The human body contains two million or so distinct proteins. Chemistry harbors the potential to endow these proteins with attributes desirable for biomedicine. The proposed research takes advantage of new chemical reactivity that is applicable in a physiological context. The overall goal is to develop a facile, general means to endow native proteins with the ability to enter the cytosol of human cells. The strategy is to O-alkylate protein carboxyl groups by using a tuned diazo compound, generating esters that are analogous to those in small- molecule prodrugs. Intracellular esterases make these modifications traceless, avoiding any compromise to proper function or potential for immunogenicity. ?Protein esterification? has an uncharted landscape. Accordingly, work will begin by exploring fundamental attributes of esterified proteins, including the mechanism of cellular uptake and the enzymology of ester hydrolysis by cellular esterases in vitro and in cellulo (Aim 1). Esterification will then be used to deliver proteins for tumor suppression (Aim 2), genome editing (Aim 3), and anti-viral activity (Aim 4). The work relies on methods and ideas from organic chemistry, enzymology, chemical biology, and related fields, and is designed to establish a new paradigm for developing chemotherapeutic agents that are capable of addressing numerous unmet medical needs.
A protein is a gene-encoded string of amino acids that folds into a three- dimensional structure. Proteins perform the molecular functions that are necessary for life, including catalysis of biochemical reactions (by enzymes), neutralization of foreign toxins (by antibodies), and stimulation of cellular activity (by hormones). The goal of this project is to develop chemical means to manipulate proteins with a precision that is unobtainable with other (e.g., genetic) methods and to endow proteins thereby with desirable attributes that could be transformative to biomedicine.
Windsor, Ian W; Palte, Michael J; Lukesh 3rd, John C et al. (2018) Sub-picomolar Inhibition of HIV-1 Protease with a Boronic Acid. J Am Chem Soc 140:14015-14018 |
Chyan, Wen; Kilgore, Henry R; Raines, Ronald T (2018) Cytosolic Uptake of Large Monofunctionalized Dextrans. Bioconjug Chem 29:1942-1949 |
Chyan, Wen; Raines, Ronald T (2018) Enzyme-Activated Fluorogenic Probes for Live-Cell and in Vivo Imaging. ACS Chem Biol 13:1810-1823 |
Chyan, Wen; Kilgore, Henry R; Gold, Brian et al. (2017) Electronic and Steric Optimization of Fluorogenic Probes for Biomolecular Imaging. J Org Chem 82:4297-4304 |
Mix, Kalie A; Lomax, Jo E; Raines, Ronald T (2017) Cytosolic Delivery of Proteins by Bioreversible Esterification. J Am Chem Soc 139:14396-14398 |
Smith, Thomas P; Windsor, Ian W; Forest, Katrina T et al. (2017) Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation. J Med Chem 60:7820-7834 |
Hoang, Trish T; Smith, Thomas P; Raines, Ronald T (2017) A Boronic Acid Conjugate of Angiogenin that Shows ROS-Responsive Neuroprotective Activity. Angew Chem Int Ed Engl 56:2619-2622 |
Burke, Eileen G; Gold, Brian; Hoang, Trish T et al. (2017) Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs. J Am Chem Soc 139:8029-8037 |
Newberry, Robert W; Raines, Ronald T (2016) A prevalent intraresidue hydrogen bond stabilizes proteins. Nat Chem Biol 12:1084-1088 |
Mix, Kalie A; Aronoff, Matthew R; Raines, Ronald T (2016) Diazo Compounds: Versatile Tools for Chemical Biology. ACS Chem Biol 11:3233-3244 |
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