Journal
AMINO ACIDS
Volume 46, Issue 4, Pages 1047-1058Publisher
SPRINGER WIEN
DOI: 10.1007/s00726-013-1661-3
Keywords
BODIPY; Cell-penetrating peptide; Miltefosine; Dual fluorescent labeling; Reversion of resistance; Monitoring of intracellular drug delivery
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Funding
- European Union [HEALTH-2007-223414]
- VI PN de I+D+I [PI09-01928, PI12-02706]
- ISCIII-Subdireccion General de Redes y Centros de Investigacion Cooperativa [RICET RD 06/0021/0006, RD12/0018/0007]
- MICINN [CTQ2010-16457, BIO2008-04487-CO3]
- MINECO [SAF2011-24899]
- Generalitat de Catalunya [SGR2009-00492]
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Therapeutic 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.
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