Issue 30, 2021

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

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
16 Apr 2021
Accepted
29 Jun 2021
First published
29 Jun 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 10242-10251

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

N. Kleczewska, P. J. Sikorski, Z. Warminska, L. Markiewicz, R. Kasprzyk, N. Baran, K. Kwapiszewska, A. Karpinska, J. Michalski, R. Holyst, J. Kowalska and J. Jemielity, Chem. Sci., 2021, 12, 10242 DOI: 10.1039/D1SC02143E

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