Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3'-deoxythymidine.
3'-Deoxythymidine (3dT) is a weakly active dideoxynucleoside in human immunodeficiency virus (HIV)-infected cells because of its slow phosphorylation by cellular thymidine kinase. 3dT diphosphate dimyristoylglycerol (3dTDP-DMG), a phospholipid prodrug, was synthesized and found in vitro to be 18- to 50-fold more effective than 3dT in CEM and HT4-6C cells. In CEM cells, the selectivity index of 3dTDP-DMG was 270 versus 48 for 3dT, an increase of 5.6-fold. In thymidine kinase-deficient mutant CEM cells infected with HIV, 3dT and zidovudine (AZT) were virtually inactive but 3dTDP-DMG retained substantial activity, suggesting that its greatly increased antiviral activity is due in part to bypass of thymidine kinase. 3dTDP-DMG was 14- to 37-fold more active than 3dT in AZT-sensitive and AZT-resistant clinical isolates of HIV; no cross-resistance with AZT was noted. The results suggest that lipid prodrugs may be utilized in some cases to confer unique metabolic advantages over the corresponding free nucleoside; in the case of 3dTDP-DMG, an 18- to 50-fold increase in antiretroviral activity was observed in LAV-infected cells. The strategy would seem to be especially useful for antiviral nucleosides which are poorly phosphorylated.
Hostetler
K Y
KY
Department of Medicine, University of California, San Diego.
Richman
D D
DD
Carson
D A
DA
Stuhmiller
L M
LM
van Wijk
G M
GM
van den Bosch
H
H
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010743:Phospholipids / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000382:microbiology; D013936:Thymidine / Q000494:pharmacology*; D013942:Thymine Nucleotides / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D010743:Phospholipids; D011355:Prodrugs; D013942:Thymine Nucleotides; C077462:3'-deoxythymidine diphosphate dimyristoylglycerol; D015215:Zidovudine; D013936:Thymidine