Oligonucleotide-Lipid Conjugates Forming G-Quadruplex Structures Are Potent and Pangenotypic Hepatitis C Virus Entry Inhibitors In Vitro and Ex Vivo

Abstract

A hepatitis C virus (HCV) epidemic affecting HIV-infected men who have sex with men (MSM) is expanding worldwide. In spite of the improved cure rates obtained with the new direct-acting antiviral drug (DAA) combinations, the high rate of reinfection within this population calls urgently for novel preventive interventions. In this study, we determined in cell culture and experiments with human colorectal tissue that lipoquads, G-quadruplex DNA structures fused to cholesterol, are efficient HCV pangenotypic entry and cell-to-cell transmission inhibitors. Thus, lipoquads may be promising candidates for the development of rectally applied gels to prevent HCV transmission.

Parallel G-quadruplex Structures Increase Cellular Uptake and Cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil Resistant Cells

“…In addition, aptamers such as AS1411 are capable to form G-quadruplex and enhance cellular uptake of several drugs or nanomaterials mediated by G-quadruplex binding proteins which are abundant at the membranes of some tumoral cells [ 57 , 58 , 59 ]. Recently parallel quadruplexes carrying lipids or positively-charged amino acids have been used as antivirals [ 60 ] and as cellular uptake enhancers for antisense oligonucleotides [ 61 , 62 ].Oligonucleotides made from several units of antiproliferative nucleosides have gained particular interest as prodrugs [ 63 ]. These oligomers are intracellularly cleaved by nucleases generating nucleoside monophosphates that are the active form of these antiproliferative nucleosides [ 64 ].…”

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

“…This synthetic strategy allowed us to obtain stable parallel cationic G-tetrads that were able to transport and internalize AS oligonucleotides inside cells and therefore inhibit the production of the luciferase reporter protein [ 27 ]. In addition, lipid-oligonucleotide conjugates forming G-quadruplex (lipoquads) have been described by some of us to be potent antiviral compounds against human immunodeficiency virus (HIV-1, HIV-2) [ 28 ] and hepatitis C virus (HCV) by inhibiting viral entry [ 28 , 29 ]. These antiviral oligonucleotides formed parallel tetramolecular structures with 6 G’s and carried cholesterol or linoleyl moieties at the 3′-end [ 28 , 29 ].…”

“…In addition, lipid-oligonucleotide conjugates forming G-quadruplex (lipoquads) have been described by some of us to be potent antiviral compounds against human immunodeficiency virus (HIV-1, HIV-2) [ 28 ] and hepatitis C virus (HCV) by inhibiting viral entry [ 28 , 29 ]. These antiviral oligonucleotides formed parallel tetramolecular structures with 6 G’s and carried cholesterol or linoleyl moieties at the 3′-end [ 28 , 29 ]. In order to gain further insight into the application of such supramolecular scaffolds in gene silencing, we have extended these studies by modifying the 3′- or the 5′-termini of such G-quadruplex nanostructure with two saturated lipids of different lengths.…”

Spectroscopic Properties of Two 5′-(4-Dimethylamino)Azobenzene Conjugated G-Quadruplex Forming Oligonucleotides

“…Qs are often modified with suitable molecules in order to tune their stability or to provide them with specific properties such as fluorescence, chemical resistance, etc. [ 13 , 14 , 15 , 16 ]. Among the great number of molecules potentially appropriate for oligonucleotide (ON) modification, azobenzene and its derivatives, characterized by an extensive aromatic core, are of particular interest.…”