Design and Implementation of Synthetic RNA Binders for the Inhibition of miR-21 Biogenesis.

Targeting RNAs using small molecules is an emerging field of medicinal chemistry and holds promise for the discovery of efficient tools for chemical biology. MicroRNAs are particularly interesting targets since they are involved in a number of pathologies such as cancers. Indeed, overexpressed microRNAs in cancer are oncogenic and various series of inhibitors of microRNAs biogenesis have been developed in recent years. Here, we describe the structure-based design of new efficient inhibitors of microRNA-21. Starting from a previously identified hit, we performed biochemical studies and molecular docking to design a new series of optimized conjugates of neomycin aminoglycoside with artificial nucleobases and amino acids. Investigation about the mode of action and the site of the interaction of the newly synthesized compounds allowed for the description of structure-activity relationships and the identification of the most important parameters for miR-21 inhibition.

Cyclodextrin-based facial amphiphiles: assessing the impact of the hydrophilic-lipophilic balance in the self-assembly, DNA complexation and gene delivery capabilities.

Exhaustive structure-efficacy relationship studies on nonviral gene delivery systems are often hampered by the ill-defined or polydisperse nature of the formulations. Facial amphiphiles based on rigid cage-type molecular scaffolds offer unique possibilities towards these studies. Taking advantage of regioselective functionalization schemes, we have synthesized a library of cationic cyclodextrin (CD) derivatives combining a range of hydrophilic and lipophilic domains. We have scrutinized how the hydrophilic-lipophilic balance (HLB) around the CD scaffold determines their self-assembly capabilities and the DNA binding and release abilities of the corresponding CD : DNA nanocomplexes (CDplexes). These features have been ultimately correlated with their capabilities to deliver a reporter luciferase-encoding pDNA into COS-7 cells. The ensemble of results demonstrates that fine tuning of the HLB is critical to induce compaction of DNA by the CD-based facial amphiphiles into transfection-productive CDplexes.

Formulation of highly functionalizable DNA nanoparticles based on 1,2-dithiolane derivatives.

We describe the formulation of synthetic virus models based on ionic compounds bearing the polymerizable 1,2-dithiolane moiety. First, cationic amphiphiles containing the polymeric inducer were prepared and used to efficiently condense a DNA plasmid (pDNA) into a highly monodisperse population of small polymeric cationic DNA nanoparticles (NPs; Dh ∼100 nm). These nonspecific cationic particles were then functionalized with anionic PEGylated conjugates, also based on the 1,2-dithiolane motifs, in order to produce stable and fully dispersible stealth DNA nanoparticles. Our results show that both ionic interactions and polymerization based on the 1,2-dithiolane pattern occur and that they produce highly functionalizable nonviral DNA NPs.