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Jeffery W. Kelly

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Jeffery W. Kelly (born August 23, 1960 in Medina, New York) is the former Dean of Graduate Studies (2000-2008) and Vice President of Academic Affairs (2000-2006) and currently is the Chairman of Molecular and Experimental Medicine and the Lita Annenberg Hazen Professor of Chemistry within the Skaggs Institute of Chemical Biology at The Scripps Research Institute in La Jolla, California.[1] His research focuses on understanding protein folding, misfolding and aggregation and on developing both chemical[2] and biological strategies[3] to ameliorate diseases caused by protein misfolding and/or aggregation. Of the 100 Ph.D. students and postdoctoral fellows who have trained in the Kelly Lab., > 40 are in tenured or tenure-track academic jobs.

Kelly received his Ph.D. in organic chemistry from the University of North Carolina at Chapel Hill (1986) and performed post-doctoral research at The Rockefeller University (1986–89). His research focuses on the chemistry and biology of protein homeostasis or proteostasis.[4] Besides studying the structural and energetic basis underlying protein folding, his laboratory also studies the etiology of neurodegenerative diseases linked to protein aggregation, including Alzheimer's disease, Parkinson's Disease, and the light chain, gelsolin and transthyretin-based amyloidoses–publishing over 300 peer-reviewed papers in this area to date (h-index = > 80). He has also provided insight into genetic diseases associated with loss of protein function, such as the lysosomal storage diseases.[5][6]

Kelly has cofounded three biotechnology companies, FoldRx Pharmaceuticals (with Susan Lindquist), now owned by Pfizer, Proteostasis Therapeutics, Inc. (with Andrew Dillin and Richard Morimoto) (a NASDAQ public company) and Misfolding Diagnostics (with Xin Jiang and Justin Chapman; a private corporation). The Kelly laboratory discovered the first regulatory agency-approved drug that slows the progression of a human amyloid disease[7][8][9] using a structure-based design approach. This drug, now called Tafamidis or Vyndaqel,[10] slowed the progression of familial amyloid polyneuropathy in an 18 month placebo controlled trial and in an 12 month extension study sponsored by FoldRx Pharmaceuticals (acquired by Pfizer in 2010).[8][9] Vyndaqel or Tafamidis [11] was approved for the treatment of Familial amyloid Polyneuropathy by the European Medicines Agency in late 2011 and by the Japanese Pharmaceuticals and Medical Devices Agency in 2013. A second statistically significant clinical trial with the repurposed Merck Non steroidal anti-inflammatory drug, diflunisal discovered by Kelly to kinetically stabilize TTR,[12][13] confirms the validity of the kinetic stabilizer mechanism to ameliorate the TTR amyloidoses.[14] Collectively, the tafamidis and diflunisal data provide compelling pharmacologic evidence for the amyloid hypothesis, the idea that active transthyretin aggregation causes the loss of post-mitotic tissue in this degenerative amyloid disease. Moreover, these data validate transthyretin as a key drug target to stop the progression of several degenerative phenotypes linked to transthyretin aggregation.

In addition to discovering the first drug that slows the progression of a human amyloid disease, the Kelly Laboratory is credited with demonstrating that transthyretin conformational changes alone are sufficient for amyloidogenesis,[15] discovering the first example of functional amyloid in mammals,[16] making major contributions toward understanding β-sheet folding, discovering the "enhanced aromatic sequon"–sequences that are more efficiently N-glycosylated by cells and which stabilize the native state of proteins that they are incorporated into as a consequence of aromatic side chain–N-glycan interactions[17] and was corresponding author on and contributed some of the key experimental data demonstrating that altering cellular protein homeostasis or proteostasis capacity has the potential to alleviate protein misfolding and aggregation diseases.[18][19]

Kelly was elected to the American Academy of Arts and Sciences in 2016 and has won numerous awards including the Biopolymers Murray Goodman Memorial Prize, 2012; The American Chemical Society, Ralph F. Hirschmann Award in Peptide Chemistry, 2012; The Protein Society Emil T. Kaiser Award, 2011; The American Peptide Society Rao Makineni Lectureship (Award), 2011; The American Peptide Society Vincent du Vigneaud Award, 2008; National Institutes of Health Merit Award, 2006; American Chemical Society Arthur C. Cope Scholar Award, 2001; SUNY at Fredonia Alumni Distinguished Achievement Award, 2000; SUNY at Fredonia Chemistry Dept. Alumni Award, 2000; The Protein Society-Dupont Young Investigator Award, 1999; The Biophysical Society National Lecturer (Award), 1999; Texas A&M Univ. Honors Program Teacher / Scholar Award, 1994 and the Searle Scholar Award, 1991.

