Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA Pharmacology
The medical staff is often powerless to treat patients affected by drug abuse or misuse and poisoning. In the case of envenomation, the treatment of choice remains horse sera administration that poses a wealth of other medical conditions and threats. Previously, we have demonstrated that DNA-based a...
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| Format: | Article |
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MDPI AG
2019-01-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/24/2/229 |
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| author | Germain Sotoing Taiwe Jérôme Montnach Sébastien Nicolas Stéphan De Waard Emmanuelle Fiore Eric Peyrin Tarek Mohamed Abd El-Aziz Muriel Amar Jordi Molgó Michel Ronjat Denis Servent Corinne Ravelet Michel De Waard |
| author_facet | Germain Sotoing Taiwe Jérôme Montnach Sébastien Nicolas Stéphan De Waard Emmanuelle Fiore Eric Peyrin Tarek Mohamed Abd El-Aziz Muriel Amar Jordi Molgó Michel Ronjat Denis Servent Corinne Ravelet Michel De Waard |
| author_sort | Germain Sotoing Taiwe |
| collection | DOAJ |
| description | The medical staff is often powerless to treat patients affected by drug abuse or misuse and poisoning. In the case of envenomation, the treatment of choice remains horse sera administration that poses a wealth of other medical conditions and threats. Previously, we have demonstrated that DNA-based aptamers represent powerful neutralizing tools for lethal animal toxins of venomous origin. Herein, we further pursued our investigations in order to understand whether all toxin-interacting aptamers possessed equivalent potencies to neutralize αC-conotoxin PrXA in vitro and in vivo. We confirmed the high lethality in mice produced by αC-conotoxin PrXA regardless of the mode of injection and further characterized myoclonus produced by the toxin. We used high-throughput patch-clamp technology to assess the effect of αC-conotoxin PrXA on ACh-mediated responses in TE671 cells, responses that are carried by muscle-type nicotinic receptors. We show that 2 out of 4 aptamers reduce the affinity of the toxin for its receptor, most likely by interfering with the pharmacophore. In vivo, more complex responses on myoclonus and mice lethality are observed depending on the type of aptamer and mode of administration (concomitant or differed). Concomitant administration always works better than differed administration indicating the stability of the complex in vivo. The most remarkable conclusion is that an aptamer that has no or a limited efficacy in vitro may nevertheless be functional in vivo probably owing to an impact on the biodistribution or pharmacokinetics of the toxin in vivo. Overall, the results highlight that a blind selection of aptamers against toxins leads to efficient neutralizing compounds in vivo regardless of the mode of action. This opens the door to the use of aptamer mixtures as substitutes to horse sera for the neutralization of life-threatening animal venoms, an important WHO concern in tropical areas. |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-22T09:49:32Z |
| publishDate | 2019-01-01 |
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| spelling | doaj.art-05d65c95d5344df6be88b623ffc86b812022-12-21T18:30:25ZengMDPI AGMolecules1420-30492019-01-0124222910.3390/molecules24020229molecules24020229Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA PharmacologyGermain Sotoing Taiwe0Jérôme Montnach1Sébastien Nicolas2Stéphan De Waard3Emmanuelle Fiore4Eric Peyrin5Tarek Mohamed Abd El-Aziz6Muriel Amar7Jordi Molgó8Michel Ronjat9Denis Servent10Corinne Ravelet11Michel De Waard12INSERM UMR 1087/CNRS UMR 6291, Institut du Thorax, Nouvelle Université à Nantes, LabEx Ion Channels, Science and Therapeutics, 8 Quai Moncousu, BP 70721 Nantes CEDEX 1, FranceINSERM UMR 1087/CNRS UMR 6291, Institut du Thorax, Nouvelle Université à Nantes, LabEx Ion Channels, Science and Therapeutics, 8 Quai Moncousu, BP 70721 Nantes CEDEX 1, FranceINSERM UMR 1087/CNRS UMR 6291, Institut du Thorax, Nouvelle Université à Nantes, LabEx Ion Channels, Science and Therapeutics, 8 Quai Moncousu, BP 70721 Nantes CEDEX 1, FranceINSERM UMR 1087/CNRS UMR 6291, Institut du Thorax, Nouvelle Université à Nantes, LabEx Ion Channels, Science and Therapeutics, 8 Quai Moncousu, BP 70721 Nantes CEDEX 