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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Biospecific Interaction Analysis (BIA) of Low-Molecular Weight DNA-Binding Drugs

Roberto Gambari, Giordana Feriotto, Cristina Rutigliano, Nicoletta Bianchi and Carlo Mischiati
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 370-377;
Roberto Gambari
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Giordana Feriotto
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Cristina Rutigliano
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Nicoletta Bianchi
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Carlo Mischiati
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Abstract

DNA-binding drugs have been reported to be able to interfere with the activity of transcription factors in a sequence-dependent manner, leading to alteration of transcription. This and similar effects could have important practical applications in the experimental therapy of many human pathologies, including neoplastic diseases and viral infections. The analysis of the biological activity of DNA-binding drugs by footprinting, gel retardation, polymerase chain reaction, and in vitro transcription studies does not allow a real time study of binding to DNA and dissociation of the generated drugs/DNA complexes. The recent development of biosensor technologies for biospecific interaction analysis (BIA) enables monitoring of a variety of molecular reactions in real-time by surface plasmon resonance (SPR). In this study, we demonstrate that molecular interactions between DNA-binding drugs (chromomycin, mithramycin, distamycin, and MEN 10567) and biotinylated target DNA probes immobilized on sensor chips is detectable by SPR technology using a commercially available biosensor. The target DNA sequences were synthetic oligonucleotides mimicking the Sp1, NF-kB, and TFIID binding sites of the long terminal repeat of the human immunodeficiency type 1 virus. The results obtained demonstrate that mithramycin/DNA complexes are less stable than chromomycin/DNA complexes; distamycin binds to both NF-kB and TATA box oligonucleotides, but distamycin/(NF-kB)DNA complexes are not stable; the distamycin analog MEN 10567 binds to the NF-kB mer and the generated drug/DNA complexes are stable. The experimental approach described in this study allows fast analysis of molecular interactions between DNA-binding drugs and selected target DNA sequences. Therefore, this method could be used to identify new drugs exhibiting differential binding activities to selected regions of viral and eukaryotic gene promoters.

Footnotes

  • Send reprint requests to: Prof. Roberto Gambari, Department of Biochemistry and Molecular Biology Via L. Borsari n.46, 44100 Ferrara, Italy. E-mail: gam{at}dns.unife.it

  • ↵1 This work was supported by CNR PF Biotecnologie, by ISS(AIDS 1998), by PRIN-98, and by Ricerca Finalizzata 1999, Ministero della Sanità, Italy. The BIAcore-1000 was obtained with a grant from the “Grandi attrezzature ad uso comune” fund of Ferrara University. N.B. and C.M. are recipients of Fondazione Italiana Ricerca sul Cancro and Associazione Italiana Ricerca sul Cancro fellowships, respectively.

  • Abbreviations:
    LTR
    long terminal repeat
    BIA
    biospecific interaction analysis
    SPR
    surface plasmon resonance
    RU
    resonance unit(s)
    • Received June 1, 1999.
    • Accepted February 4, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Biospecific Interaction Analysis (BIA) of Low-Molecular Weight DNA-Binding Drugs

Roberto Gambari, Giordana Feriotto, Cristina Rutigliano, Nicoletta Bianchi and Carlo Mischiati
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 370-377;

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Biospecific Interaction Analysis (BIA) of Low-Molecular Weight DNA-Binding Drugs

Roberto Gambari, Giordana Feriotto, Cristina Rutigliano, Nicoletta Bianchi and Carlo Mischiati
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 370-377;
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