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Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7

A fundamental mechanism of the innate immune system is the recognition, via extra- and intracellular pattern-recognition receptors, of pathogen-associated molecular patterns. A prominent example is represented by foreign nucleic acids, triggering the activation of several signaling pathways. Among t...

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Autores principales: Hellmuth, Isabell, Freund, Isabel, Schlöder, Janine, Seidu-Larry, Salifu, Thüring, Kathrin, Slama, Kaouthar, Langhanki, Jens, Kaloyanova, Stefka, Eigenbrod, Tatjana, Krumb, Matthias, Röhm, Sandra, Peneva, Kalina, Opatz, Till, Jonuleit, Helmut, Dalpke, Alexander H., Helm, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364167/
https://www.ncbi.nlm.nih.gov/pubmed/28392787
http://dx.doi.org/10.3389/fimmu.2017.00312
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author Hellmuth, Isabell
Freund, Isabel
Schlöder, Janine
Seidu-Larry, Salifu
Thüring, Kathrin
Slama, Kaouthar
Langhanki, Jens
Kaloyanova, Stefka
Eigenbrod, Tatjana
Krumb, Matthias
Röhm, Sandra
Peneva, Kalina
Opatz, Till
Jonuleit, Helmut
Dalpke, Alexander H.
Helm, Mark
author_facet Hellmuth, Isabell
Freund, Isabel
Schlöder, Janine
Seidu-Larry, Salifu
Thüring, Kathrin
Slama, Kaouthar
Langhanki, Jens
Kaloyanova, Stefka
Eigenbrod, Tatjana
Krumb, Matthias
Röhm, Sandra
Peneva, Kalina
Opatz, Till
Jonuleit, Helmut
Dalpke, Alexander H.
Helm, Mark
author_sort Hellmuth, Isabell
collection PubMed
description A fundamental mechanism of the innate immune system is the recognition, via extra- and intracellular pattern-recognition receptors, of pathogen-associated molecular patterns. A prominent example is represented by foreign nucleic acids, triggering the activation of several signaling pathways. Among these, the endosomal toll-like receptor 7 (TLR7) is known to be activated by single-stranded RNA (ssRNA), which can be specifically influenced through elements of sequence structure and posttranscriptional modifications. Furthermore, small molecules TLR7 agonists (smTLRa) are applied as boosting adjuvants in vaccination processes. In this context, covalent conjugations between adjuvant and vaccines have been reported to exhibit synergistic effects. Here, we describe a concept to chemically combine three therapeutic functions in one RNA bioconjugate. This consists in the simultaneous TLR7 stimulation by ssRNA and smTLRa as well as the therapeutic function of the RNA itself, e.g., as a vaccinating or knockdown agent. We have hence synthesized bioconjugates of mRNA and siRNA containing covalently attached smTLRa and tested their function in TLR7 stimulation. Strikingly, the bioconjugates displayed decreased rather than synergistically increased stimulation. The decrease was distinct from the antagonistic action of an siRNA bearing a Gm motive, as observed by direct comparison of the effects in the presence of otherwise stimulatory RNA. In summary, these investigations showed that TRL7 activation can be impeded by bioconjugation of small molecules to RNA.
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spelling pubmed-53641672017-04-07 Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7 Hellmuth, Isabell Freund, Isabel Schlöder, Janine Seidu-Larry, Salifu Thüring, Kathrin Slama, Kaouthar Langhanki, Jens Kaloyanova, Stefka Eigenbrod, Tatjana Krumb, Matthias Röhm, Sandra Peneva, Kalina Opatz, Till Jonuleit, Helmut Dalpke, Alexander H. Helm, Mark Front Immunol Immunology A fundamental mechanism of the innate immune system is the recognition, via extra- and intracellular pattern-recognition receptors, of pathogen-associated molecular patterns. A prominent example is represented by foreign nucleic acids, triggering the activation of several signaling pathways. Among these, the endosomal toll-like receptor 7 (TLR7) is known to be activated by single-stranded RNA (ssRNA), which can be specifically influenced through elements of sequence structure and posttranscriptional modifications. Furthermore, small molecules TLR7 agonists (smTLRa) are applied as boosting adjuvants in vaccination processes. In this context, covalent conjugations between adjuvant and vaccines have been reported to exhibit synergistic effects. Here, we describe a concept to chemically combine three therapeutic functions in one RNA bioconjugate. This consists in the simultaneous TLR7 stimulation by ssRNA and smTLRa as well as the therapeutic function of the RNA itself, e.g., as a vaccinating or knockdown agent. We have hence synthesized bioconjugates of mRNA and siRNA containing covalently attached smTLRa and tested their function in TLR7 stimulation. Strikingly, the bioconjugates displayed decreased rather than synergistically increased stimulation. The decrease was distinct from the antagonistic action of an siRNA bearing a Gm motive, as observed by direct comparison of the effects in the presence of otherwise stimulatory RNA. In summary, these investigations showed that TRL7 activation can be impeded by bioconjugation of small molecules to RNA. Frontiers Media S.A. 2017-03-24 /pmc/articles/PMC5364167/ /pubmed/28392787 http://dx.doi.org/10.3389/fimmu.2017.00312 Text en Copyright © 2017 Hellmuth, Freund, Schlöder, Seidu-Larry, Thüring, Slama, Langhanki, Kaloyanova, Eigenbrod, Krumb, Röhm, Peneva, Opatz, Jonuleit, Dalpke and Helm. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Hellmuth, Isabell
Freund, Isabel
Schlöder, Janine
Seidu-Larry, Salifu
Thüring, Kathrin
Slama, Kaouthar
Langhanki, Jens
Kaloyanova, Stefka
Eigenbrod, Tatjana
Krumb, Matthias
Röhm, Sandra
Peneva, Kalina
Opatz, Till
Jonuleit, Helmut
Dalpke, Alexander H.
Helm, Mark
Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7
title Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7
title_full Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7
title_fullStr Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7
title_full_unstemmed Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7
title_short Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7
title_sort bioconjugation of small molecules to rna impedes its recognition by toll-like receptor 7
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364167/
https://www.ncbi.nlm.nih.gov/pubmed/28392787
http://dx.doi.org/10.3389/fimmu.2017.00312
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