A New Class of Lipidic Immunomodulators that Activate TLR-Dependent Cascades and Cytokine Secretion

Abstract

Cationic lipids are positively charged amphiphilic molecules which, for most of them, form positively charged liposomes, sometimes in combination with a neutral helper lipid. Such liposomes are mainly used as efficient DNA, RNA or protein carriers for gene therapy or immunization trials. Over the past decade, significant progress has been made in the understanding of the cellular pathways and mechanisms involved in lipoplex-mediated gene transfection (1) but the interaction of cationic lipids with cell components and the consequences of such an interaction on cell physiology remains poorly described. Recently, trying to explain the immunoadjuvant properties (2) of a cationic lipid discovered in our group (N-t-butyl-N’-tetradecyl-3-tetradecylamino-propionamidine-diC14-amidine), we identified its agonistic interaction with the Toll-like receptor 4 (TLR4), the natural sensor of LPS (the bacterial lipopolysaccharide). This activation seems specific of the shape and characteristics of the molecule since increasing the length of the hydrocarbon chains by 2 methyl groups suppresses its activity. This cationic lipid has only limited features in common with LPS species from different bacterial origin such as short hydrocarbon chains and the presence of a polar headgroup. However, the number of chains (2 versus generally 6 to 7) and the polar headgroup (small alkylated cationic amidinium group versus the bulky polar anionic headgroup of LPS) make the two molecules look very different but surprisingly such dissimilar structures are capable of activating the same receptor(3). As compared with other adjuvants being currently developed, the chemistry of amidine derivatives is rather simple, allowing the quick development and screening of new derivatives.1- Mol Ther. (2005) −11(3):336-472- Mol Ther. (2005) 11 (6), 960-9683- Prog Lipid Res. (2008) 47(5):340-7