Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases alpha, beta, and gamma by the 5'-triphosphates of carbovir, 3'-azido-3'-deoxythymidine, 2',3'-dideoxyguanosine and 3'-deoxythymidine. A novel RNA template for the evaluation of antiretroviral drugs

Carbovir (the carbocyclic analog of 2'-3'-didehydro-2',3'-dideoxyguanosine) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. Assays were developed to assess the mechanism of inhibition by the 5'-triphosphate of carbovir of HIV-1 reverse trans...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 1991-01, Vol.266 (3), p.1754-1762
Main Authors: W B Parker, E L White, S C Shaddix, L J Ross, R W Buckheit, Jr, J M Germany, J A Secrist, 3rd, R Vince, W M Shannon
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Antiviral Agents - metabolism
Antiviral Agents - pharmacology
Base Sequence
Biological and medical sciences
Deoxyguanine Nucleotides - metabolism
Deoxyguanine Nucleotides - pharmacology
Dideoxynucleotides
DNA - biosynthesis
DNA - metabolism
DNA Polymerase I - antagonists & inhibitors
DNA Polymerase II - antagonists & inhibitors
DNA Polymerase III - antagonists & inhibitors
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
HIV-1 - enzymology
Humans
In Vitro Techniques
Kinetics
Molecular Sequence Data
Reverse Transcriptase Inhibitors
RNA - metabolism
Templates, Genetic
Thymine Nucleotides - metabolism
Thymine Nucleotides - pharmacology
Transferases
Zidovudine - analogs & derivatives
Zidovudine - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Carbovir (the carbocyclic analog of 2'-3'-didehydro-2',3'-dideoxyguanosine) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. Assays were developed to assess the mechanism of inhibition by the 5'-triphosphate of carbovir of HIV-1 reverse transcriptase using either RNA or DNA templates that contain all four natural nucleotides. Carbovir-TP was a potent inhibitor of HIV-1 reverse transcriptase using either template with Ki values similar to that observed by AZT-TP, ddGTP, and ddTTP. The kinetic constants for incorporation of these nucleotide analogs into DNA by HIV-1 reverse transcriptase using either template were similar to the values seen for their respective natural nucleotides. In addition, the incorporation of either carbovir-TP or AZT-TP in the presence of dGTP or dTTP, respectively, indicated that the mechanism of inhibition by these two nucleotide analogs was due to their incorporation into the DNA resulting in chain termination. Carbovir-TP was not a potent inhibitor of DNA polymerase alpha, beta, or gamma, or DNA primase. Given the potent activity of carbovir-TP against HIV-1 reverse transcriptase and its lack of activity against human DNA polymerases, we believe that further evaluation of this compound as a potential drug for the treatment of HIV-1 infection is warranted.
ISSN:0021-9258
1083-351X
DOI:10.1016/s0021-9258(18)52360-7