1, FranceCNRS, DPM UMR 5063, University Grenoble Alpes, 38041 Grenoble, FranceCNRS, DPM UMR 5063, University Grenoble Alpes, 38041 Grenoble, FranceZoology Department, Faculty of Science, Minia University, 61519 El-Minia, EgyptService d’Ingénierie Moléculaire des Protéines, Institut des Sciences du Vivant Frédéric Joliot, Commissariat à l’Energie Atomique, Université Paris-Saclay, F-91191 Gif sur Yvette, FranceService d’Ingénierie Moléculaire des Protéines, Institut des Sciences du Vivant Frédéric Joliot, Commissariat à l’Energie Atomique, Université Paris-Saclay, F-91191 Gif sur Yvette, FranceINSERM UMR 1087/CNRS UMR 6291, Institut du Thorax, Nouvelle Université à Nantes, LabEx Ion Channels, Science and Therapeutics, 8 Quai Moncousu, BP 70721 Nantes CEDEX 1, FranceService d’Ingénierie Moléculaire des Protéines, Institut des Sciences du Vivant Frédéric Joliot, Commissariat à l’Energie Atomique, Université Paris-Saclay, F-91191 Gif sur Yvette, FranceCNRS, DPM UMR 5063, University Grenoble Alpes, 38041 Grenoble, FranceINSERM UMR 1087/CNRS UMR 6291, Institut du Thorax, Nouvelle Université à Nantes, LabEx Ion Channels, Science and Therapeutics, 8 Quai Moncousu, BP 70721 Nantes CEDEX 1, FranceThe medical staff is often powerless to treat patients affected by drug abuse or misuse and poisoning. In the case of envenomation, the treatment of choice remains horse sera administration that poses a wealth of other medical conditions and threats. Previously, we have demonstrated that DNA-based aptamers represent powerful neutralizing tools for lethal animal toxins of venomous origin. Herein, we further pursued our investigations in order to understand whether all toxin-interacting aptamers possessed equivalent potencies to neutralize αC-conotoxin PrXA in vitro and in vivo. We confirmed the high lethality in mice produced by αC-conotoxin PrXA regardless of the mode of injection and further characterized myoclonus produced by the toxin. We used high-throughput patch-clamp technology to assess the effect of αC-conotoxin PrXA on ACh-mediated responses in TE671 cells, responses that are carried by muscle-type nicotinic receptors. We show that 2 out of 4 aptamers reduce the affinity of the toxin for its receptor, most likely by interfering with the pharmacophore. In vivo, more complex responses on myoclonus and mice lethality are observed depending on the type of aptamer and mode of administration (concomitant or differed). Concomitant administration always works better than differed administration indicating the stability of the complex in vivo. The most remarkable conclusion is that an aptamer that has no or a limited efficacy in vitro may nevertheless be functional in vivo probably owing to an impact on the biodistribution or pharmacokinetics of the toxin in vivo. Overall, the results highlight that a blind selection of aptamers against toxins leads to efficient neutralizing compounds in vivo regardless of the mode of action. This opens the door to the use of aptamer mixtures as substitutes to horse sera for the neutralization of life-threatening animal venoms, an important WHO concern in tropical areas.http://www.mdpi.com/1420-3049/24/2/229αC-conotoxin PrXADNA aptameroligonucleotidetoxin neutralizationcone peptidevenom |
| spellingShingle | Germain Sotoing Taiwe Jérôme Montnach Sébastien Nicolas Stéphan De Waard Emmanuelle Fiore Eric Peyrin Tarek Mohamed Abd El-Aziz Muriel Amar Jordi Molgó Michel Ronjat Denis Servent Corinne Ravelet Michel De Waard Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA Pharmacology Molecules αC-conotoxin PrXA DNA aptamer oligonucleotide toxin neutralization cone peptide venom |
| title | Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA Pharmacology |
| title_full | Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA Pharmacology |
| title_fullStr | Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA Pharmacology |
| title_full_unstemmed | Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA Pharmacology |
| title_short | Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA Pharmacology |
| title_sort | aptamer efficacies for in vitro and in vivo modulation of αc conotoxin prxa pharmacology |
| topic | αC-conotoxin PrXA DNA aptamer oligonucleotide toxin neutralization cone peptide venom |
| url | http://www.mdpi.com/1420-3049/24/2/229 |
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