Jeffery Kelly, PhD
Scripps Research Joint Appointments
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
Ph.D. (Organic Chemistry), The University of North Carolina at Chapel Hill, 1986B.S. (Chemistry), State University of New York at Fredonia, 1982
Professional Experience
2018-2018 co-Chair, Chemistry, Scripps Research2017-2018 Co-Chair, Molecular Medicine, Scripps Research
2008-2017 Chairman, Molecular and Experimental Medicine (MEM), Scripps Research
2000-2008 Dean of Graduate and Postgraduate Studies, Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research
2000-2006 Vice President, Academic Affairs, Scripps Research
1997-1997 Professor of Chemistry, Texas A&M University
1995-1997 Associate Professor of Chemistry, Texas A&M University
1996-1996 Visiting Investigator, Sloan-Kettering Institute
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
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 National Institutes of Health Merit Award, 2006 The American Peptide Society Vincent du Vigneaud Award, 2008 The American Peptide Society Rao Makineni Lectureship (Award), 2011 The Protein Society Emil Thomas Kaiser Award, 2011 American Chemical Society Ralph F. Hirschmann Award in Peptide Chemistry, 2012 Biopolymers Murray Goodman Memorial Prize, 2012 Royal Society of Chemistry Jeremy Knowles Award, 2016 American Academy of Arts and Sciences, Elected member, 2016 Jacob and Louise Gabbay Award in Biotechnology and Medicine, 2016 American Institute of Chemists Chemical Pioneer Award, 2017 National Academy of Inventors, elected Fellow, 2019 E.B. Hershberg Award for Important Discoveries in Medicinally Active Substances, 2019 American Chemical Society, Medicinal Chemistry Division Hall of Fame Election, 2021 American Chemical Society, Medicinal Chemistry Div., Edward E. Smissman Award, 2021 Royal Society Robert Robinson Award in Synthetic Organic Chemistry–SuFEx team, 2022 Breakthrough Prize in Life SciencesSelected References
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.
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.
Sekijima, Y.; Wiseman, R.L.; Matteson, J.; Hammarström, P.; Miller, S.R.; Balch, W.E.; Kelly, J.W. "Biological and Chemical Basis for Tissue Selective Amyloid Disease" Cell 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.