In vitro and in vivo properties of therapeutic oligonucleotides containing non-chiral 3' and 5' thiophosphate linkages
Autor: | Martina Brigitte Duschmalé, Marianne R. Møller, Konrad Bleicher, Jesper Wengel, Nanna Albæk, Henrik Frydenlund Hansen, Jörg Duschmalé, Erich Koller, Klaus Jensen, Troels Koch |
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Rok vydání: | 2019 |
Předmět: |
RNA Stability
Ribonuclease H Oligonucleotides Phosphorothioate Oligonucleotides Stereoisomerism Biology Kidney 01 natural sciences Thiophosphate Phosphates 03 medical and health sciences chemistry.chemical_compound Mice Chemical Biology and Nucleic Acid Chemistry In vivo Cell Line Tumor Genetics Animals Humans RNase H Lung 030304 developmental biology 0303 health sciences Nuclease 010405 organic chemistry Oligonucleotide Kidney metabolism 0104 chemical sciences Mice Inbred C57BL Biochemistry chemistry Liver Apolipoprotein B-100 biology.protein Female RNA Long Noncoding |
Zdroj: | Nucleic Acids Research Duschmalé, J, Hansen, H F, Duschmalé, M, Koller, E, Albaek, N, Møller, M R, Jensen, K, Koch, T, Wengel, J & Bleicher, K 2020, ' In vitro and in vivo properties of therapeutic oligonucleotides containing non-chiral 3' and 5' thiophosphate linkages ', Nucleic acids research, vol. 48, no. 1, pp. 63-74 . https://doi.org/10.1093/nar/gkz1099 |
ISSN: | 1362-4962 |
Popis: | The introduction of non-bridging phosphorothioate (PS) linkages in oligonucleotides has been instrumental for the development of RNA therapeutics and antisense oligonucleotides. This modification offers significantly increased metabolic stability as well as improved pharmacokinetic properties. However, due to the chiral nature of the phosphorothioate, every PS group doubles the amount of possible stereoisomers. Thus PS oligonucleotides are generally obtained as an inseparable mixture of a multitude of diastereoisomeric compounds. Herein, we describe the introduction of non-chiral 3′ thiophosphate linkages into antisense oligonucleotides and report their in vitro as well as in vivo activity. The obtained results are carefully investigated for the individual parameters contributing to antisense activity of 3′ and 5′ thiophosphate modified oligonucleotides (target binding, RNase H recruitment, nuclease stability). We conclude that nuclease stability is the major challenge for this approach. These results highlight the importance of selecting meaningful in vitro experiments particularly when examining hitherto unexplored chemical modifications. |
Databáze: | OpenAIRE |
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