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Título

A BODIPY-embedding miltefosine analog linked to cell-penetrating Tat(48-60) peptide favors intracellular delivery and visualization of the antiparasitic drug

AutorGarcía de la Torre, Beatriz CSIC ORCID; Hornillos, Valentín CSIC ORCID; Luque-Ortega, Juan Román CSIC ORCID ; Abengozar, M. A. CSIC; Amat-Guerri, Francisco CSIC; Ulises Acuña, A.; Rivas, Luis CSIC ORCID ; Andreu, David
Palabras claveBODIPY
Cell-penetrating peptides
Miltefosine
Dual fluorescent labeling
Reversion of resistance
Monitoring of intracellular drug delivery
Fecha de publicaciónabr-2014
EditorSpringer Nature
CitaciónAmino Acids 46(4): 1047-1058 (2014)
ResumenTherapeutic application of many drugs is often hampered by poor or denied access to intracellular targets. A case in point is miltefosine (MT), an orally active antiparasitic drug, which becomes ineffective when parasites develop dysfunctional uptake systems. We report here the synthesis of a fluorescent BODIPY-embedding MT analogue with appropriate thiol functionalization allowing linkage to the cell-penetrating Tat(48-60) peptide through disulfide or thioether linkages. The resulting constructs are efficiently internalized into the otherwise MT-invulnerable R40 Leishmania strain, resulting in fast parasite killing, and hence successful avoidance of the resistance. In the disulfide-linked conjugate, an additional fluoro tag on the Tat moiety allows to monitor its reductive cleavage within the cytoplasm. Terminally differentiated cells such as peritoneal macrophages, impervious to MT unless infected by Leishmania, can uptake the drug in its Tat-conjugated form. The results afford proof-of-principle for using CPP vectors to avert drug resistance in parasites, and/or for tackling leishmaniasis by modulating macrophage uptake. © 2014 Springer-Verlag Wien.
Versión del editorhttp://dx.doi.org/10.1007/s00726-013-1661-3
URIhttp://hdl.handle.net/10261/97131
DOI10.1007/s00726-013-1661-3
Identificadoresdoi: 10.1007/s00726-013-1661-3
issn: 0939-4451
issn: 1438-2199
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