Stephen B.H. Kent

We apply the tools of chemistry to elucidate the molecular basis of the biological functions of proteins. Ultimately we want to be able to design and build protein molecules with pre-determined, controlled properties. This is a scientific problem of great timeliness with the completion of the genome sequencing projects, which impact broadly across the natural sciences.

In the post-genome era it will be imperative to understand the principles that govern the numerous and diverse activities of proteins in the biological world. These principles can best be elucidated by combining a number of scientific disciplines. To that end, we have established general synthetic access to the world of proteins. This enables us to focus the most advanced physical and chemical techniques in conjunction with all the tools of molecular biology to elucidate the molecular basis of the biochemical and biological actions of the protein molecule.

The emphasis in our research program is on collaborative science. This creates unique opportunities for people drawn to the application of chemistry to biological systems. Thus, techniques such as Xray crystallography, nuclear magnetic resonance (NMR), and Fourier-transform infrared (FTIR) spectroscopy can be applied to protein systems that have been labeled in a non-perturbing fashion with probe nuclei to act as local reporter groups. This enables the fruitful application of these powerful methods to complex protein systems. Synthetic organic and peptidomimetic chemistry can also be used to systematically dissect the molecular basis of enzyme activity by varying the covalent structure of a protein in a completely general yet controlled fashion, and correlating these precise changes with effects on protein function.

We apply the tools of chemistry to elucidate the molecular basis of the biological functions of proteins. Ultimately we want to be able to design and build protein molecules with pre-determined, controlled properties. This is a scientific problem of great timeliness with the completion of the genome sequencing projects, which impact broadly across the natural sciences.

In the post-genome era it will be imperative to understand the principles that govern the numerous and diverse activities of proteins in the biological world. These principles can best be elucidated by combining a number of scientific disciplines. To that end, we have established general synthetic access to the world of proteins. This enables us to focus the most advanced physical and chemical techniques in conjunction with all the tools of molecular biology to elucidate the molecular basis of the biochemical and biological actions of the protein molecule.

The emphasis in our research program is on collaborative science. This creates unique opportunities for people drawn to the application of chemistry to biological systems. Thus, techniques such as Xray crystallography, nuclear magnetic resonance (NMR), and Fourier-transform infrared (FTIR) spectroscopy...

Biomimetic synthesis of lispro insulin via a chemically synthesized ‘mini-proinsulin’ prepared by oxime-forming ligation.
Youhei Sohma, Stephen B. H. Kent,
J Am Chem Soc, 131, 16313-8 (2009). 

A one-pot approach to neoglycopeptides using orthogonal native chemical ligation and click chemistry.
Dong Jun Lee, Kalyaneswar Mandal, Paul W. R. Harris, Margaret A. Brimble, Stephen B. H. Kent.
Organic Letters, 11, 5270-3 (2009). 

Total chemical synthesis and racemic protein crystallography used to determine the X-ray structure of plectasin by direct methods.
Kalyaneswar Mandal, Brad L. Pentelute, Valentina Tereshko, Anthony A. Kossiakoff, Stephen B. H. Kent,
Protein Science,
18, 1146-1154 (2009). Cover  

Dynamics of ‘flap’ structures in three HIV-1 protease/inhibitor complexes probed by total chemical synthesis and pulse-EPR spectroscopy.
Vladimir Yu. Torbeev, Kalyaneswar Mandal, Sanjib Senapati, Eduardo Perozo, Stephen B. H. Kent,
J Am Chem Soc,
131, 884-5 (2009). 

Crystal structure of chemically synthesized HIV-1 protease and a ketomethylene isostere inhibitor based on the p2/NC cleavage site.
V. Yu. Torbeev, K. Mandal, V. A. Terechko, S. B. H. Kent,
Bioorganic & Medicinal Chemistry Letters, 18, 4554-7 (2008).  

Mirror image forms of snow flea antifreeze protein prepared by total chemical synthesis have identical antifreeze activities.
Brad L. Pentelute, Zachary P. Gates, Jennifer Dashnau, Jane M. Vanderkooi, Stephen B. H. Kent,
J Am Chem Soc, 130, 9702-9707 (2008). 

