S-acyl-2-thioethyl (SATE) pronucleotides are potent inhibitors of HIV-1 replication in T-lymphoid cells cross-resistant to deoxycytidine and thymidine analogs.
The biological evaluation of mononucleotide prodrugs (pronucleotides) of various nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT), zalcitabine (ddC) and lamivudine (3TC) was reported in human T-lymphoid MOLT-4/8 cells which were grown continuously for more than 1 year in a medium containing cytarabine (Ara-C). In this cell line, expression of deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) was decreased in comparison to parental cells (3.8 and 2.9-fold, respectively). The lower mRNA level of TK1 correlated significantly with lower enzyme activity, whereas no dCK activity was detectable. In Ara-C-resistant cells, anti-HIV-1 effects of ddC, 3TC and AZT were more than 100-fold lower compared with parental cells. In contrast, the corresponding mononucleoside phosphotriesters bearing S-acyl-2-thioethyl (SATE) groups as biolabile phosphate protection retained anti-HIV-1 activity due to their ability to bypass the first monophosphorylation step catalyzed by dCK or TK1. The results demonstrate that in vitro selection of T-lymphoid cells in the presence of Ara-C results in cross-resistance to deoxycytidine (ddC, 3TC) and thymidine (AZT) analogs and that these cellular resistance mechanisms can be bypassed by the use of bis(SATE) pronucleotides.
Gröschel
B
B
Institute of Medical Virology, Johann Wolfgang Goethe University Frankfurt/M., Paul-Ehrlich-Str. 40, 60596 M., Frankfurt, Germany.
Cinatl
J
J
Périgaud
C
C
Gosselin
G
G
Imbach
J-L
JL
Doerr
H W
HW
Cinatl
J
J
D019380:Anti-HIV Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D003561:Cytarabine / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004351:Drug Resistance; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000821:virology; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D003561:Cytarabine; D003841:Deoxycytidine; D013937:Thymidine Kinase; D003842:Deoxycytidine Kinase; D013936:Thymidine