Inhibition of reverse transcriptase from feline immunodeficiency virus by analogs of 2'-deoxyadenosine-5'-triphosphate.
The replication of feline immunodeficiency virus (FIV) in cultured cells was inhibited by 2',3'-dideoxyadenosine (ddA) and by 9-(2-phosphonylmethoxyethyl)adenine (PMEA) with IC50 values of 0.98 and 0.95 microM, respectively. The effects of the presumed active forms of these inhibitors, ddATP and PMEA-diphosphate (PMEApp), upon the FIV reverse transcriptase (RT) were examined with two different template-primer systems. Both of these compounds were potent inhibitors of the FIV RT in reactions with primed phi X-174 DNA, yielding Ki values of 8.8 nM for ddATP and 5.0 nM for PMEApp. However, they were both poor inhibitors of the reaction with poly(rU)-oligo(dA); concentrations of ddATP or PMEApp greater than 10 microM were required to inhibit this reaction by 50%. Further analysis of the reaction with poly(rU)-oligo(dA) revealed that even in the absence of inhibitors the primers were extended by less than 20 nucleotides. In contrast, high molecular weight products were obtained in reactions with phi X-174 DNA. These results suggest that the reaction of FIV RT with poly(rU)-oligo(dA) is not highly processive. The high degree of termination encountered during this reaction with poly(rU)-oligo(dA) may be responsible for the low inhibitory potential of ddATP and PMEApp.
Cronn
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RC
Division of Biological Sciences, University of Montana, Missoula 59812.
Remington
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KM
Preston
B D
BD
North
T W
TW
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D016048:Dideoxyadenosine / Q000494:pharmacology*; D016089:Immunodeficiency Virus, Feline / Q000201:enzymology* / Q000302:isolation & purification; D007700:Kinetics; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D013698:Templates, Genetic
D000998:Antiviral Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D016048:Dideoxyadenosine; C053001:adefovir; D000225:Adenine