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Issue 6, 2017
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Self-neutralizing oligonucleotides with enhanced cellular uptake

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There is tremendous potential for oligonucleotide (ON) therapeutics, but low cellular penetration due to their polyanionic nature is a major obstacle. We addressed this problem by developing a new approach for ON charge neutralization in which multiple branched charge-neutralizing sleeves (BCNSs) are attached to the internucleoside phosphates of ON by phosphotriester bonds. The BCNSs are terminated with positively charged amino groups, and are optimized to form ion pairs with the neighboring phosphate groups. The new modified ONs can be prepared by standard automated phosphoramidite chemistry in good yield and purity. They possess good solubility and hybridization properties, are not involved in non-standard intramolecular aggregation, have low cytotoxicity, adequate chemical stability, improved serum stability, and above all, display significantly enhanced cellular uptake. Thus, the new ON derivatives exhibit properties that make them promising candidates for the development of novel therapeutics or research tools for modulation of the expression of target genes.

Graphical abstract: Self-neutralizing oligonucleotides with enhanced cellular uptake

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Supplementary files

Article information

23 Nov 2016
29 Dec 2016
First published
04 Jan 2017

Org. Biomol. Chem., 2017,15, 1363-1380
Article type

Self-neutralizing oligonucleotides with enhanced cellular uptake

I. Yanachkov, B. Zavizion, V. Metelev, L. J. Stevens, Y. Tabatadze, M. Yanachkova, G. Wright, A. M. Krichevsky and D. R. Tabatadze, Org. Biomol. Chem., 2017, 15, 1363
DOI: 10.1039/C6OB02576E

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