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Stephen Kent

InstitutionUniversity of Chicago
DepartmentBiochemistry and Molecular Biology
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    Collapse Overview 
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    Stephen Kent set out to understand the chemical basis of enzyme catalysis. In a life-long pursuit of that goal, Kent has developed advanced synthetic chemistries, and used them to elucidate the molecular basis of protein function. His early work gave unique insights into the fundamental physicochemical principles underlying polymer-supported peptide synthesis (solid phase peptide synthesis (SPPS)), and led to the identification and minimization of chronic side reactions then affecting SPPS. The resulting highly optimized methods for the chemical synthesis of peptides were commercialized in partnership with Applied Biosystems and became used throughout the world. Kent applied this highly optimized SPPS to studies of the hepatitis B virus and the human immunodeficiency virus (HIV). This work culminated in the idenitifcation, with Robert Neurath, of the immunodominant B- and T-cell epitiopes of the hepatitis B virus, key information for the development of improved hepatitis B vaccines. The highly optimized SPPS methods were also applied to total chemical synthesis of the HIV-1 protease, and led to the determination (with collaborators) of the original crystal structures of the HIV-1 protease enzyme protein molecule complexed with canonical inhibitors. These HIV-1 protease structural data were made freely available and formed the basis of worldwide programs in structure-based drug design that led to the commercial development and rapid introduction of the highly effective ‘protease inhibitor’ class of AIDS therapeutics.

    The Kent research group pioneered a radically novel approach to the total synthesis of protein molecules, based on the ‘chemical ligation’ principle: chemoselective condensation in aqueous solution of unprotected peptide segments. This principle is embodied in the novel ‘native chemical ligation’ and ‘kinetically-controlled ligation’ chemistries developed by Kent and his colleagues. Chemical ligation has enabled the routine total chemical synthesis of a wide range of high purity, meticulously characterized protein molecules and the consequent general application of physical and organic chemistries to the world of proteins.

    In the past few years, the Kent lab has pioneered the use of mirror image protein molecules (‘D-proteins’) to facilitate the determination of the X-ray structures of recalcitrant proteins by racemic and quasi-racemic crystallography. Even more recently, the Kent lab has reported the first efficient route to a total chemical synthesis of human insulin, making use of a unique ester-linked polypeptide as a chemical-surrogate for the proinsulin polypeptide chain found in Nature. Currently, the Kent lab and its collaborators are employing a systematic {chemical protein synthesis plus protein phage display} approach to the development of D-proteins as a novel class of molecules for antagonizing the action of natural protein molecules. Such D-protein antagonists may have significant advantages as human therapeutics.

    Collapse Biography 
    Collapse education and training
    Victoria University of Wellington, New ZealandB.Sc.1968Chemistry & Biochemistry
    Massey University, New ZealandM.Sc.1970Chemistry & Biochemistry
    University of California, BerkeleyPh.D.1974Organic Chemistry & Protein NMR
    Rockefeller University, R.B. Merrifield Lab1977Solid Phase Peptide Synthesis
    Collapse awards and honors
    2018Inaugural Scoffone Award, Italian Peptide Society
    2017Prelog Medal, ETH Zurich
    2013Leach Medal, Lorne Conference on Protein Structure & Function
    2011Bader National Award in Bioorganic Chemistry, American Chemical Society
    2010Akabori Memorial Medal, Japanese Peptide Society
    2010Rudinger Memorial Medal, European Peptide Society
    2009Merrifield Award, American Peptide Society
    2004du Vigneaud Award, American Peptide Society
    2002Kaiser Award, The Protein Society
    1994Hirschmann National Award in Peptide Chemistry, American Chemical Society

    Collapse Research 
    Collapse research activities and funding
    R21AI111409     (KENT, STEPHEN B.H.)Jun 13, 2014 - May 31, 2016
    Novel Approaches to the Total Chemical Synthesis of Lasso Peptides as a Scaffold
    Role: Principal Investigator

