Document Detail


Effects of nucleotide analogues on human immunodeficiency virus type 1 integrase.
MedLine Citation:
PMID:  8609889     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We extended our previous study with 3'-azido-3'-deoxythymidine nucleotides [Proc. Natl. Acad. Sci. USA 91:5771-5775 (1994)] and examined the effects on human immunodeficiency virus type 1 (HIV-1) integrase of the nucleotides of three nucleoside analogues currently under evaluation in clinical trials: beta-D-2',3'-didehydro-3'-deoxythymidine, beta-D-2'-ara-fluoro-2', 3'-dideoxyadenosine, and beta-L-2',3'-dideoxy-3'-thiacytidine. Beta-D-2',3'-Didehydro-3'-deoxythymidine and beta-D-2'-ara-fluoro-2',3'-dideoxyadenosine nucleotides had IC50 values for strand transfer of 100 and 200 microM, respectively, whereas the corresponding 2',3'-dideoxynucleoside triphosphates, ddT triphosphate and ddA triphosphate, did not inhibit the integrase at 800 and 200 microM, respectively. Beta-L-2',3'-Dideoxy-3'-thiacytidine triphosphate had no effect up to 500 microM. The L-enantiomers of 5-fluoro-2',3'-dideoxycytidine monophosphate and triphosphate had IC50 values of approximately 40 microM, whereas their D-enantiomer isomers showed no inhibition at 200 microM. NAD, pyridoxal phosphate, and coumermycin A1, which exhibit no antiviral activity but are typically used to probe nucleotide binding sites, were also tested. NAD was inactive, and its etheno derivative exhibited activity at 1 mM. In contrast, pyridoxal phosphate (IC50 = 18 microM and coumermycin A1 (IC50 = 5 microM were potent inhibitors. None of the coumermycin monomeric derivatives were active integrase inhibitors. The physiological ribonucleotides ATP and GTP inhibited HIV-1 integrase at or near cellular concentrations, suggesting that they may regulate HIV-1 integrase activity in cells. In general, the active nucleotides tested inhibited binding of HIV-1 integrase to its substrate DNA an inhibited an integrase deletion mutant containing only amino acids 50-212, indicating that nucleotides bind to the enzyme catalytic core. Consisently, the choice of nucleophile in the 3'-processing reaction was blocked to the same extent regardless of the nucleotide used (water, glycerol, or the viral DNA hydroxyl) by the enzyme. These observations suggest new strategies for antiviral drug development that could be based on nucleotide analogues as inhibitors of HIV-1 integrase.
Authors:
A Mazumder; N Neamati; J P Sommadossi; G Gosselin; R F Schinazi; J L Imbach; Y Pommier
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular pharmacology     Volume:  49     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1996 Apr 
Date Detail:
Created Date:  1996-05-30     Completed Date:  1996-05-30     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  621-8     Citation Subset:  IM; X    
Affiliation:
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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MeSH Terms
Descriptor/Qualifier:
Antiviral Agents / pharmacology*
Base Sequence
Binding Sites
DNA / metabolism
DNA Nucleotidyltransferases / antagonists & inhibitors*,  metabolism
Enzyme Inhibitors / pharmacology*
HIV-1 / drug effects*,  enzymology
Integrases
Molecular Sequence Data
Nucleotides / pharmacology*
Virus Replication / drug effects
Grant Support
ID/Acronym/Agency:
AI-25899/AI/NIAID NIH HHS; AI-33239/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Enzyme Inhibitors; 0/Nucleotides; 9007-49-2/DNA; EC 2.7.7.-/DNA Nucleotidyltransferases; EC 2.7.7.-/Integrases

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