Inhibition of HIV-1 replication in cultured cells with phosphorylated dideoxyuridine derivatives encapsulated in immunoliposomes.
Among the 2',3'-dideoxynucleoside 5'-triphosphates containing a physiological base, 2',3'-dideoxyuridine 5'-triphosphate (ddUTP) has been reported to be among the most powerful inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) in cell-free systems. However, in contrast to other dideoxynucleosides, 2',3'-dideoxyuridine (ddU) is inactive in treatment of HIV-infected cells in culture, since it is a poor substrate for cellular nucleoside kinases. This problem cannot be overcome by the use of phosphorylated ddU because such compounds are unable to cross cell membranes. To promote entry and thus bypass the limiting steps of intracellular phosphorylation, we have encapsulated mono- and tri-phosphorylated ddU in liposomes coupled to monoclonal antibodies (immunoliposomes). We investigated antiviral effects in two human T cell lines (MT-4, CEM). We observed that ddU nucleotides remain phosphorylated for several weeks after encapsulation in immunoliposomes, and potent antiviral activity is obtained when these drugs are delivered into infected cells by cell-specific antibodies (ED50 < or = 1 microM on CEM). In contrast, no inhibition was observed with non-targeted liposomes containing phosphorylated ddU, or with empty liposomes, whether targeted or not.
Zelphati
O
O
Centre d'Immunologie, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique de Marseille-Luminy Case 906, France.
Degols
G
G
Loughrey
H
H
Leserman
L
L
Pompon
A
A
Puech
F
F
Maggio
A F
AF
Imbach
J L
JL
Gosselin
G
G
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D054306:Dideoxynucleotides; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008081:Liposomes; D010766:Phosphorylation; D014500:Uracil Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D014542:Uridine Monophosphate / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D054306:Dideoxynucleotides; D008081:Liposomes; D014500:Uracil Nucleotides; C083401:2',3'-dideoxyuridine 5'-monophosphate; C063034:2',3'-dideoxyuridine-5'-triphosphate; D014542:Uridine Monophosphate