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

Abstract

It is shown that the antiprotozoal 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 refer 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 high-(K a ~ 10 6 M -1 for berenil) and a lower (K a ~ 10 5 M -1 for pentamidine) affinity heparin binding of these agents, similar to that reported for DNA. Drug-chondroitin sulfate complexes (K a ~ 10 4 -10 5 M -1 ) could only be detected at low ionic strength. These results imply that besides nucleic acids, GAGs may be another pharmacological target for diarylamidine drugs.

Ultrafast Dynamics of a Triazene: Excited-State Pathways and the Impact of Binding to the Minor Groove of DNA and Further Biomolecular Systems

“…Under the experimental and also physiological conditions 18,20 diminazene is doubly protonated. Using dispersion-corrected density functional theory (DFT-D3) for geometry optimizations, we could characterize six local minima on the electronic ground-state potential energy surface of the doubly protonated diminazene as pairs with "E-azo, s-trans" (ET), "E-azo, s-cis" (EC), and "Z-azo, s-trans" (ZT) structure.…”

RX-207, a Small Molecule Inhibitor of Protein Interaction with Glycosaminoglycans (SMIGs), Reduces Experimentally Induced Inflammation and Increases Survival Rate in Cecal Ligation and Puncture (CLP)-Induced Sepsis

“…Spectroscopic analysis of RX-207 was carried out to study its interaction with the respective GAGs (Figure 7). Heparin induced dose-dependent hypochromism [25], a reduction in max that is experimental proof of RX-207 binding to the GAG. UV hypochromism is due to electronic interactions between the planar quinazolinone moieties of RX-207 molecules (dimers or oligomers) arranged proximally along the heparin chain.…”

Relaxation Dynamics of the Triazene Compound Berenil in DNA-Minor-Groove Confinement after Photoexcitation

“…The double protonated dicationic form is the dominant hydrogenation state, under experimental and physiological conditions. 23,31 There are two possibilities for the hydrogen saturation of the central linear triazene functional group of berenil. Since the two tautomeric forms are mirror images, only one of them is considered in this study.…”