Cytosolic Delivery of Proteins by Bioreversible Esterification

Cloaking its carboxyl
groups with a hydrophobic moiety is shown
to enable a protein to enter the cytosol of a mammalian cell. Diazo
compounds derived from (p-methylphenyl)­glycine were
screened for the ability to esterify the green fluorescent protein
(GFP) in an aqueous environment. Esterification of GFP with 2-diazo-2-(p-methylphenyl)-N,N-dimethylacetamide
was efficient. The esterified protein entered the cytosol by traversing
the plasma membrane directly, like a small-molecule prodrug. As with
prodrugs, the nascent esters are substrates for endogenous esterases,
which regenerate native protein. Thus, esterification could provide
a general means to deliver native proteins to the cytosol.