Thursday, November 8, 2007 - 1:10 PM

Pharmacologic Enhancement Of The Chemistry And Biology Of Cellular Protein Folding

Laura Segatori, Chemical and Biomolecular Engineering, Rice University, Houston, TX 77251 and Jeffrey W. Kelly, Chemistry, The Scripps Research Institute, 10050 N. Torrey Pines Road, La Jolla, CA 92037.

Loss-of-function diseases caused by defective proteins are typically ameliorated by intravenous administration of the appropriate recombinant protein. Restoring the cellular folding and function of these altered endogenous proteins represents a powerful new therapeutic strategy to ameliorate a wide variety of diseases. To demonstrate proof of principle, we correct the folding and trafficking defects in multiple lysosomal storage diseases where therapeutic options are currently unavailable. A small molecule that enhances the capacity of cellular protein folding partially restores the folding and function of several glycolipid-processing enzymes whose deficiencies lead to glycolipid storage associated with central nervous system (CNS) abnormalities. A further enhancement in folding, trafficking and function is observed when such folding modulators are used in combination with molecules that stabilize the specific disease-associated enzyme in the endoplasmic reticulum, so called pharmacologic chaperones. Protein misfolding is now appreciated to cause diseases in multiple therapeutic areas owing to the central role that folding plays in the fundamental dogma associated with molecular information transfer in biology. Thus, therapeutic strategies based on the use of folding modulators discussed in this study are believed to have far reaching implication in the cure of a diverse range of misfolding diseases.