Peptide-Oligonucleotide Hybrids in Antisense Therapy

Abstract

Antisense technology provides outstanding promise for treatment of human disease, having broad applicability and high specificity. Although advances have been made in antisense oligonucleotide chemistry, leading to increased plasma and cellular stability, and decreased toxicity, considerable potential remains for the enhancement of oligonucleotide uptake for targeted delivery of oligonucleotides. One promising avenue for achieving this is via linkage of antisense oligonucleotides to peptide carriers. This review looks at the current status of developments in this area.

Pharmacokinetic Analysis of Polyamide Nucleic-Acid-Cell Penetrating Peptide Conjugates Targeted against HIV-1 Transactivation Response Element

“…Several efforts to improve their in vitro cellular uptake by conjugating PNAs with various cell-permeating peptides, lipids, or antibiotics have had mixed results (Koppelhus and Nielsen, 2003). Although it has been reported that naked PNA can be taken up in vivo (McMahon et al, 2002, Pierce et al, 2005, Boffa et al, 2007, its cellular uptake in in vitro cell-culture systems has been negligible (Kaushik et al, 2002a;Chaubey et al, 2005;Tripathi et al, 2005).…”

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).…”

“…GAPDH was used as the target because it is produced at high levels in most cell types and thus is representative of a general class of high-abundance proteins. The peptides used in this study were selected because of their demonstrated ability to increase cellular uptake and/or alter intracellular localization (34,35). In contrast to molecular materials, these conjugates can be purified and isolated simply by centrifugation and further allow the control of control oligonucleotide and peptide stoichiometries.…”

Intravitreal treatment with antisense oligonucleotides targeting tumor necrosis factor-α in murine herpes simplex virus type 1 retinitis

“…The mechanisms of action include blockage of translation and splicing of the DNA-RNA hybrid by RNase H. Therefore, antisense oligonucleotides may be useful for the specific down-regulation of individual protein synthesis, thus permitting a wide variety of potential therapeutic application [20][21][22].…”