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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...

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Autores principales: Juliano, Rudolph L, Wang, Ling, Tavares, Francis, Brown, Edward G, James, Lindsey, Ariyarathna, Yamuna, Ming, Xin, Mao, Chengqiong, Suto, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
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.
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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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