Differences in the inhibition of human immunodeficiency virus type 1 reverse transcriptase DNA polymerase activity by analogs of nevirapine and [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1", 2"-oxathiole-2",2"-dioxide] (TSAO).
We compared the inhibition of HIV-1 reverse transcriptase (RT) by 1-[2',5'-bis-O-(t-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'- spiro-5"-(4"-amino-1", 2"-oxathiole-2",2"-dioxide)-3-ethylthymine (TSAOe3T) and the nonnucleoside RT inhibitor (NNRTI) 9-aminonevirapine (9-NH2N). Both compounds were equally effective against p51/p66 heterodimeric RT RNA-dependent DNA polymerase activity, although TSAOe3T was a much better inhibitor of the p51/p51 and p66/p66 RT homodimers. Inhibition by TSAOe3T and 9-NH2N combinations was essentially additive. TSAOe3T did not protect either free RT or the RT-template/ primer-deoxynucleoside triphosphate ternary complex from irreversible inactivation by the photolabel 9-azidonevirapine. Slight protection of the RT-template/primer binary complex was noted, but only at high TSAOe3T/photolabel ratios. Analysis of RT polymerization product profiles under both continuous- and single-processive cycle conditions showed that 9-NH2N prevented the formation of full-length product with a corresponding accumulation of smaller polymerization products. In contrast, all products formed in the absence of inhibitor, including full-length product, were noted in TSAOe3T-inhibited reactions, albeit at reduced levels. TSAOe3T thus inhibits HIV-1 RT by a different mechanism than NNRTI such as nevirapine. Our data suggest that TSAOe3T and 9-NH2N interact differently with HIV-1 RT, perhaps by binding to distinct sites on the enzyme.
Arion
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Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Fletcher
R S
RS
Borkow
G
G
Camarasa
M J
MJ
Balzarini
J
J
Dmitrienko
G I
GI
Parniak
M A
MA
D000998:Antiviral Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D010777:Photochemistry; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
C102279:1-(2',5'-bis-O-(t-butyldimethylsilyl)ribofuranosyl)-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)-3-ethylthymine; C102278:9-aminonevirapine; D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D001569:Benzodiazepines; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D004259:DNA-Directed DNA Polymerase; D013936:Thymidine