Tuesday, October 10, 2017

Cytosolic Delivery of Proteins by Bioreversible Esterification

Kalie A. Mix, Jo E. Lomax, and Ronald T. Raines

J. Am. Chem. Soc., Article ASAP

DOI: 10.1021/jacs.7b06597

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.

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