A BODIPY-embedding miltefosine analog linked to cell-penetrating Tat(48-60) peptide favors intracellular delivery and visualization of the antiparasitic drug.
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.
Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, 08003, Barcelona, Spain.
Beatriz G
BG
de la Torre
Valentín
V
Hornillos
Juan R
JR
Luque-Ortega
M A
MA
Abengózar
Francisco
F
Amat-Guerri
A Ulises
AU
Acuña
Luis
L
Rivas
David
D
Andreu
D000871:Anthelmintics / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D001896:Boron Compounds / Q000737:chemistry* / Q000493:pharmacokinetics*; D002460:Cell Line; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000493:pharmacokinetics; D015195:Drug Design; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000469:parasitology; D015394:Molecular Structure; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000493:pharmacokinetics
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000871:Anthelmintics; D001896:Boron Compounds; D057846:Cell-Penetrating Peptides; D054322:tat Gene Products, Human Immunodeficiency Virus; D010767:Phosphorylcholine; C039128:miltefosine