Once it had been realized that G-quadruplexes exist in the cell and are involved in regulation of genomic processes, the quest for ligands recognizing these noncanonical structures was underway. Many organic compounds that tightly associate with G-quadruplexes have been identified. However, the specificity of G-quadruplex-binding ligands towards individual structures remains problematic, as the common recognition element of these ligands is the G-tetrad. In this paper, we focus on G-quadruplex-duplex hybrids (QDH) containing a hairpin duplex incorporated as a stem-loop into the G-quadruplex core. The presence of a stem-loop renders QDH amenable to sequence-specific recognition by duplex-binding drugs. Should the thermodynamic crosstalk between the stem-loop and the tetraplex core be sufficiently strong, the drug binding to the loop would lead to the stabilization of the entire structure. We studied the stabilizing influence of the minor groove-binders netropsin and Hoechst 33258 on a family of QDH structures, as well as a G-quadruplex and a hairpin modeling the G-quadruplex core and the stem-loop of the QDH's. We found that the binding of either drug results in an enhancement of the thermal stability of all DNA structures, as expressed by increases in the melting temperature, T. Analysis of the hierarchical order of increases in T revealed that the drug-induced stabilization arises from drug binding to the G-quadruplex domain of a QDH and the stem-loop, if the latter contains an all-AT binding site. This result attests to the thermodynamic crosstalk between the stem-loop and the tetraplex core of a QDH. Given the existing library of minor groove-binding drugs recognizing mixed A·T and G·C DNA sequences, our results point to an untapped avenue for sequence-specific recognition of QDH structures in vitro and, possibly, in vivo; thereby, opening the way for selective stabilization of four-stranded DNA structures at predetermined genomic loci, with implications for the control of genomic events.
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http://dx.doi.org/10.3390/life12040597 | DOI Listing |
Biochim Biophys Acta Gen Subj
December 2024
Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, India. Electronic address:
The interaction of drugs with DNA is crucial for understanding their mechanism of action, particularly in the context of gene expression regulation. Erdafitinib (EDB), a pan-FGFR (fibroblast growth factor receptor) inhibitor approved by the FDA, is a potent anticancer agent used primarily in the treatment of urothelial carcinoma. In this study, the binding interaction between EDB and calf thymus DNA (ctDNA) was assessed using molecular docking, UV-absorption spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) spectroscopy.
View Article and Find Full Text PDFInt J Biol Macromol
January 2025
Department of Chemistry, Faculty of Science and Letters, Istanbul Technical University, Maslak, Istanbul 34469, Türkiye. Electronic address:
Cladribine is a deoxyadenosine analog prodrug originally developed to treat hairy-cell leukemia and other lymphoproliferative diseases. However, it is now primarily used in the treatment of relapsing types of multiple sclerosis (MS). Understanding how medications interact with dsDNA is crucial for developing more effective and efficient medications.
View Article and Find Full Text PDFPhotochem Photobiol Sci
November 2024
Faculty of Sciences and Letters, Department of Chemistry, Istanbul Technical University, Istanbul, 34469, Turkey.
Acta Trop
December 2024
Microbiota Research Center, Istinye University, Istanbul 34010, Turkey; School of Science, College of Science and Engineering, University of Derby, Derby DE22 1GB, UK. Electronic address:
DNA minor groove binders exhibit a high degree of sequence specificity and have a variety of biological actions including antiviral, anticancer, antibacterial, and anti-protozoal properties. Since it is the location of non-covalent interactions, the minor groove of double helical B-DNA is gaining significant interest as therapeutic targets. For the purpose of this investigation, the synthesis of five novel DNA minor groove binding agents was accomplished and antiparasitic efficacies were determined against Acanthamoeba castellanii of the T4 genotype in vitro.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
Department of Chemistry, National Institute of Technology Nagaland, Chumukedima, Dimapur, Nagaland 797103, India. Electronic address:
The present study focuses on binding association of Camptothecin (CMT) towards natural deoxy-ribonucleic acid (salmon testes, ST) under physiological conditions of pH 7.4. Extensive spectroscopic and computational techniques have been employed to elucidate thermodynamics of the said interaction.
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