Document Detail

Phosphorylation of 3'-azido-2',3'-dideoxyuridine and preferential inhibition of human and simian immunodeficiency virus reverse transcriptases by its 5'-triphosphate.
MedLine Citation:
PMID:  2480079     Owner:  NLM     Status:  MEDLINE    
3'-Azido-2',3'-dideoxyuridine-5'-triphosphate was found to be a potent and highly selective inhibitor of human immunodeficiency virus type 1 and simian immunodeficiency virus reverse transcriptases. The affinity of 3'-azido-2',3'-dideoxyuridine-5'-triphosphate for the reverse transcriptases was similar to that observed for 3'-azido-3'-deoxythymidine-5'-triphosphate. Both compounds were competitive inhibitors with respect to the normal substrate dTTP and served at least 100 times better as substrates than did dTTP. In contrast, cellular DNA polymerase alpha showed an about 60-times-higher preference for dTTP as substrate than for either inhibitor. The phosphorylation of thymidine in human peripheral blood mononuclear cell extracts was inhibited in a competitive manner by both 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine, with apparent inhibition constants of 290 and 3.4 microM, respectively. The Michaelis-Menten constant, Km, for thymidine was 7.0 microM. 3'-Azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine both served as substrates, with apparent Km values of 67 and 1.4 microM, respectively. The maximal rates of phosphorylation with 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine were 40 and 30%, respectively, of the rate with thymidine. The different affinities of 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine for the thymidine kinase and the Km values observed with these compounds as substrates may explain the difference in effects on human immunodeficiency virus type 1 replication in infected peripheral blood mononuclear cells observed when equimolar concentrations of the two compounds are compared.
B F Eriksson; C K Chu; R F Schinazi
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  33     ISSN:  0066-4804     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  1989 Oct 
Date Detail:
Created Date:  1990-01-03     Completed Date:  1990-01-03     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1729-34     Citation Subset:  IM; X    
Veterans Administration Medical Center (Atlanta), Decatur, Georgia 30033.
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MeSH Terms
Cells, Cultured
Chromatography, High Pressure Liquid
DNA Polymerase II / antagonists & inhibitors
HIV / drug effects,  enzymology*
Phosphotransferases / metabolism
Reverse Transcriptase Inhibitors*
Simian immunodeficiency virus / drug effects,  enzymology*
Thymidine Kinase / metabolism
Zidovudine / analogs & derivatives*,  pharmacology
Grant Support
Reg. No./Substance:
0/Reverse Transcriptase Inhibitors; 30516-87-1/Zidovudine; 84472-85-5/3'-azido-2',3'-dideoxyuridine; EC 2.7.-/Phosphotransferases; EC Kinase; EC phosphotransferase; EC 2.7.7.-/DNA Polymerase II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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