    R01DK089934     (KENT, STEPHEN B.H.)Aug 1, 2010 - May 31, 2015
    Design, Total Synthesis & Properties of Novel Chemical Analogs of Human Insulin
    Role: Principal Investigator

    R01GM075993     (KENT, STEPHEN B.H.)Sep 23, 2005 - Jul 31, 2011
    A Systematic Approach to the Chemical Synthesis of G-Protein Coupled Receptors
    Role: Principal Investigator

    R01DK069764     (WEISS, MICHAEL AARON)Sep 30, 2004 - Mar 31, 2015
    How mutations in proinsulin cause diabetes: a protein-misfolding disease
    Role: Co-Principal Investigator

    R01GM048897     (KENT, STEPHEN B.H.)Aug 1, 1993 - Jul 31, 1998
    Role: Principal Investigator

    P01GM048870     (OLSON, ARTHUR J.)Sep 30, 1992 - Aug 31, 2008
    Drug Design Cycle targeting HIV Protease Drug Resistance
    Role: Co-Principal Investigator

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    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Dhayalan B, Kent SBH, Fetter-Pruneda I. A Chemical Counterpart to the Resolution Step of Nature's Intein-Mediated Protein Splicing. ACS Chem Biol. 2024 Jan 19; 19(1):9-14. PMID: 38096499; PMCID: PMC10804359.
      Citations:    Fields:    Translation:Cells
    2. Kent SJ, Juno JA. Vaccination after prior COVID-19 infection: Implications for dose sparing and booster shots. EBioMedicine. 2021 Oct; 72:103586. PMID: 34536815; PMCID: PMC8440136.
      Citations: 3     Fields:    Translation:HumansCells
    3. Leiske MN, Lai M, Amarasena T, Davis TP, Thurecht KJ, Kent SJ, Kempe K. Interactions of core cross-linked poly(2-oxazoline) and poly(2-oxazine) micelles with immune cells in human blood. Biomaterials. 2021 07; 274:120843. PMID: 33984635.
      Citations: 4     Fields:    Translation:HumansCells
    4. Marinec PS, Landgraf KE, Uppalapati M, Chen G, Xie D, Jiang Q, Zhao Y, Petriello A, Deshayes K, Kent SBH, Ault-Riche D, Sidhu SS. A Non-immunogenic Bivalent d-Protein Potently Inhibits Retinal Vascularization and Tumor Growth. ACS Chem Biol. 2021 03 19; 16(3):548-556. PMID: 33621466.
      Citations: 4     Fields:    Translation:HumansAnimalsCells
    5. Kumar M, Mandal K, Blakeley MP, Wymore T, Kent SBH, Louis JM, Das A, Kovalevsky A. Visualizing Tetrahedral Oxyanion Bound in HIV-1 Protease Using Neutrons: Implications for the Catalytic Mechanism and Drug Design. ACS Omega. 2020 May 26; 5(20):11605-11617. PMID: 32478251; PMCID: PMC7254801.
      Citations: 3     
    6. Fu C, Demir B, Alcantara S, Kumar V, Han F, Kelly HG, Tan X, Yu Y, Xu W, Zhao J, Zhang C, Peng H, Boyer C, Woodruff TM, Kent SJ, Searles DJ, Whittaker AK. Low-Fouling Fluoropolymers for Bioconjugation and In Vivo Tracking. Angew Chem Int Ed Engl. 2020 03 16; 59(12):4729-4735. PMID: 31951063.
      Citations: 9     Fields:    Translation:Cells
    7. Kent SBH. Novel protein science enabled by total chemical synthesis. Protein Science. 2019; 28:313–328.
    8. Kent SBH. Novel protein science enabled by total chemical synthesis. Protein Sci. 2019 02; 28(2):313-328. PMID: 30345579; PMCID: PMC6319755.
      Citations: 22     Fields:    
    9. Kent SB. Racemic & quasi-racemic protein crystallography enabled by chemical protein synthesis. Curr Opin Chem Biol. 2018 10; 46:1-9. PMID: 29626784.
