Protein Chemistry

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT The majority of drugs in the extant pharmacopeia are small molecules. Half of those small molecules act on extracellular targets, and half act on intracellular targets. A minority of drugs are proteins, and virtually all of those proteins are antibodies, hormones, or enzymes that act on extracellular targets. The proposed research program will endow proteins with the ability to enter cells and act on intracellular targets. The program takes advantage of new chemical reactivity that uses tuned diazo compounds to esterify protein carboxyl groups in water. The resulting esterified proteins are analogous to small- molecule prodrugs in enabling traversal of the plasma membrane of human cells. Ester hydrolysis catalyzed by intracellular esterases makes the modifications traceless, avoiding any compromise to proper function. “Protein esterification” has an uncharted landscape. Accordingly, the work will begin by exploring fundamental attributes of esterified proteins, including their mechanism of cellular uptake and the enzymology of ester hydrolysis by cellular esterases. Specific systems will be enlisted to assess the generality of this delivery method and provide opportunities for discovery. In particular, esterification will be used to deliver particular proteins that elicit cytotoxicity or tumor suppression, or control genome editing. The delivery strategy will also be used to anchor oligonucleotides and other beneficial moieties on the cell surface and generalize the selective degradation of cellular proteins. These broad and far- reaching efforts will provide high-impact advances in biomedicine, chemical biology, and allied fields.