Controlling G-quadruplex formation via lipid modification of oligonucleotide sequences

Vialet, Brune; Gissot, Arnaud; Delzor, Romain; Barthélémy, Philippe

doi:10.1039/c7cc05693a

Cited by 15 publications

(17 citation statements)

References 28 publications

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“…Recently, some research groups have synthesized modified lipid G-quadruplexes showing their similarities to lipid-based micelles in size and proving their efficiency as supramolecular scaffolds to promote cargo release [ 38 , 39 , 40 ]. Inspired by these results and by our previous findings based on delivering ASOs using G-quadruplex nanostructures modified with cationic amino acids [ 27 ], we envisaged engineering two series of G-quadruplex forming oligonucleotides varying the number of guanosines in the oligonucleotide chain (TG 4 T and TG 6 T) and containing two saturated lipids of different length (C8 and C14), which were introduced at either the 3′- or 5′-termini of the G-rich oligonucleotide chain.…”

Section: Resultsmentioning

confidence: 99%

Tuning G-Quadruplex Nanostructures with Lipids. Towards Designing Hybrid Scaffolds for Oligonucleotide Delivery

Grijalvo

Eres

Gargallo

et al. 2020

IJMS

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Two G-quadruplex forming oligonucleotides [d(TG4T)4 and d(TG6T)4] were selected as two tetramolecular quadruplex nanostructures because of their demonstrated ability to be modified with hydrophobic molecules. This allowed us to synthesize two series of G-quadruplex conjugates that differed in the number of G-tetrads, as well as in the terminal position of the lipid modification. Both solution and solid-phase syntheses were carried out to yield the corresponding lipid oligonucleotide conjugates modified at their 3′- and 5′-termini, respectively. Biophysical studies confirmed that the presence of saturated alkyl chains with different lengths did not affect the G-quadruplex integrity, but increased the stability. Next, the G-quadruplex domain was added to an 18-mer antisense oligonucleotide. Gene silencing studies confirmed the ability of such G-rich oligonucleotides to facilitate the inhibition of target Renilla luciferase without showing signs of toxicity in tumor cell lines.

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Section: Resultsmentioning

confidence: 99%

Tuning G-Quadruplex Nanostructures with Lipids. Towards Designing Hybrid Scaffolds for Oligonucleotide Delivery

Grijalvo

Eres

Gargallo

et al. 2020

IJMS

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“…ON/LON γ and ON/LON δ were designed by broadening the specific binding zone between ON/LON α and ON/ LON β with bla CTX-M-15 gene. The previously published sequence of k-LON SC 28 was used as negative control. As outlined above, cellular uptake is an important feature for the ON strategy.…”

Section: Discussionmentioning

confidence: 99%

“…physicochemical characterization of micelles. Expectedly, while ONs remain in aqueous solution without specific self-organization (no significant population of objects in water by DLS), LON amphiphiles organize themselves in micelles and larger objects 24,28,29 . The mean size of micellar population of different sequences measured by Dynamic Light Scattering (DLS) in extracellular salt conditions (145 mM Na + and 5 mM K + ) ranged around 10 nm (Supplementary Table 1), independently on the oligonucleotide sequence, with negative zeta potential (−24 to −37 mV for 5 µM and 30 µM aqueous concentration respectively), as expected regarding polyanion structure of oligonucleotides.…”

Section: Synthesis Of On and Lipid On (Lon)mentioning

confidence: 99%

“…LONs' size of micelles was first determined in previously described conditions extracellular salt (145 mM Na + Cl − and 5 mM K + Cl − ) 28 , first at 30 µM as previously published 24 and then compared to our 5 µM relevant concentration. Expectedly, LONs presented negative zeta potential, dependent on their concentration, ionic.…”

Section: Dynamic Light Scattering (Dls) Characterizationmentioning

confidence: 99%

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Lipid oligonucleotides as a new strategy for tackling the antibiotic resistance

Kauss

Arpin

Bientz

et al. 2020

Sci Rep

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Antibiotic resistance has become a major issue in public health especially for one of the most used antibiotics; the third-generation cephalosporins. one of the main resistance mechanisms in Enterobacteriaceae, is the production of extended-Spectrum β-lactamases. Here, we demonstrated that the oligonucleotide therapy is an efficient approach to reduce the resistance of bacteria to antibiotic treatment. Lipid oligonucleotides (LONs) were proved to be efficient strategies in both delivering the oligonucleotide sequences in the prokaryotic cells and decreasing the Minimum inhibitory concentration of resistant bacteria to a third generation cephalosporin, the ceftriaxone. Accordingly, we demonstrated the strong antimicrobial potential of this Lon strategy targeting the ß-lactamase activity on both clinical and laboratory strains. our results support the concept that the self-delivery of oligonucleotide sequences via lipid conjugation may be extended to other antimicrobial drugs, which opens novel ways to struggle against the antibiotic resistance.

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“…Our experiments are consistent with a previous study reporting micelle formation for other DNA-based amphiphilic conjugates depended on the presence of Mg 2+ [ 15 , 16 ]. In another study, the authors also suggested that Mg 2+ stabilizes all the lipid-oligonucleotides micellar assemblies, probably due to the Mg 2+ -mediated neutralization of the oligonucleotide negative charges [ 53 ].…”

Section: Figurementioning

confidence: 99%

Amphiphilic “Like-A-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery

et al. 2020

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The conjugation of lipophilic groups to oligonucleotides is a promising approach for improving nucleic acid-based therapeutics’ intracellular delivery. Lipid oligonucleotide conjugates can self-aggregate in aqueous solution, which gains much attention due to the formation of micellar particles suitable for cell endocytosis. Here, we describe self-association features of novel “like-a-brush” oligonucleotide conjugates bearing three dodecyl chains. The self-assembly of the conjugates into 30–170 nm micellar particles with a high tendency to aggregate was shown using dynamic light scattering (DLS), atomic force (AFM), and transmission electron (TEM) microscopies. Fluorescently labeled conjugates demonstrated significant quenching of fluorescence intensity (up to 90%) under micelle formation conditions. The conjugates possess increased binding affinity to serum albumin as compared with free oligonucleotides. The dodecyl oligonucleotide conjugate and its duplex efficiently internalized and accumulated into HepG2 cells’ cytoplasm without any transfection agent. It was shown that the addition of serum albumin or fetal bovine serum to the medium decreased oligonucleotide uptake efficacy (by 22.5–36%) but did not completely inhibit cell penetration. The obtained results allow considering dodecyl-containing oligonucleotides as scaffold compounds for engineering nucleic acid delivery vehicles.

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Controlling G-quadruplex formation via lipid modification of oligonucleotide sequences

Cited by 15 publications

References 28 publications

Tuning G-Quadruplex Nanostructures with Lipids. Towards Designing Hybrid Scaffolds for Oligonucleotide Delivery

Tuning G-Quadruplex Nanostructures with Lipids. Towards Designing Hybrid Scaffolds for Oligonucleotide Delivery

Lipid oligonucleotides as a new strategy for tackling the antibiotic resistance

Amphiphilic “Like-A-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery

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