      Citations: 4     Fields:    Translation:HumansAnimalsCells
    10. Dang B, Chhabra S, Pennington MW, Norton RS, Kent SBH. Reinvestigation of the biological activity of d-allo-ShK protein. J Biol Chem. 2017 07 28; 292(30):12599-12605. PMID: 28596383; PMCID: PMC5535034.
      Citations: 2     Fields:    Translation:AnimalsCells
    11. Dang B, Shen R, Kubota T, Mandal K, Bezanilla F, Roux B, Kent SB. Inversion of the Side-Chain Stereochemistry of Indvidual Thr or Ile Residues in a Protein Molecule: Impact on the Folding, Stability, and Structure of the ShK Toxin. Angew Chem Int Ed Engl. 2017 03 13; 56(12):3324-3328. PMID: 28194851; PMCID: PMC5507063.
      Citations: 5     Fields:    Translation:Cells
    12. Gates ZP, Baxa MC, Yu W, Riback JA, Li H, Kent SB, Sosnick TR, Roux B. Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core. Proc Natl Acad Sci U S A. 2017 02 28; 114(9):2241-2246. PMID: 28193869; PMCID: PMC5338507.
      Citations: 11     Fields:    Translation:AnimalsCells
    13. Dhayalan B, Mandal K, Rege N, Weiss MA, Eitel SH, Meier T, Schoenleber RO, Kent SB. Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin. Chemistry. 2017 Jan 31; 23(7):1709-1716. PMID: 27905149; PMCID: PMC5636692.
      Citations: 3     Fields:    Translation:Cells
    14. Gates ZP, Dhayalan B, Kent SB. Obviation of hydrogen fluoride in Boc chemistry solid phase peptide synthesis of peptide-athioesters. Chem Commun (Camb). 2016 Nov 29; 52(97):13979-13982. PMID: 27847960.
      Citations: 1     Fields:    Translation:Cells
    15. Boerema DJ, Tereshko VA, Zhang J, Kent SB. Chemical synthesis and enzymatic properties of RNase A analogues designed to enhance second-step catalytic activity. Org Biomol Chem. 2016 Sep 21; 14(37):8804-8814. PMID: 27714155.
      Citations: 1     Fields:    Translation:AnimalsCells
    16. Dang B, Kubota T, Mandal K, Correa AM, Bezanilla F, Kent SB. Elucidation of the Covalent and Tertiary Structures of Biologically Active Ts3 Toxin. Angew Chem Int Ed Engl. 2016 07 18; 55(30):8639-42. PMID: 27244051; PMCID: PMC5001624.
      Citations: 5     Fields:    Translation:AnimalsCells
    17. Dhayalan B, Fitzpatrick A, Mandal K, Whittaker J, Weiss MA, Tokmakoff A, Kent SB. Efficient Total Chemical Synthesis of (13) C=(18) O Isotopomers of Human Insulin for Isotope-Edited FTIR. Chembiochem. 2016 Mar 02; 17(5):415-20. PMID: 26715336; PMCID: PMC5477233.
      Citations: 8     Fields:    Translation:HumansCells
    18. Mandal K, Dhayalan B, Avital-Shmilovici M, Tokmakoff A, Kent SB. Crystallization of Enantiomerically Pure Proteins from Quasi-Racemic Mixtures: Structure Determination by X-Ray Diffraction of Isotope-Labeled Ester Insulin and Human Insulin. Chembiochem. 2016 Mar 02; 17(5):421-5. PMID: 26707939.
      Citations: 4     Fields:    Translation:Cells
    19. Uppalapati M, Lee DJ, Mandal K, Li H, Miranda LP, Lowitz J, Kenney J, Adams JJ, Kent SB, Sidhu SS, Ault-Riché D. A Potent d-Protein Antagonist of VEGF-A is Nonimmunogenic, Metabolically Stable, and Longer-Circulating in Vivo. ACS Chem Biol. 2016 Apr 15; 11(4):1058-65. PMID: 26745345.
