Source: Interfolio F180
Jeffery Kelly
Research Focus
Chemical Biology and Biophysical Chemistry.
A central focus of our research is to understand the principles of protein folding and to comprehend the basis for misfolding and/or aggregation diseases such that we can develop novel therapeutic strategies using chemistry, biophysical and biological approaches.
A multidisciplinary approach to understanding degenerative diseases linked to protein aggregation is a main focus of our laboratory. We concentrate on Alzheimer's disease, as well as the transthyretin- and light-chain-based amyloid diseases. Mechanistic studies of protein aggregation have led to small molecule and macromolecular amyloid fibril inhibition strategies, including the drug, tafamidis, discovered by the Kelly lab and sold by Pfizer. Our efforts to seek an aggregate structure-proteotoxicity relationship have led to 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. We also use cell-based screens to discover mediators of the protein homeostasis network, including stress-responsive signaling pathway activators (in collaboration with the Wiseman lab) and autophagy activators, which should be generally useful to ameliorate amyloid diseases.
Investigation into lysosomal storage diseases are underway wherein small molecules that enhance the proteostasis network capacity of the secretory pathway and pharmacologic chaperones are being sought 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 biological studies carried out in collaboration with several laboratories.
The Kelly lab in collaboration with the Wong lab discovered the enhanced aromatic sequon-sequences that are more efficiently N-glycosylated by cellls and which stabilize the native state of proteins that they are incoporated into as a consequence of aromatic side chain-N-glycan interactions. Using chemically synthesized WW domain analogs wherein we vary the aromatic side chain and the sugar, we are learning a great deal about the underpinnings of this stabilizing interaction.
Developing synthetic methodology to accomplish medicinal chemistry towards the development of drugs for several activators of proteostasis capacity is a central component of the lab. In addition, we use these methods to scrutinize the hypothesis that we can discover drugs via our Inverse Drug Discovery approach.
Education
B.S. (Chemistry), State University of New York at Fredonia, 1982Ph.D. (Organic Chemistry), The University of North Carolina at Chapel Hill, 1986
Professional Experience
2018-2021Faculty representative on TSRI Board of Directors2017- 2018 Co-Chairman, Department of Chemistry, The Scripps Research Institute
2008-2017 Chairman, Molecular and Experimental Medicine, The Scripps Research Institute
2000-2008 Dean of Graduate and Postgraduate Studies, Scripps Graduate Program, The Scripps Research Institute
2000-2006 Vice President, Academic Affairs, The Scripps Research Institute
1997-1997 Professor of Chemistry, Texas A&M University
1996-1996 Visiting Investigator, Memorial Sloan-Kettering Institute
1995-1997 Associate Professor of Chemistry, Texas A&M University
1989-1995 Assistant Professor of Chemistry, Texas A&M University
1986-1989 NIH Postdoctoral Fellow with Dr. E. Thomas Kaiser, The Rockefeller University
Awards & Professional Activities
2022 Breakthrough Prize in Life Sciences2019 E. B Hershberg Award for Important Discoveries in Medicinally Active Substances, American Chemical Society
2017 Elected Fellow, National Academy of Inventors
2017 Chemical Pioneer Award, American Institute of Chemists
2021 Horizon Prize Team Award, Royal Society of Chemistry
2021 Edward E. Smissman Award, American Chemical Society, Medicinal Chemistry Div.
2019 Medicinal Chemistry Division Hall of Fame Election, American Chemical Society
2016 Jacob and Louise Gabbay Award in Biotechnology and Medicine, Brandeis University
2016 Elected Member, American Academy of Arts and Sciences
2016 Jeremy Knowles Award, Royal Society of Chemistry
2012 Murray Goodman Memorial Prize, Biopolymers
2012 Ralph F. Hirschmann Award in Peptide Chemistry, American Chemical Society
2011 Emil Thomas Kaiser Award, The Protein Society
2011 Rao Makineni Lectureship, The American Peptide Society
2008 Vincent du Vigneaud Award, The American Peptide Society
2006 Merit Award, National Institutes of Health
2001 Arthur C. Cope Scholar Award, American Chemical Society
2000 Alumni Distinguished Achievement Award, State University of New York at Fredonia
2000 Chemistry Department Alumni Award, State University of New York at Fredonia
1999 Dupont Young Investigator Award, The Protein Society
1999 National Lecturer (Award), The Biophysical Society
1995 Honors Program Teacher / Scholar Award, Texas A&M University
1994 Camille Dreyfus Teacher-Scholar Award, The Camille & Henry Dreyfus Foundation
1991 Searle Scholar Award, Searle Scholars Program
1987 NIH Postdoctoral Fellowship, The Rockefeller University
1985 Rohm and Haas Organic Division Fellowship, American Chemical Society
1986 North Carolina Centennial Scholarship, American Chemical Society
1982 Outstanding Senior in Chemistry, American Institute of Chemists
Selected Publications
Deechongkit, S.; Nguyen, H.; Powers, E. T.; Dawson, P. E.; Gruebele, M.; Kelly, J. W. Context-dependent contributions of backbone hydrogen bonding to ß-sheet folding energetics. Nature 2004, 430, 101-105.
[View]
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.
[View]
Sekijima, Y.; Wiseman, R. L.; Matteson, J.; Hammarström, P.; Miller, S. R.; Sawkar, A. R.; Balch, W. E.; Kelly, J. W. The biological and chemical basis for tissue-selective amyloid disease. 2005, 121, 73-85.
Balch, W. E.; Morimoto, R. I.; Dillin, A.; Kelly, J. W. Adapting proteostasis for disease intervention. Science 2008, 319, 916-919.
[View]