Neurodegenerative diseases devastate millions of patients worldwide. These diseases typically target older individuals. In roughly 50 years over a quarter of the world will be over 65 years of age. The fastest growing demographic group in the developed world is people 85 and older. Said individuals have a very high probability (>50% and increasing with age) of acquiring one of these diseases. These diseases are currently untreatable, aside from alleviating the symptoms, and they can't be definitively diagnosed before death. These diseases are due to protein conformational changes involving formation of a toxic, soluble aggregate. Experimental studies have been unable to elucidate this structure. Computer simulations have, however, provided atomic resolution models for this state, and it was found that different proteins form the same rare structure during amyloidosis. This structure is being targeted here for the design of potential therapeutic and diagnostic agents. Specifically this proposal focuses on design of stable ?-sheet structures, their biophysical characterization, and binding to amyloidogenic proteins both during aggregation in solution (to test their ability to inhibit the process) and when the designed compounds are immobilized (to test their diagnostic ability). The designed compounds will be tested against various peptide/protein systems, including transthyretin, A(1-42), amylin, and the prion protein.
The specific aims of this project are: (1) Design small, stable ?-sheet peptides/hairpins; (2) Test the ability of designed peptides to inhibit amyloid formation in solution; (3) Immobilize designs on agarose beads and test the ability of designed peptides to bind toxic oligomers; and (4) Characterize the structural properties of the designs and determine the spectroscopic signatures for ?-sheet.
The population is aging and the incidence of amyloid diseases is growing to epidemic proportions. Currently most of these diseases cannot be definitively diagnosed without an autopsy and therapeutics are lacking. New approaches are needed to attack these debilitating diseases.
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