Bioreversible Protein Labeling For Cellular Delivery

A growing number of potential chemotherapeutic agents are proteins. A major challenge to the use of proteins as intracellular drugs is their traversal of the negatively charged glycocalyx and cell membrane. Many methods have been developed over the past several decades to try to overcome this obstacle, including liposome carriers, various polymers, cell-penetrating peptides, and changes to the protein itself. All of these methods have downsides, including cytotoxicity, low delivery yields, and irreversible changes to the proteins. Here, we present two complementary methods of bioreversible protein modification that endow cell permeability, and we demonstrate their efficacy using the green fluorescent protein (GFP). The first method labels lysine residues with a module that combines the trimethyl lock scaffold to enable bioreversibility in the presence of cellular esterases, and a boronic acid moiety to promote cellular entry by increasing contact with the glycocalyx. This modification enables cellular upt...