Drugs for Protein Misfolding

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Summary UCLA researchers in the Department of Neurology with an international team of scientists have developed compounds for therapeutic use in protein misfolding diseases.   Background Protein misfolding is the underlying cause of a number of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) as well systemic diseases such as Type-2 diabetes and prion diseases. In each of these diseases, a protein adopts an altered conformation composed of β-sheets and is found in large deposits that are toxic to cells. For example, AD patients are known to have large β-sheet rich deposits composed of the protein, amyloid-β. Currently, these diseases have no therapeutics and with a global aging population present a huge financial burden.   Innovation UCLA researchers have developed novel compounds based on the β-sheet rich structure adopted by the proteins in the aggregated state. The small molecules bind the β-sheet structure and suppress their formation. They also disassemble pre-formed aggregates robustly. The small molecules have shown to be neuro-protective against amyloid-β induced aggregation and toxicity in cultured cells.   Applications Therapeutic in Alzheimer’s disease Therapeutic in Parkinson’s disease Therapeutic for protein misfolding disease   Advantages Applicable to broad range of protein misfolding diseases Prevents formation of new aggregates Breaks pre-formed aggregates   Related Materials Rational Design of ß-Sheet Ligands against Aß42-induced toxicity. K. Hochdörffer, J. März-Berberich, L. Nagel-Steger, M. Epple, W. Meyer-Zaika, A.H.C. Horn, H. Sticht, S. Sinha, G. Bitan, T. Schrader, J. Am. Chem. Soc. 2011