      Citations: 29     Fields:    Translation:Humans
    20. Dang B, Dhayalan B, Kent SB. Enhanced Solvation of Peptides Attached to "Solid-Phase" Resins: Straightforward Syntheses of the Elastin Sequence Pro-Gly-Val-Gly-Val-Pro-Gly-Val-Gly-Val. Org Lett. 2015 Jul 17; 17(14):3521-3. PMID: 26110966.
      Citations: 4     Fields:    
    21. Bunker RD, Mandal K, Bashiri G, Chaston JJ, Pentelute BL, Lott JS, Kent SB, Baker EN. A functional role of Rv1738 in Mycobacterium tuberculosis persistence suggested by racemic protein crystallography. Proc Natl Acad Sci U S A. 2015 Apr 07; 112(14):4310-5. PMID: 25831534; PMCID: PMC4394262.
      Citations: 18     Fields:    Translation:HumansCells
    22. Kent SB. The critical role of peptide chemistry in the life sciences. J Pept Sci. 2015 Mar; 21(3):136-8. PMID: 25643657.
      Citations: 6     Fields:    Translation:HumansCells
    23. Kent SB, Alewood PF. Editorial overview: synthetic biomolecules. Curr Opin Chem Biol. 2014 Oct; 22:viii-xi. PMID: 25438804.
      Citations: 1     Fields:    Translation:HumansAnimals
    24. Dang B, Kubota T, Correa AM, Bezanilla F, Kent SB. Total chemical synthesis of biologically active fluorescent dye-labeled Ts1 toxin. Angew Chem Int Ed Engl. 2014 Aug 18; 53(34):8970-4. PMID: 24989851; PMCID: PMC5477175.
      Citations: 10     Fields:    Translation:AnimalsCells
    25. Okamoto R, Mandal K, Sawaya MR, Kajihara Y, Yeates TO, Kent SB. (Quasi-)racemic X-ray structures of glycosylated and non-glycosylated forms of the chemokine Ser-CCL1 prepared by total chemical synthesis. Angew Chem Int Ed Engl. 2014 May 12; 53(20):5194-8. PMID: 24692304.
      Citations: 7     Fields:    Translation:Cells
    26. Okamoto R, Mandal K, Ling M, Luster AD, Kajihara Y, Kent SB. Total chemical synthesis and biological activities of glycosylated and non-glycosylated forms of the chemokines CCL1 and Ser-CCL1. Angew Chem Int Ed Engl. 2014 May 12; 53(20):5188-93. PMID: 24644239.
      Citations: 6     Fields:    Translation:Cells
    27. Kent SB. Bringing the science of proteins into the realm of organic chemistry: total chemical synthesis of SEP (synthetic erythropoiesis protein). Angew Chem Int Ed Engl. 2013 Nov 11; 52(46):11988-96. PMID: 24127351.
      Citations: 7     Fields:    Translation:HumansCells
    28. Dang B, Kubota T, Mandal K, Bezanilla F, Kent SB. Native chemical ligation at Asx-Cys, Glx-Cys: chemical synthesis and high-resolution X-ray structure of ShK toxin by racemic protein crystallography. J Am Chem Soc. 2013 Aug 14; 135(32):11911-9. PMID: 23919482; PMCID: PMC3838204.
      Citations: 26     Fields:    Translation:HumansAnimalsCells
    29. Avital-Shmilovici M, Mandal K, Gates ZP, Phillips NB, Weiss MA, Kent SB. Fully convergent chemical synthesis of ester insulin: determination of the high resolution X-ray structure by racemic protein crystallography. J Am Chem Soc. 2013 Feb 27; 135(8):3173-85. PMID: 23343390; PMCID: PMC3625376.
      Citations: 22     Fields:    Translation:Cells
    30. Gates ZP, Stephan JR, Lee DJ, Kent SB. Rapid formal hydrolysis of peptide-athioesters. Chem Commun (Camb). 2013 Jan 28; 49(8):786-8. PMID: 23233036.
      Citations: 12     Fields:    Translation:Cells
