Department of Chemistry
The Skaggs Institute for Chemical Biology
Faculty, Graduate Program
Bioorganic and Biophysical Chemistry
The central focus of our research is to understand the principles of protein folding and to comprehend the basis for misfolding diseases such that we can develop novel therapeutic strategies using chemistry, biophysical and cell biology approaches.
A multidisciplinary approach to understanding amyloid diseases is the main focus of our laboratory. We concentrate on Alzheimer's disease, as well as the transthyretin- and gelsolin-based amyloid diseases. Mechanistic studies of amyloidosis lead to small molecule and macromolecular amyloid fibril inhibition strategies, as well as insight into the etiology of these pathologies. Chemical synthesis of small molecule inhibitors designed to manipulate protein energetics is a significant component of our research program.
Several projects in the lysosomal storage disease area are underway wherein small molecule inhibitors are being used to correct genetic defects in the folding and trafficking of enzymes that are critical for lysosome function and therefore life.
All of the projects discussed thus far utilize bioorganic and biophysical chemistry approaches in combination with cell biology studies carried out in collaboration with the Balch Laboratory.
Studies directed at understanding the principles of b-sheet folding utilizing rapid kinetic and thermodynamic measurements are ongoing and focused on the WW domain, a 34-residue 3-stranded b-sheet. Chemical synthesis of the WW domain allows us to incorporate unique amino acids into the fold to probe structural determinants of transition state and ground state structure.
Developing synthetic methodology to prepare oxime ethers, thioimidates, and the like is also a component of the laboratory.
B.S., Chemistry, State University of New York at Fredonia, 1982
Ph.D., Chemistry, The University of North Carolina at Chapel Hill
Searle Scholar Award in Biomedical Sciences, 1991-1994
Camille and Henry Dreyfus Teacher Scholar Award, 1994
Texas A&M University Teacher Scholar Award, 1994-1995
The Biophysical Society National Lecturer, 1999
The Protein Society - Dupont Young Investigator Award, 1999
Alumni Distinguished Achievement Award, State University of New York at Fredonia, 2000
Arthur C. Cope Scholar Award, American Chemical Society, 2001
Deechongkit, S.; Nguyen, H.; Dawson, P.E.; Gruebele, M.; Kelly, J.W. "Context Dependent Contributions of Backbone H-Bonding to b-Sheet Folding Energetics" Nature 2004, 430, 101-105.
Cohen,F.: Kelly, J.W. "Therapeutic Approaches to Protein Folding Diseases" Nature, 2003, 426, 905-910.
Hammarstrom, P.; Wiseman, R.L.; Powers, E.T.; Kelly, J.W., "Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics" Science 2003, 299, 713-716.
Sawkar, A.; Cheng, W-C.; Beutler, E.; Wong, C.-H.; Balch, W.E.; Kelly, J.W. "Chemical Chaperones Increase the Cellular Activity of N370S β glucosidase; A Therapeutic Strategy for Gaucher's Disease" Proc.Natl.Acad.Sci., 2002, 99, 15428-15433.