Modeling the therapeutic efficacy of NFκBsynthetic decoy oligodeoxynucleotides (ODNs)

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dc.citation.articleNumber4en_US
dc.citation.journalTitleBMC Systems Biologyen_US
dc.citation.volumeNumber12en_US
dc.contributor.authorWang, Zhipengen_US
dc.contributor.authorPotoyan, Davit A.en_US
dc.contributor.authorWolynes, Peter G.en_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2018-07-11T17:18:36Zen_US
dc.date.available2018-07-11T17:18:36Zen_US
dc.date.issued2018en_US
dc.description.abstractBackground: Transfection of NF κB synthetic decoy Oligodeoxynucleotides (ODNs) has been proposed as a promising therapeutic strategy for a variety of diseases arising from constitutive activation of the eukaryotic transcription factor NF κB. The decoy approach faces some limitations under physiological conditions notably nuclease-induced degradation. Results: In this work, we show how a systems pharmacology model of NF κB regulatory networks displaying oscillatory temporal dynamics, can be used to predict quantitatively the dependence of therapeutic efficacy of NF κB synthetic decoy ODNs on dose, unbinding kinetic rates and nuclease-induced degradation rates. Both deterministic mass action simulations and stochastic simulations of the systems biology model show that the therapeutic efficacy of synthetic decoy ODNs is inversely correlated with unbinding kinetic rates, nuclease-induced degradation rates and molecular stripping rates, but is positively correlated with dose. We show that the temporal coherence of the stochastic dynamics of NF κB regulatory networks is most sensitive to adding NF κB synthetic decoy ODNs having unbinding time-scales that are in-resonance with the time-scale of the limit cycle of the network. Conclusions: The pharmacokinetics/pharmacodynamics (PK/PD) predicted by the systems-level model should provide quantitative guidance for in-depth translational research of optimizing the thermodynamics/kinetic properties of synthetic decoy ODNs.en_US
dc.identifier.citationWang, Zhipeng, Potoyan, Davit A. and Wolynes, Peter G.. "Modeling the therapeutic efficacy of NFκBsynthetic decoy oligodeoxynucleotides (ODNs)." <i>BMC Systems Biology,</i> 12, (2018) BMC: https://doi.org/10.1186/s12918-018-0525-6.en_US
dc.identifier.doihttps://doi.org/10.1186/s12918-018-0525-6en_US
dc.identifier.urihttps://hdl.handle.net/1911/102383en_US
dc.language.isoengen_US
dc.publisherBMCen_US
dc.rightsThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleModeling the therapeutic efficacy of NFκBsynthetic decoy oligodeoxynucleotides (ODNs)en_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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