Sequence-selective binding to DNA of cis- and trans-butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine

Christian Bailly, Isaac O. Donkor, Dean Gentle, Martin Thornalley, Michael J. Waring

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Footprinting experiments using both DNase I and methidium propyl- EDTA·Fe(II) have been used to investigate the sequence selectivity in binding to DNA of pentamidine and four butamidine analogues active against the Pneumocystis carinii pathogen, which afflicts patients with acquired immunodeficiency syndrome. In common with pentamidine, the butamidine drugs, which contain cis- or trans-1,4-but-2-ene linkers and either bis(amidine) or bis(imidazolidine) terminal groups, bind selectively to DNA sequences composed of at least 4 consecutive A·T base pairs. None of the drugs tolerates the presence of a G·C base pair within the binding site. Consistently in the DNase I and methidium propyl-EDTA·Fe(II) footprinting experiments, the cis-isomers produce stronger footprints than do the trans- isomers, despite their similar hydrogen-bonding potentialities. The present experimental data support the view that the conformation of the drug plays a determining role in the binding reaction. Starting from the known structure of a pentamidine-oligonucleotide complex, it is possible to rationalize the different capacities of the cis- and trans-butamidine analogues to recognize defined DNA sequences in terms of the radius of curvature of the molecule and the distance between the positively charged terminal groups. Together, these features constitute critical factors favoring (cis-conformation) or hampering (trans-conformation) the fitting of the drugs into the minor groove of DNA. In terms of structure-activity relationships, the AT-specific recognition of DNA by this series of butamidine derivatives cannot be directly correlated with their potencies against Pneumocystis carinii pneumonia.

Original languageEnglish (US)
Pages (from-to)313-322
Number of pages10
JournalMolecular pharmacology
Volume46
Issue number2
StatePublished - Aug 1 1994

Fingerprint

Pentamidine
Pneumocystis Pneumonia
Deoxyribonuclease I
DNA
Base Pairing
Pharmaceutical Preparations
Imidazolidines
Amidines
Pneumocystis carinii
Hydrogen Bonding
Structure-Activity Relationship
Oligonucleotides
Acquired Immunodeficiency Syndrome
Binding Sites
butamidine

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Sequence-selective binding to DNA of cis- and trans-butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine. / Bailly, Christian; Donkor, Isaac O.; Gentle, Dean; Thornalley, Martin; Waring, Michael J.

In: Molecular pharmacology, Vol. 46, No. 2, 01.08.1994, p. 313-322.

Research output: Contribution to journalArticle

Bailly, Christian ; Donkor, Isaac O. ; Gentle, Dean ; Thornalley, Martin ; Waring, Michael J. / Sequence-selective binding to DNA of cis- and trans-butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine. In: Molecular pharmacology. 1994 ; Vol. 46, No. 2. pp. 313-322.
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