NickFects,Phosphorylated Derivatives of Transportan 10 for Cellular Delivery of Oligonucleotides |
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Authors: | Nikita Oskolkov Piret Arukuusk Dana-Maria Copolovici Staffan Lindberg Helerin Margus Kärt Padari Margus Pooga Ülo Langel |
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Institution: | 1.Laboratory of Molecular Biotechnology, Institute of Technology,University of Tartu,Tartu,Estonia;2.Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences,Stockholm University,Stockholm,Sweden;3.Department of Developmental Biology, Institute of Molecular and Cell Biology,University of Tartu,Tartu,Estonia |
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Abstract: | Oligonucleotide-based gene regulation has a high potential in gene therapy, but the plasma membrane is impermeable for nucleic
acid polymers and, consequently, an efficient and non-toxic transfection agent is needed for their delivery into the cell.
In this study we present a novel series, NickFects, of chemically modified TP10 peptide-based delivery vectors used for the
cellular delivery of single-stranded oligonucleotides. These carriers, obtained by replacement of Ile8 by threonine in stearyl-TP10
and by modifying of tyrosine and/or threonine, respectively, by phosphorylation formed 300–500 nm in size peptide:oligonucleotide
nanocomplexes with negative surface charges. The highest splice-correcting effect was obtained when phosphorotiate 2′-O-methyl
oligonucleotides were transduced into cells by NickFect1 (NF1) or NickFect2 (NF2). In addition, we also show how a small modification
(one or two negative charges) in peptide sequence can affect its ability to deliver ONs into cells and increase their potency
in the splicing redirection assay. Our studies demonstrate that NF1 and NF2 have higher transfection efficacy for oligonucleotides
as compared to the most commonly used transfection agent Lipofectamine™ 2000 and lead to higher biological response in cells. |
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