Specific antiviral activity of a poly(L-lysine)-conjugated oligodeoxyribonucleotide sequence complementary to vesicular stomatitis virus N protein mRNA initiation site.

Abstract

Antisense oligonucleotides represent an interesting tool for selective inhibition of gene expression, but their efficient introduction within intact cells proved to be difficult to realize. As a step toward this goal, small (13- or 15-mer) synthetic oligodeoxyribonucleotides have been coupled at their 3' ends to epsilon-amino groups of lysine residues of poly(L-lysine) (Mr, 14,000). A 15-mer oligonucleotide-poly(L-lysine) conjugate complementary to the initiation region of vesicular stomatitis virus (VSV) N-protein mRNA specifically inhibits the synthesis of VSV proteins and exerts an antiviral activity against VSV when added in the cell culture medium at doses as low as 100 nM. Neither synthesis of cellular proteins nor multiplication of encephalomyocarditis virus was affected significantly by this oligonucleotide conjugate. The data suggest that oligonucleotide-poly(L-lysine) conjugates might become effective for studies on gene expression regulation and for antiviral chemotherapy.

Peptide antisense nanoparticles

“…On a molecular level, significant research has been devoted toward creating materials incorporating peptides and oligonucleotides because these types of chimeric structures have been shown to increase the knockdown of target proteins (34)(35)(36)(37)(38)(39)(40)(41)(42)(43). However, molecular methods of preparing these materials are relatively inefficient, limit sequence diversity because of incompatible chemistries, require orthogonal protecting groups on nucleosides and amino acids (44), and can generate undesired side products (45).…”

Les oligonucléotides antisens : outils de génétique moléculaire et agents thérapeutiques

“…Nous avons testé des oligos antisens portant d'autres modifications : dérivés méthylphosphonates, phosphorothioates, analogues a, oligos couplés à une chaîne polylysine (Il a été montré que la conjugaison à ce polycation facilite la pénétration dans les fibroblastes en culture et conduit à un effet inhibiteur du virus de la stomatite vési culaire à des concentrations de l'ordre de 100 nM [8]). Aucun des oligos testés à ce jour ne possède un effet trypa nocide spécifique en culture (Verspieren et coll., résultats non publiés).…”

Drug delivery systems based on nucleic acid nanostructures

“…The realization of these structures implies the use of synthetic organic polymers. The first DNA polymer conjugates date back to the late 1980s, where poly(L-lysine)-block-DNA was used as anti-viral agent [29,30]. Nowadays, nucleic acid-polymer hybrid materials are already in clinical use [31].…”