References

  1. ^ The Kelly Group, Scripps.edu, Retrieved December 10, 2010
  2. ^ Johnson, S.; Green, N.; Adamanski-Werner, S.; Kelly, J.W. "Native State Kinetic Stabilization as a Strategy to Ameliorate Protein Misfolding Diseases: A focus on the Transthyretin Amyloidoses" Acct. Chem. Res. 2005 38, 911-921.
  3. ^ Balch, W.E.; Morimoto, R.I.; Dillin, A.; Kelly, J.W. “Adapting Proteostasis For Disease Intervention” Science 2008 319, 916-919.
  4. ^ Lindquist, S.L.; Kelly, J.W. “Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases–Progress and Prognosis” Cold Spring Harbor Perspect. Biol. doi10.1101 / cshperspect.a004507 2011, 307-340.
  5. ^ Mu, T-W.; Ong, D.S.T.; Wang, Y-J; Balch, W. E.; Yates, J.R.; Segatori, L.; Kelly, J.W. .”Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding Diseases” Cell 2008 134, 769-781.
  6. ^ Sawkar, A.R.; 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 Disease " Proc. Natl. Acad. Sci., 2002, 99, 15428-15433.
  7. ^ Razavi, H.; Palaninathan, S.K. Powers, E.T.; Wiseman, R.L.; Purkey, H.E.; Mohamadmohaideen, N.N.; Deechongkit, S.; Chiang, K.P.; Dendle, M.T.A.; Sacchettini, J.C.; Kelly, J.W. "Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation and Mechanism of Action" Angew. Chem. Int. Ed. 2003, 42, 2758-2761.
  8. ^ a b Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Lozeron, P.; Suhr, O.B.; Campistol, J.M.; Conceiçao, I.; Schmidt, H.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Wilson, A.; Grogan, D.R. “Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial” Neurology 2012, 79, 785-792
  9. ^ a b Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Suhr, O.B.; Conceiçao, I.; Schmidt, H. H. J.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Grogan, D.R. “Long-term Effects of Tafamidis for the Treatment of Transthyretin Familial Amyloid Polyneuropathy” J. Neurology 2013 260, 2802-2814.
  10. ^ Johnson, S.M.; Connelly, S.; Fearns, C.; Powers, E.T.; Kelly, J.W. “The Transthyretin Amyloidoses: From Delineating the Molecular Mechanism of Aggregation Linked to Pathology to a Regulatory Agency Approved Drug” J. Mol. Biol. 2012 421, 185-203.
  11. ^ Bulawa, C.E.; Connelly, S.; DeVit, M.; Wang, L. Weigel, C.;Fleming, J. Packman, J.; Powers, E.T.; Wiseman, R.L.; Foss, T.R.; Wilson, I.A.; Kelly, J.W.; Labaudiniere, R. “Tafamidis, A Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade” Proc. Natl. Acad. Sci. 2012 109, 9629-9634.
  12. ^ Adamanski-Werner, S.L., Kumar, P.S., Sacchettini, J.C., Kelly, J.W. "Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis" J. Med. Chem. 2004 47, 355-374
  13. ^ Sekijima, Y.,;Dendle, M.; Kelly, J.W. " Orally Administered Diflunisal Stabilizes Transthyretin Against Denaturation–A New Therapeutic Strategy for Amyloidosis" Amyloid 2006 13, 236-249
  14. ^ Berk, J.L.; Suhr, O.; Obici, L.; Sekijima, Y.; Zeldenrust, S.R.; Yamashita, T.; Hennegan, M.A.; Gorevic, P.D.; Litchy, W.J.; Wiseman, J.F.; Nordh, E.; Corato, M.; Lozza, A.; Cortese, A,; Robinson-Papp, J.; Colton, T.; Rybin, D.V.; Bisbee, A.B.; Ando, Y.; Ikeda, S,; Seldin, D.C.; Merlini, G.; Skinner, M.; Kelly, J.W.; Dyck, P.J. “Repurposing Diflunisal for Familial Amyloid Polyneuropathy–a Randomized Clinical Trial” J. Am. Med. Assoc. 2013 310, 2658-2667.
  15. ^ Colon, W.; Kelly, J.W. "Partial Denaturation of Transthyretin is Sufficient for Amyloid Fibril Formation In Vitro." Biochemistry, 1992, 31, 8654-8660.
  16. ^ Fowler, D.M.; Koulov, A.V.; Alory-Jost, C.; Marks, M.S.; Balch, W.E; Kelly, J.W. "Functional Amyloid Formation Within Mammalian Tissue " PLoS Biology 2006, 4, 100-107.
  17. ^ Culyba, E.K.; Price, J.L.; Hanson, S.R.; Dhar, A,; Wong, C-H.; Gruebele, M.; Powers, E.T.; Kelly, J.W. “Protein Native State Stabilization by Placing Aromatic Side Chains in N-Glycosylated Reverse Turns” Science 2011, 331, 571-575.
  18. ^ Balch, W.E.; Morimoto, R.I.; Dillin, A.; Kelly, J.W. “Adapting Proteostasis For Disease Intervention” Science 2008, 319, 916-919.
  19. ^ Shoulders, M.D.; Ryno, L.M.; Genereux, J.C.; Moresco, J.J.; Tu, P.G. Wu, C.; Yates, J.R.; Su, A.I.; Kelly, J.W.; Wiseman, R.L. “Stress-Independent Activation of XBP1s and/or ATF6 Reveals Three Functionally Diverse ER Proteostasis Environments” Cell Reports 2013 3, 1279-1292.

