HIV-1 integrase inhibition by flavones and caffeic acid phenethylester (Meeting abstract). NLM AIDSLINE Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.

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HIV-1 integrase inhibition by flavones and caffeic acid phenethylester (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 34:A1668 1993. Unique Identifier : AIDSLINE ICDB/93692609
Fesen MR; Horiguchi S; Leteurtre F; Kohn KW; Pommier Y; Lab. of Molecular Pharmacology, DTP, DCT, NCI, Bethesda, MD 20892

Abstract: Genomic integration is essential for HIV-1 provirus expression and viral replication. We have used purified recombinant HIV-1 integrase (IN) and oligonucleotides to study the structure-activity relationship of 47 flavone derivatives. Minimal requirements for activity were hydroxylations at positions 3',4', 3 and 7. Hydroxylations at positions 5', 5, or 6 increased potency. Saturation of the double bond at position 2-3 eliminated activity as did glycosylation or methoxy substitutions. Flavones were minimally selective for inhibition of IN strand transfer (ST) that is, the ratio of the IC50 for ST and 3' dinucleotide cleavage was 1 to 3. By contrast, this ratio was 10 for caffeic acid phenethyl ester (CAPE). Structure activity requirements for IN inhibition by flavones are consistent with those reported for DNA gyrase, tyrosine kinase or topoisomerase II inhibition. The common phosphate transfer site of these enzymes may be the site of flavone binding. As IN has only one active site to perform cleavage and ST, and as ST likely requires a higher order of IN polymerization, CAPE, a highly selective inhibitor of the ST step, may be acting by blocking IN polymerization.
Keywords: Caffeic Acids/*PHARMACOLOGY DNA Nucleotidyltransferases/*ANTAGONISTS & INHIB DNA Topoisomerase (ATP-Hydrolysing)/ANTAGONISTS & INHIB Flavones/METABOLISM/*PHARMACOLOGY Protein-Tyrosine Kinase/ANTAGONISTS & INHIB ABSTRACTKWDcaffeicacids/KWDpharmacologydnanucleotidyltransferases/KWDantagonists&inhibdnatopoisomerase(atp-hydrolysing)/antagonists&inhibflavones/metabolism/KWDpharmacologyprotein-tyrosinekinase/antagonists&inhibabstract
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M9370997

Copyright © 1993 - National Library of Medicine. Reproduced under license with the National Library of Medicine, Bethesda, MD.

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