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dc.contributor.authorDiez-Torrubia, Alberto-
dc.contributor.authorCabrera, Silvia-
dc.contributor.authorCastro, Sonia de-
dc.contributor.authorGarcía-Aparicio, Carlos-
dc.contributor.authorMulder, Gwenn-
dc.contributor.authorDe Meester, Ingrid-
dc.contributor.authorCamarasa Rius, María José-
dc.contributor.authorBalzarini, Jan-
dc.contributor.authorVelázquez, Sonsoles-
dc.contributor.authorDiez-Torrubia, Alberto-
dc.date.issued2013-
dc.identifierdoi: 10.1016/j.ejmech.2013.10.001-
dc.identifierissn: 0223-5234-
dc.identifiere-issn: 1768-3254-
dc.identifier.citationEuropean Journal of Medicinal Chemistry 70: 456- 468 (2013)-
dc.identifier.urihttp://hdl.handle.net/10261/101502-
dc.description.abstractWe herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding tetrapeptide amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug.-
dc.description.sponsorshipWe thank Ria Van Berwaer and Leentje Persoons for excellent technical assistance. We also thank the Spanish MEC/MICINN (Project SAF2009-13914-C02 and SAF2012-39760-C02), the Comunidad de Madrid (BIPEDD-2-CM ref S-2010/BMD-2457), and the KU Leuven (GOA No. 10/014) for financial support. A Juan de la Cierva contract to S.d.C. (JDC-MICINN) from the Spanish Ministry of Science and Innovation is also gratefully acknowledged. We very much appreciated the helpful discussions with Dr. Judit Tulla- Puche and Prof. Fernando Albericio (IRB Barcelona, Spain).-
dc.publisherElsevier-
dc.rightsclosedAccess-
dc.subjectAcyclovir-
dc.subjectAntiviral-
dc.subjectProdrug-
dc.subjectPeptide-
dc.subjectSolid-phase synthesis-
dc.titleNovel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme-
dc.typeartículo-
dc.identifier.doihttp://dx.doi.org/10.1016/j.ejmech.2013.10.001-
dc.relation.publisherversionhttp://dx.doi.org/10.1016/j.ejmech.2013.10.001-
dc.date.updated2014-09-01T11:17:33Z-
dc.description.versionPeer Reviewed-
dc.language.rfc3066eng-
dc.contributor.funderMinisterio de Educación y Ciencia (España)-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderComunidad de Madrid-
dc.contributor.funderUniversity of Leuven-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004837es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100012818es_ES
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