X-ray structure of snow flea antifreeze protein determined by racemic crystallization of synthetic protein enantiomers.
Brad L. Pentelute, Zachary P. Gates, Valentina Tereshko, , Jennifer Dashnau, Jane M. Vanderkooi, Anthony A. Kossiakoff, Stephen B. H. Kent,
J Am Chem Soc, 130, 9695-9701 (2008). 

Convergent chemical synthesis and crystal structure of a 203 amino acid ‘covalent dimer’ HIV-1 protease enzyme molecule.
Vladimir Yu. Torbeev, Stephen B. H. Kent,
Angew Chem Int Ed Eng, 46, 1667-70 (2007).  

Convergent chemical synthesis and high resolution X-ray structure of human lysozyme.
Thomas Durek, Vladimir Yu. Torbeev, Stephen B. H. Kent,
Proc. Natl. Acad. Sci. USA, 104, 4846-4851 (2007) 

Towards the total chemical synthesis of integral membrane proteins: a general method for the synthesis of hydrophobic peptide-αthioester building blocks.
Erik C.B. Johnson, Stephen B.H. Kent,
Tetrahedron Letters, 48, 1795-99 (2007).  

Kinetically-controlled ligation for the convergent chemical synthesis of proteins.
Duhee Bang, Brad Pentelute, Stephen B.H. Kent,
Angew Chem Int Ed Eng, 45, 3985-3988 (2006). Cover 

Insights into the mechanism and catalysis of the native chemical ligation reaction.
Erik C.B. Johnson, Stephen B.H. Kent,
J. Am. Chem. Soc., 128, 6640-6 (2006). 

Dissecting the energetics of protein α-helix C-cap termination through chemical protein synthesis.
Duhee Bang, Alexey V. Gribenko, Valentina Tereshko, Anthony A. Kossiakoff, Stephen B. Kent*,
George I. Makhatadze*,
Nature Chemical Biology, 2, 139-43 (2006). Cover 

Total chemical synthesis and X-ray crystal structure of a protein diastereomer: [D-Gln35]Ubiquitin.
Duhee Bang, George I. Makhatadze, Valentina Tereshko, Anthony A. Kossiakoff, Stephen B. Kent,
Angew. Chem. Int. Ed. Eng., 44, 3852-3856 (2005). 

A one-pot chemical synthesis of Crambin.
Duhee Bang, Stephen B.H. Kent,
Angew. Chem. Int. Ed. Eng. 116: 2588-2592 (2004). 

Biomimetic synthesis of lispro insulin via a chemically synthesized ‘mini-proinsulin’ prepared by oxime-forming ligation.
Youhei Sohma, Stephen B. H. Kent,
J Am Chem Soc, 131, 16313-8 (2009). 

A one-pot approach to neoglycopeptides using orthogonal native chemical ligation and click chemistry.
Dong Jun Lee, Kalyaneswar Mandal, Paul W. R. Harris, Margaret A. Brimble, Stephen B. H. Kent.
Organic Letters, 11, 5270-3 (2009). 

Total chemical synthesis and racemic protein crystallography used to determine the X-ray structure of plectasin by direct methods.
Kalyaneswar Mandal, Brad L. Pentelute, Valentina Tereshko, Anthony A. Kossiakoff, Stephen B. H. Kent,
Protein Science,
18, 1146-1154 (2009). Cover  

Dynamics of ‘flap’ structures in three HIV-1 protease/inhibitor complexes probed by total chemical synthesis and pulse-EPR spectroscopy.
Vladimir Yu. Torbeev, Kalyaneswar Mandal, Sanjib Senapati, Eduardo Perozo, Stephen B. H. Kent,
J Am Chem Soc,
131, 884-5 (2009). 

Crystal structure of chemically synthesized HIV-1 protease and a ketomethylene isostere inhibitor based on the p2/NC cleavage site.
V. Yu. Torbeev, K. Mandal, V. A. Terechko, S. B. H. Kent,
Bioorganic & Medicinal Chemistry Letters, 18, 4554-7 (2008).