Cytosolic Delivery of Proteins by Bioreversible Esterification

J Am Chem Soc. 2017 Oct 18;139(41):14396-14398. doi: 10.1021/jacs.7b06597. Epub 2017 Oct 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CHO Cells
  • Cricetulus
  • Cytosol / metabolism*
  • Esterases / metabolism
  • Esterification
  • Esters / chemistry*
  • Esters / metabolism
  • Green Fluorescent Proteins / chemistry*
  • Green Fluorescent Proteins / metabolism*
  • Prodrugs / chemistry
  • Prodrugs / metabolism


  • Esters
  • Prodrugs
  • Green Fluorescent Proteins
  • Esterases