Effect of Topoisomerase Inhibitors on the in Vitro HIV DNA Integration Reaction

Carteau, Sandrine; Mouscadet, Jean François; Goulaouic, Hélène; Subra, Frédéric; Auclair, Christian

doi:10.1006/bbrc.1993.1573

Cited by 47 publications

(28 citation statements)

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“…Most of them can be classified into three groups: DNA ligands, C-terminal domain ligands, and compounds that interfere with the catalytic domain of the protein. The first family contains nonspecific intercalating agents (Carteau et al, 1993;Fesen et al, 1993) as well as more specific oligonucleotide targeting IN binding sites on both long terminal repeats (LTRs; Mouscadet et al, 1994).…”

Section: Generalmentioning

confidence: 99%

QSAR analysis of caffeoyl naphthalene sulfonamide derivatives as HIV-1 integrase inhibitors

et al. 2007

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Human immunodeficiency virus type 1 (HIV-1) integrase is a potential target for anti-HIV therapy. It is an essential enzyme required for replication of the acquired immunodeficiency syndrome (AIDS) virus. Caffeoyl naphthalene sulfonamide derivatives act against HIV integrase and thus have the potential to become a part of an anti-HIV drug regimen. Although caffeoyl naphthalene sulfonamide derivatives have all the features required of good anti-HIV agents such as the presence of bis-catechol moieties, polyaromatic rings, and a central linker, they do SO 2 NH Ac 2 caffeoyl-NH AcO AcO O O H O H O A c 2 -caffeoyl caffeoyl Ac 2 caffeoyl = acetylated caffeoyl groupnot perform well as anti-HIV agents in cell-based assays, that is, they do not stop viral replication at nontoxic concentration. We carried out a quantitative structure-activity relationship (QSAR) study of caffeoyl naphthalene sulfonamide derivatives via the software WIN CAChe 6.1 and STATISTICA to improve its activity. QSAR reveals that if partition coefficient, connectivity index, and shape index of these molecules are altered, the activity is likely to increase. On the basis of the QSAR model, we designed a new series of compounds, calculated the activities, and found that they were more potent than the existing compounds.

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Section: Generalmentioning

confidence: 99%

QSAR analysis of caffeoyl naphthalene sulfonamide derivatives as HIV-1 integrase inhibitors

et al. 2007

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“…Similarly, accumulation of 3'-azido-2',3'-dideoxyguanosine diphosphate (AZGDP) upon incubation of 3'-azido-2',3'-dideoxyguanosine with CEM cells has also been demonstrated (7). The present study was initiated to determine the effects of AZTMP and other AZT metabolites on another potentially important viral target, the integrase (8)(9)(10).…”

mentioning

confidence: 99%

Inhibition of human immunodeficiency virus type 1 integrase by 3'-azido-3'-deoxythymidylate.

Mazumder

Cooney²,

Agbaria³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The effects of 3'-azido-3'-deoxythymidine (AZT) and three of its intracellular metabolites, azido-thymidine mono-, di-, and triphosphates, on the human immunodeficiency virus type 1 Integrase have been determined. AZT mono-, di-, and triphosphate have an IC50 for integration between 110 and 150 FM, whereas AZT does not inhibit the integrase. The inhibition by AZT monophosphate can be partially reversed by coincubation with either thymidine monophosphate or 2',3'-ddeoxythymldine monophosphate, suggesting that either of these monophosphates can bind to the integrase but that the azido group at the 3' position could be responsible for the inhibition. Integrase inhibition is associated with reduced enzyme-DNA binding but does not appear to be competitive with respect to the DNA substrate. Inhibition of an integrase deletion mutant containing only amino acids 50-212 suggests that these nucleotides bind in the catalytic core. Concentrations up to 1 mM AZT monophosphate can accumulate in vivo, indicating that integrase inhibition may contribute to the antiviral effects of AZT. The increasing incidence of AZT-resistant virus strains may, therefore, be associated with mutations not only in the reverse transcriptase but also in the human immundeficiency virus integrase. Finally, these observations suggest that additional strategies for antiviral drug development could be based upon nucleotide analogs as inhibitors of human immunodeficiency virus integrase.The first clinically approved drug in the treatment ofAIDS was 3'-azido-3'-deoxythymidine (AZT). This thymidine analog is converted to AZT monophosphate (AZTMP), diphosphate (AZTDP), and triphosphate (AZTTP) by thymidine, thymidylate, and nucleoside diphosphate kinases, respectively (1). The antiretroviral effect of AZT is attributed to AZTTP, which interferes with viral DNA replication by two mechanisms (2). (i) It can competitively inhibit the human immunodeficiency virus (HIV) reverse transcriptase against normal dTTP for DNA polymerization; and (ii) it can act as a chain terminator of the nascent viral DNA chain. The major limitation to AZT therapy is bone marrow suppression, leading to anemia or neutropenia (3). The most likely mechanism for AZT-induced toxicity could be incorporation ofAZT into newly synthesized host (i.e., nonviral) DNA and inhibition of strand elongation due to chain termination (4).Studies on the cellular metabolism ofAZT have shown that AZTMP accumulates in vivo because it is a competitive substrate inhibitor of thymidylate kinase that converts AZ-

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“…As a result most of these compounds exhibit high toxicity due to their activity on the host genome. Several studies with DNA binders suggested that IN inhibition does not necessarily correlate with DNA binding [32,94].…”

Section: Dna Bindersmentioning

confidence: 99%

HIV-1 Integrase: From Biology to Chemotherapeutics

Zeinalipour-Loizidou

Nicolaou²,

Nicolaides³

et al. 2007

CHR

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AIDS has claimed the lives of 25 million people worldwide, an additional 40 million people are HIV-infected and new cases are being diagnosed every year. Despite the fact that HAART has moved AIDS from the category of terminal diseases to that of treatable chronic illnesses, its long-term therapeutic success may be compromised by the development of resistance to the currently used drugs. Despite the availability of RT, PR and fusion inhibitors, the development of further drugs such as inhibitors that target the third enzyme IN is essential for the clinical management of HIV-infected patients. The absence of cellular homolgues to IN and the unique nature of the reactions catalyzed by IN, make it an ideal target for drug design. Considerable progress towards designing HIV-1 IN inhibitors has been made over the last years and several lead compounds have been identified, synthesized and clinically studied. This review focuses on the existing knowledge of the biology of HIV-1 IN with emphasis on the mechanism of integration, structure and function and the technologies for measuring IN activity. This is followed by the current trends on designing HIV-1 IN inhibitors with the aid of molecular informatics and a review on the main classes of HIV-1 IN inhibitors reported this far with special emphasis on the clinical candidates.

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Effect of Topoisomerase Inhibitors on the in Vitro HIV DNA Integration Reaction

Cited by 47 publications

References 0 publications

QSAR analysis of caffeoyl naphthalene sulfonamide derivatives as HIV-1 integrase inhibitors

QSAR analysis of caffeoyl naphthalene sulfonamide derivatives as HIV-1 integrase inhibitors

Inhibition of human immunodeficiency virus type 1 integrase by 3'-azido-3'-deoxythymidylate.

HIV-1 Integrase: From Biology to Chemotherapeutics

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