DNA chain termination activity and inhibition of human immunodeficiency virus reverse transcriptase by carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine triphosphate.

Abstract

Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, NSC 614846) is an anti-retroviral agent that may be useful in the treatment of AIDS. We have examined the ability of (-)-enantiomeric carbovir triphosphate to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (EC 2.7.7.49). A comparison of inhibition kinetics was made with 3'-azido-2',3'-dideoxythymidine triphosphate and phosphonoformate. Inhibition of the reverse transcriptase was evaluated using poly(rA).oligo(dT)12-18, poly(rC).oligo(dG)12-18, or influenza virion RNA template with a specific oligodeoxynucleotide as primer. (-)-Carbovir 5'-triphosphate was shown to be a potent inhibitor of HIV-1 reverse transcriptase with an apparent Ki similar to that of 3'-azido-2',3'-dideoxythymidine triphosphate. Chain elongation studies utilizing an MS2 RNA template showed that (-)-carbovir 5'-triphosphate terminated transcription at positions identical to those where dideoxy-GTP terminated. This indicates that (-)-carbovir 5'-monophosphate is incorporated into the newly synthesized DNA and terminates transcription at that point. We conclude that (-)-carbovir 5'-triphosphate is a potent inhibitor of the HIV-1 reverse transcriptase enzyme and that (-)-carbovir most likely inhibits HIV by activity at the triphosphate level by a combination of direct competition for binding of the natural deoxynucleoside triphosphates to the reverse transcriptase and chain termination.

• Authors: D C Orr, H T Figueiredo, C L Mo, C R Penn, J M Cameron
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 267 Issue 6 Pg. 4177-82 (Feb 25 1992) ISSN: 0021-9258 [Print] United States
• PMID: 1371285 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• DNA, Viral
• Dideoxynucleosides
• Reverse Transcriptase Inhibitors
• carbovir
• Zidovudine
• HIV Reverse Transcriptase
• RNA-Directed DNA Polymerase

Topics

• Antiviral Agents (pharmacology)
• Base Sequence
• DNA, Viral (drug effects, genetics)
• Dideoxynucleosides (pharmacology)
• Escherichia coli (metabolism)
• HIV Reverse Transcriptase
• HIV-1 (drug effects, enzymology)
• Kinetics
• Molecular Sequence Data
• RNA-Directed DNA Polymerase (metabolism)
• Reverse Transcriptase Inhibitors
• Transcription, Genetic (drug effects)
• Zidovudine (pharmacology)