title: Self-neutralizing oligonucleotides with enhanced cellular uptake.
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.
authors.affiliation: ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com and GLSynthesis, Inc., One Innovation Drive, Worcester, MA 01605, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Yanachkov
authors.affiliation: ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com.
authors.forename: Boris
authors.initials: B
authors.lastname: Zavizion
authors.affiliation: 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.
authors.forename: Valeri
authors.initials: V
authors.lastname: Metelev
authors.affiliation: ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Stevens
authors.affiliation: ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com.
authors.forename: Yekaterina
authors.initials: Y
authors.lastname: Tabatadze
authors.affiliation: ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com and GLSynthesis, Inc., One Innovation Drive, Worcester, MA 01605, USA.
authors.forename: Milka
authors.initials: M
authors.lastname: Yanachkova
authors.affiliation: GLSynthesis, Inc., One Innovation Drive, Worcester, MA 01605, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Krichevsky
authors.affiliation: ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA. dtabatadze@zatapharmaceuticals.com.
authors.forename: David R
authors.identifier: http://orcid.org/0000-0001-5131-3857
authors.initials: DR
authors.lastname: Tabatadze
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D009841:Oligonucleotides