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Nucleic Acids Res. 2018 Feb 28;46(4):1601-1613. doi: 10.1093/nar/gkx1320.

Structure-activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides.

Author information

1
Initos Pharmaceuticals LLC, Chapel Hill, NC 27599, USA.
2
UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.
3
Chemogenics Biopharma, Research Triangle Park, NC 27709, USA.
4
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
5
Southern Research Institute, Birmingham, AL 35205, USA.

Abstract

The pharmacological effects of antisense and siRNA oligonucleotides are hindered by the tendency of these molecules to become entrapped in endomembrane compartments thus failing to reach their targets in the cytosol or nucleus. We have previously used high throughput screening to identify small molecules that enhance the escape of oligonucleotides from intracellular membrane compartments and have termed such molecules OECs (oligonucleotide enhancing compounds). Here, we report on the structure-activity relationships of a family of OECs that are analogs of a hit that emerged from our original screen. These studies demonstrate key roles for the lipophilic aromatic groups, the tertiary nitrogen, and the carbamate moiety of the parent compound. We have also investigated the intracellular site of action of the OECs and have shown that activity is due to the release of oligonucleotides from intermediate endosomal compartments rather than from early endosomes or from highly acidic downstream compartments. At high concentrations of OECs toxicity occurs in a manner that is independent of caspases or of lysosomal cathepsins but instead involves increased plasma membrane permeability. Thus, in addition to describing specific characteristics of this family of OECs, the current study provides insights into basic mechanisms of oligonucleotide trafficking and their implications for oligonucleotide delivery.

PMID:
29361039
PMCID:
PMC5829638
DOI:
10.1093/nar/gkx1320
[Indexed for MEDLINE]
Free PMC Article

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