Phosphorothioate analogs of m7GTP are enzymatically stable inhibitors of cap-dependent translation

  • Bioorg Med Chem Lett. 2009 Apr 1;19(7):1921-5. doi: 10.1016/j.bmcl.2009.02.053.
Joanna Kowalska  1 ,  Maciej Lukaszewicz ,  Joanna Zuberek ,  Marcin Ziemniak ,  Edward Darzynkiewicz ,  Jacek Jemielity
Affiliations
  • 1. Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-089 Warsaw, Poland.
PMID: 19269171 DOI: 10.1016/j.bmcl.2009.02.053
Abstract

We report synthesis and properties of a pair of new potent inhibitors of translation, namely two diastereomers of 7-methylguanosine 5'-(1-thiotriphosphate). These new analogs of mRNA 5'cap (referred to as m(7)GTPalphaS (D1) and (D2)) are recognized by translational factor eIF4E with high affinity and are not susceptible to hydrolysis by Decapping Scavenger pyrophosphatase (DcpS). The more potent of diastereomers, m(7)GTPalphaS (D1), inhibited cap-dependent translation in rabbit reticulocyte lysate approximately 8-fold and approximately 15-fold more efficiently than m(7)GTP and m(7)GpppG, respectively. Both analogs were also significantly more stable in RRL than unmodified ones.

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