Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy

dc.creatorAcosta, Javier
dc.creatorPérez, Elena
dc.creatorSánchez-Murcia, Pedro Alejandro
dc.creatorFillat, Cristina
dc.creatorFernández-Lucas, Jesús
dc.date2021-02-26T20:07:44Z
dc.date2021-02-26T20:07:44Z
dc.date2021
dc.date.accessioned2023-10-03T19:59:50Z
dc.date.available2023-10-03T19:59:50Z
dc.identifier2218-273X
dc.identifierhttps://hdl.handle.net/11323/7937
dc.identifierhttps://doi.org/10.3390/biom11010120
dc.identifierCorporación Universidad de la Costa
dc.identifierREDICUC - Repositorio CUC
dc.identifierhttps://repositorio.cuc.edu.co/
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/9173704
dc.descriptionHerein we report the first proof for the application of type II 2′-deoxyribosyltransferase from Lactobacillus delbrueckii (LdNDT) in suicide gene therapy for cancer treatment. To this end, we first confirm the hydrolytic ability of LdNDT over the nucleoside-based prodrugs 2′-deoxy-5-fluorouridine (dFUrd), 2′-deoxy-2-fluoroadenosine (dFAdo), and 2′-deoxy-6-methylpurine riboside (d6MetPRib). Such activity was significantly increased (up to 30-fold) in the presence of an acceptor nucleobase. To shed light on the strong nucleobase dependence for enzymatic activity, different molecular dynamics simulations were carried out. Finally, as a proof of concept, we tested the LdNDT/dFAdo system in human cervical cancer (HeLa) cells. Interestingly, LdNDT/dFAdo showed a pronounced reduction in cellular viability with inhibitory concentrations in the low micromolar range. These results open up future opportunities for the clinical implementation of nucleoside 2′-deoxyribosyltransferases (NDTs) in cancer treatment.
dc.formatapplication/pdf
dc.formatapplication/pdf
dc.languageeng
dc.publisherCorporación Universidad de la Costa
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dc.rightsCC0 1.0 Universal
dc.rightshttp://creativecommons.org/publicdomain/zero/1.0/
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightshttp://purl.org/coar/access_right/c_abf2
dc.sourceBiomolecules
dc.sourcehttps://www.mdpi.com/2218-273X/11/1/120
dc.subjectChemotherapy
dc.subjectSuicide gene therapy
dc.subjectNucleoside analogues
dc.subject2′-deoxyribosyltransferase
dc.subjectStructural bioinformatics
dc.subjectMolecular dynamics
dc.titleMolecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
dc.typeArtículo de revista
dc.typehttp://purl.org/coar/resource_type/c_6501
dc.typeText
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:eu-repo/semantics/publishedVersion
dc.typehttp://purl.org/redcol/resource_type/ART
dc.typeinfo:eu-repo/semantics/acceptedVersion
dc.typehttp://purl.org/coar/version/c_ab4af688f83e57aa


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