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chemical protein synthesis
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racemic protein crystallography
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mirror image proteins
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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.
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