Glycosaminoglycans are potential pharmacological targets for classic DNA minor groove binder drugs berenil and pentamidine

Abstract

It is shown that the antiprotozoal drugs berenil and pentamidine, conventional minor groove binders of DNA, form non-covalent complexes with polyanionic glycosaminoglycans. Induced circular dichroism (CD) spectra as well as UV hypochromism confirmed drug binding to the asymmetric template of heparin and chondroitin 6-sulfate. The biphasic nature of the CD signals refers to intermolecular chiral exciton coupling between the dicationic guest molecules forming a right- or a left-handed helical array along the GAG chains. Quantitative evaluation of the spectroscopic data measured in pH 7.0 buffer solution (80 mM NaCl) indicated a higher (K_a ∼ 10⁶ M⁻¹ for berenil) and a lower (K_a ∼ 10⁵ M⁻¹ for pentamidine) affinity heparin binding of these agents, similar to that reported for DNA. Drug–chondroitin sulfate complexes (K_a ∼ 10⁴–10⁵ M⁻¹) could be detected only at low ionic strength. These results imply that besides nucleic acids, GAGs may be another pharmacological targets for diarylamidine drugs.