| Characterization of a naphthalene derivative inhibitor of retroviral integrases. | |
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MedLine Citation:
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PMID: 15018700 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The retroviral integrase protein (IN) is essential for virus replication and, therefore, an attractive target for the development of inhibitors to treat human immunodeficiency virus (HIV) infection. Diverse classes of compounds that are active against this protein have been discovered using in vitro assays. Here we describe the synthesis of a novel compound, 3,8-dibromo-7-amino-4-hydroxy-2-naphthalenesulfonic acid (2BrNSA), which inhibits the in vitro activities of the full-length HIV-1 and avian sarcoma virus (ASV) integrases, and the isolated catalytic core fragment of the ASV protein (residues 52-207). The compound also inhibits retroviral reverse transcriptase in vitro, but the IC(50) for the HIV-1 enzyme is almost two orders of magnitude higher than for HIV-1 integrase. The inhibitor was found to be active in cell culture, preventing reporter gene transduction of HeLa cells by both ASV and HIV-1 vectors. Neither viral attachment nor uptake into cells appeared to be affected in these transfections, whereas accumulation of vector DNA and its joining to host DNA were both drastically reduced in the presence of the inhibitor. Propagation of two different strains of replication-competent HIV-1 in human peripheral blood mononuclear cells (PBMCs) was also reduced by the inhibitor, allowing survival of a substantial number of cells in the treated cultures. Based on these and other results we speculate that binding of 2BrNSA to integrase in infected cells interferes not only with its catalytic activity but also with critical interactions that are required for the formation or function of the reverse transcriptase complex. Its activity in cell culture suggests that this inhibitor may provide a valuable new lead for further development of drugs that target early steps in the HIV life cycle. |
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Authors:
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R Daniel; C B Myers; J Kulkosky; K Taganov; J G Greger; G Merkel; I T Weber; R W Harrison; A M Skalka |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: AIDS research and human retroviruses Volume: 20 ISSN: 0889-2229 ISO Abbreviation: AIDS Res. Hum. Retroviruses Publication Date: 2004 Feb |
Date Detail:
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Created Date: 2004-03-15 Completed Date: 2004-05-19 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 8709376 Medline TA: AIDS Res Hum Retroviruses Country: United States |
Other Details:
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Languages: eng Pagination: 135-44 Citation Subset: IM; X |
Affiliation:
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Fox Chase Cancer Center, Institute for Cancer Research, Philadelphia, Pennsylvania 19111-2497, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Avian Sarcoma Viruses
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drug effects,
enzymology,
genetics Base Sequence DNA, Viral / genetics HIV Integrase Inhibitors / chemistry, pharmacology* HIV-1 / drug effects*, enzymology*, genetics Hela Cells Humans Integrase Inhibitors / chemistry, pharmacology Naphthalenes / chemistry, pharmacology* Transduction, Genetic Virus Replication / drug effects |
| Grant Support | |
ID/Acronym/Agency:
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AI40385/AI/NIAID NIH HHS; CA06927/CA/NCI NIH HHS; CA71515/CA/NCI NIH HHS; GM62920/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA, Viral; 0/HIV Integrase Inhibitors; 0/Integrase Inhibitors; 0/Naphthalenes |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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