Significant Papers

1992 Colon, W.; Kelly, J.W. "Partial Denaturation of Transthyretin is Sufficient for Amyloid Fibril Formation In Vitro." Biochemistry, 31 8654-8660.

2001 Jager, M.; Nguyen, H.; Crane, J.C.; Kelly, J.W.; Gruebele, M. "The Folding Mechanism of a β-Sheet: The WW Domain" J. Mol. Biol., 311, 373-393.

2001 Hammarstrom, P.; Schneider, F.; Kelly, J.W. "Trans-Suppression of Misfolding In An Amyloid Disease" Science 293, 2459-2461.

2002 Sawkar, A.R.; 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 Disease " Proc. Natl. Acad. Sci. 99, 15428-15433.

2003 Hammarstrom, P.; Wiseman, R. L.; Powers, E.T.; Kelly, J.W. "Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics" Science 299, 713-716.

2004 Deechongkit, S.; Nguyen, H.; Dawson, P.E.; Gruebele, M.; Kelly, J.W. “Context Dependent Contributions of Backbone H-Bonding to β-Sheet Folding Energetics” Nature 430, 101-105.

2005 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 121, 73-85.

2006 Fowler, D.M.; Koulov, A.V.; Alory-Jost, C.; Marks, M.S.; Balch, W.E; Kelly, J.W. "Functional Amyloid Formation Within Mammalian Tissue " PLoS Biology 4, 100-107.

2008 Mu, T-W.; Ong, D.S.T.; Wang, Y-J; Balch, W. E.; Yates, J.R.; Segatori, L.; Kelly, J.W. .”Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding Diseases” Cell 134, 769-781.

2008 Balch, W.E.; Morimoto, R.I.; Dillin, A.; Kelly, J.W. “Adapting Proteostasis For Disease Intervention” Science 319, 916-919.

2011 Culyba, E.K.; Price, J.L.; Hanson, S.R.; Dhar, A,; Wong, C-H.; Gruebele, M.; Powers, E.T.; Kelly, J.W. “Protein Native State Stabilization by Placing Aromatic Side Chains in N-Glycosylated Reverse Turns” Science 331, 571-575.

2012 Bulawa, C.E.; Connelly, S.; DeVit, M.; Wang, L. Weigel, C.;Fleming, J. Packman, J.; Powers, E.T.; Wiseman, R.L.; Foss, T.R.; Wilson, I.A.; Kelly, J.W.; Labaudiniere, R. “Tafamidis, A Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade” Proc. Natl. Acad. Sci. 109, 9629-9634.

2013 Chen, W; Enck, S.; Price, J.L.; Powers, D.L.; Powers, E.T.; Wong, C-H.; Dyson, H.J.; Kelly, J.W. “The Structural and Energetic Basis of Protein-Carbohydrate Interactions” J. Am. Chem. Soc. 135, 9877-9884.

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