Selective esterase-ester pair for targeting small molecules with cellular specificity

Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4756-61. doi: 10.1073/pnas.1111943109. Epub 2012 Mar 12.


Small molecules are important tools to measure and modulate intracellular signaling pathways. A longstanding limitation for using chemical compounds in complex tissues has been the inability to target bioactive small molecules to a specific cell class. Here, we describe a generalizable esterase-ester pair capable of targeted delivery of small molecules to living cells and tissue with cellular specificity. We used fluorogenic molecules to rapidly identify a small ester masking motif that is stable to endogenous esterases, but is efficiently removed by an exogenous esterase. This strategy allows facile targeting of dyes and drugs in complex biological environments to label specific cell types, illuminate gap junction connectivity, and pharmacologically perturb distinct subsets of cells. We expect this approach to have general utility for the specific delivery of many small molecules to defined cellular populations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Biocatalysis / drug effects
  • Cell Survival / drug effects
  • Cells / drug effects*
  • Cells / metabolism*
  • Coculture Techniques
  • Esterases / metabolism*
  • Esters / metabolism*
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / metabolism
  • Gap Junctions / drug effects
  • Gap Junctions / metabolism
  • HeLa Cells
  • Hippocampus / cytology
  • Humans
  • Hydrolysis / drug effects
  • Mice
  • Microscopy, Fluorescence
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Organ Specificity / drug effects
  • Permeability / drug effects
  • Rats
  • Small Molecule Libraries / pharmacology*


  • Esters
  • Fluorescent Dyes
  • Small Molecule Libraries
  • Esterases