2. Academic Validation
  3. Cellular delivery of dinucleotides by conjugation with small molecules: targeting translation initiation for anticancer applications

Cellular delivery of dinucleotides by conjugation with small molecules: targeting translation initiation for anticancer applications

  • Chem Sci. 2021 Jun 29;12(30):10242-10251. doi: 10.1039/d1sc02143e.
Natalia Kleczewska 1,  Pawel J Sikorski 1,  Zofia Warminska 1 2,  Lukasz Markiewicz 1,  Renata Kasprzyk 1 2 3,  Natalia Baran 1 4,  Karina Kwapiszewska 5,  Aneta Karpinska 5,  Jaroslaw Michalski 5,  Robert Holyst 5,  Joanna Kowalska 3,  Jacek Jemielity 1
Affiliations

Affiliations

  • 1 Centre of New Technologies, University of Warsaw Banacha 2c 02-097 Warsaw Poland j.jemielity@cent.uw.edu.pl.
  • 2 College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw Banacha 2c 02-097 Warsaw Poland.
  • 3 Division of Biophysics Institute of Experimental Physics, Faculty of Physics University of Warsaw Pasteura 5 02-093 Warsaw Poland jkowalska@fuw.edu.pl.
  • 4 Faculty of Biology University of Warsaw I. Miecznikowa 1 02-096 Warsaw Poland.
  • 5 Institute of Physical Chemistry Polish Academy of Sciences Kasprzaka 44/52 01-224 Warsaw Poland.
PMID: 34377411 DOI: 10.1039/d1sc02143e
Abstract

Targeting cap-dependent translation initiation is one of the experimental approaches that could lead to the development of novel anti-cancer therapies. Synthetic dinucleoside 5',5'-triphosphates Cap Analogs are potent antagonists of eukaryotic translation initiation factor 4E (eIF4E) in vitro and could counteract elevated levels of eIF4E in Cancer cells; however, transformation of these compounds into therapeutic agents remains challenging - they do not easily penetrate into cells and are susceptible to enzymatic cleavage. Here, we tested the potential of several small molecule ligands - folic acid, biotin, glucose, and Cholesterol - to deliver both hydrolyzable and cleavage-resistant Cap Analogs into cells. A broad structure-activity relationship (SAR) study using model fluorescent probes and cap-ligand conjugates showed that Cholesterol greatly facilitates uptake of Cap Analogs without disturbing the interactions with eIF4E. The most potent Cholesterol conjugate identified showed apoptosis-mediated cytotoxicity towards Cancer cells.

Figures
Products