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Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides
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 mole...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829638/ https://www.ncbi.nlm.nih.gov/pubmed/29361039 http://dx.doi.org/10.1093/nar/gkx1320 |
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author | Juliano, Rudolph L Wang, Ling Tavares, Francis Brown, Edward G James, Lindsey Ariyarathna, Yamuna Ming, Xin Mao, Chengqiong Suto, Mark |
author_facet | Juliano, Rudolph L Wang, Ling Tavares, Francis Brown, Edward G James, Lindsey Ariyarathna, Yamuna Ming, Xin Mao, Chengqiong Suto, Mark |
author_sort | Juliano, Rudolph L |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5829638 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58296382018-03-06 Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides Juliano, Rudolph L Wang, Ling Tavares, Francis Brown, Edward G James, Lindsey Ariyarathna, Yamuna Ming, Xin Mao, Chengqiong Suto, Mark Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry 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. Oxford University Press 2018-02-28 2018-01-18 /pmc/articles/PMC5829638/ /pubmed/29361039 http://dx.doi.org/10.1093/nar/gkx1320 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Chemical Biology and Nucleic Acid Chemistry Juliano, Rudolph L Wang, Ling Tavares, Francis Brown, Edward G James, Lindsey Ariyarathna, Yamuna Ming, Xin Mao, Chengqiong Suto, Mark Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides |
title | Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides |
title_full | Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides |
title_fullStr | Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides |
title_full_unstemmed | Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides |
title_short | Structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides |
title_sort | structure–activity relationships and cellular mechanism of action of small molecules that enhance the delivery of oligonucleotides |
topic | Chemical Biology and Nucleic Acid Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829638/ https://www.ncbi.nlm.nih.gov/pubmed/29361039 http://dx.doi.org/10.1093/nar/gkx1320 |
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