Synthesis of a novel archaeal tetraether-type lipid containing a diorthoester group as a helper lipid for gene delivery

J. Barbeau (1) , N. Belmadi (2) , T. Montier (2, 3, 4) , T. Le Gall (2, 3, 4) , S. Dalençon (1) , L. Lemiègre (1) , T. Benvegnu (1)

1 ISCR - Institut des Sciences Chimiques de Rennes
2 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
3 SynNanoVect
4 IFR148 ScInBioS

As an alternative to recombinant virus, synthetic carriers are widely developed for providing efficient and safe DNA delivery. To reach the nucleus where nucleic acid (NA) constructs are transcripted, chemical complexes have to overcome serious cellular traps such as endosomal escape and intracellular trafficking. Here, the design and the multi-step synthesis of a stabilizing tetraether lipid analogue of archaeal counterparts containing a diorthoester moiety in the middle of the bridging chain were described. The key step involved a double coupling reaction between two diether alcohols and a diketene acetal. Under aqueous acidic conditions, the diorthoester function of the tetraether lipid can be hydrolysed to yield two monopolar diether lipids. Applied to gene delivery in association with a cationic lipid, this new helper bipolar tetraether lipid led to lipid-DNA complexes with sizes and potential zeta values depending on the charge ratios (+/-). In addition, preliminary in vitro transfection assays supported the interest of these novel bipolar lipid-based lipoplex formulations compared to standard Lipofectamine-based formulations. © 2016 Elsevier Ltd. All rights reserved.

Mots clés: Archaeal tetraether lipid; Helper lipid; Diorthoester moiety; DNA complexation; Transfection

Domaines: Chimie; Autre

J. Barbeau, N. Belmadi, T. Montier, T. Le Gall, S. Dalençon, et al.. Synthesis of a novel archaeal tetraether-type lipid containing a diorthoester group as a helper lipid for gene delivery. Tetrahedron Letters, 2016, 57 (27-28), pp.2976--2980. ⟨10.1016/j.tetlet.2016.05.090⟩. ⟨hal-01341581⟩