils. As such, this structure, which we call alpha-sheet, represents a new target for amyloid therapeutics and diagnostics. We have designed, synthesized, and tested compounds to be complementary to this 'toxic' structure and they inhibit amyloid formation of A-beta (Alzheimer's Disease), transthyretin (systemic amyloid disease and heart disease), and amylin (type 2 diabetes) by specifically binding the toxic oligomers, which in turn neutralizes the toxic species. These alpha-sheet compounds represent a novel platform for attacking these diseases and the hope of disease-modifying treatments and early diagnosis.