    31. Mandal K, Uppalapati M, Kenney J, Lowitz J, Sidhu SS, Kent SB, Ault-Riché D. Chemical synthesis and X-ray structure of a heterochiral {D-protein antagonist plus vascular endothelial growth factor} protein complex by racemic crystallography. Proc Natl Acad Sci U S A. 2012 Sep 11; 109(37):14779-84. PMID: 22927390; PMCID: PMC3443191.
      Citations: 37     Fields:    Translation:Cells
    32. Torbeev VY, Kent SB. Ionization state of the catalytic dyad Asp25/25' in the HIV-1 protease: NMR studies of site-specifically 13C labelled HIV-1 protease prepared by total chemical synthesis. Org Biomol Chem. 2012 Aug 14; 10(30):5887-91. PMID: 22659831; PMCID: PMC3437676.
      Citations: 10     Fields:    Translation:Cells
    33. Yeates TO, Kent SB. Racemic protein crystallography. Annu Rev Biophys. 2012; 41:41-61. PMID: 22443988.
      Citations: 46     Fields:    Translation:HumansAnimalsCells
    34. Mandal K, Pentelute BL, Bang D, Gates ZP, Torbeev VY, Kent SB. Design, total chemical synthesis, and X-ray structure of a protein having a novel linear-loop polypeptide chain topology. Angew Chem Int Ed Engl. 2012 Feb 06; 51(6):1481-6. PMID: 22213444.
      Citations: 14     Fields:    Translation:Cells
    35. Liu S, Pentelute BL, Kent SB. Convergent chemical synthesis of [lysine(24,38,83)] human erythropoietin. Angew Chem Int Ed Engl. 2012 Jan 23; 51(4):993-9. PMID: 22180156; PMCID: PMC3472960.
      Citations: 12     Fields:    Translation:HumansCells
    36. Torbeev VY, Raghuraman H, Hamelberg D, Tonelli M, Westler WM, Perozo E, Kent SB. Protein conformational dynamics in the mechanism of HIV-1 protease catalysis. Proc Natl Acad Sci U S A. 2011 Dec 27; 108(52):20982-7. PMID: 22158985; PMCID: PMC3248522.
      Citations: 45     Fields:    Translation:Cells
    37. Mandal K, Kent SB. Total chemical synthesis of biologically active vascular endothelial growth factor. Angew Chem Int Ed Engl. 2011 Aug 22; 50(35):8029-33. PMID: 21744452; PMCID: PMC3478761.
      Citations: 11     Fields:    Translation:Cells
    38. Pollock SB, Kent SB. An investigation into the origin of the dramatically reduced reactivity of peptide-prolyl-thioesters in native chemical ligation. Chem Commun (Camb). 2011 Feb 28; 47(8):2342-4. PMID: 21173985.
      Citations: 25     Fields:    Translation:Cells
    39. Sohma Y, Hua QX, Whittaker J, Weiss MA, Kent SB. Design and folding of [GluA4(ObetaThrB30)]insulin ("ester insulin"): a minimal proinsulin surrogate that can be chemically converted into human insulin. Angew Chem Int Ed Engl. 2010 Jul 26; 49(32):5489-93. PMID: 20509131; PMCID: PMC3311283.
      Citations: 14     Fields:    Translation:HumansCells
    40. Lee DJ, Mandal K, Harris PW, Brimble MA, Kent SB. A one-pot approach to neoglycopeptides using orthogonal native chemical ligation and click chemistry. Org Lett. 2009 Nov 19; 11(22):5270-3. PMID: 19842689.
      Citations: 11     Fields:    Translation:Cells
    41. Kent SB. Total chemical synthesis of proteins. Chem Soc Rev. 2009 Feb; 38(2):338-51. PMID: 19169452.
      Citations: 157     Fields:    Translation:HumansCells
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