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Org Biomol Chem. 2017 Feb 7;15(6):1363-1380. doi: 10.1039/c6ob02576e.

Self-neutralizing oligonucleotides with enhanced cellular uptake.

Author information

1
ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com and GLSynthesis, Inc., One Innovation Drive, Worcester, MA 01605, USA.
2
ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com.
3
ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com and Department of Chemistry, Moscow State University, Leninskye gory1/40, Moscow 119991, Russian Federation.
4
GLSynthesis, Inc., One Innovation Drive, Worcester, MA 01605, USA.
5
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USA.

Abstract

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.

PMID:
28074950
PMCID:
PMC5696787
DOI:
10.1039/c6ob02576e
[Indexed for MEDLINE]
Free PMC Article

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