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

Herein 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.

• Autores: Acosta, Javier; Pérez, Elena; Sánchez-Murcia, Pedro Alejandro; Fillat, Cristina; Fernández-Lucas, Jesús; Rosas, Ennis
• Tipo de recurso: Article of journal
• Fecha de publicación: 2021
• Institución: Corporación Universidad de la Costa
• Repositorio: REDICUC - Repositorio CUC
• Idioma: eng
• OAI Identifier: oai:repositorio.cuc.edu.co:11323/7937
• Acceso en línea: https://hdl.handle.net/11323/7937; https://doi.org/10.3390/biom11010120; https://repositorio.cuc.edu.co/
• Palabra clave: Chemotherapy; Suicide gene therapy; Nucleoside analogues; 2′-deoxyribosyltransferase; Structural bioinformatics; Molecular dynamics
• Rights: openAccess
• License: CC0 1.0 Universal