Cellular delivery of dinucleotides by conjugation with small molecules: targeting translation initiation for anticancer applications
Natalia Kleczewska, Pawel J. Sikorski, Zofia Warminska, Łukasz Markiewicz, Renata Kasprzyk, Natalia Baran, Karina Kwapiszewska, Aneta Karpińska, Jarosław Michalski, Robert Hołyst, Joanna Kowalska, Jacek Jemielity
Abstract
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.