title: S-acyl-2-thioethyl (SATE) pronucleotides are potent inhibitors of HIV-1 replication in T-lymphoid cells cross-resistant to deoxycytidine and thymidine analogs.
abstract: 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.
authors.affiliation: Institute of Medical Virology, Johann Wolfgang Goethe University Frankfurt/M., Paul-Ehrlich-Str. 40, 60596 M., Frankfurt, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Gröschel
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
authors.forename: C
authors.initials: C
authors.lastname: Périgaud
authors.forename: G
authors.initials: G
authors.lastname: Gosselin
authors.forename: J-L
authors.initials: JL
authors.lastname: Imbach
authors.forename: H W
authors.initials: HW
authors.lastname: Doerr
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
mesh_terms: 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*
chemical_list: 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