Sequence Specificity of Dimeric Bisbenzimidazoles to AT-Sequences of DNA of Different Nucleotide Composition Determined by Footprinting

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Abstract

The study aimed to investigate the site-specificity of binding to DNA of three series of minor groove ligands - dimeric bisbenzimidazoles DB2(n), DB2P(n), and DB2Py(n) - using DNAase I footprinting. The compounds consist of two bisbenzimidazole units linked by oligomethylene linkers of varying lengths (n), with structural modifications to enhance DNA-binding properties. The binding specificity of the compounds was determined using DNAase I footprinting. The DB2(n) and DB2P(n) series are analogs of Hoechst 33342, modified by removing hydrophobic ethoxyphenol cores and introducing hydrophilic aminomethylene groups. The DB2Py(n) series incorporates a pyrrolcarboxamide group, a structural unit of the AT-specific antibiotic netropsin. The interaction of these compounds with DNA sequences was analyzed to identify their binding preferences. All studied compounds demonstrated specificity for AT-rich DNA sequences. The DB2P(n) and DB2(n) series exhibited increased affinity for (AATT)3 and TTTT sequences. The DB2Py(n) series showed high specificity to AT-rich regions, with a preference for the TTTT motif. None of the compounds interacted with sequences containing fewer than four AT base pairs. These findings highlight the influence of structural modifications on DNA-binding specificity and affinity. The study revealed that dimeric bisbenzimidazoles DB2(n), DB2P(n), and DB2Py(n) exhibit distinct binding preferences for AT-rich DNA sequences, with DB2Py(n) showing a pronounced affinity for the TTTT motif. The results demonstrate the potential of these compounds as tools for targeting specific DNA sequences, with implications for molecular biology and drug design.

About the authors

D. S. Naberezhnov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health

Moscow, 119991 Russia; Moscow, 115522 Russia

A. F. Arutuynyan

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Moscow, 119991 Russia

A. D. Beniaminov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Moscow, 119991 Russia

N. M. Smirnov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Moscow, 119991 Russia

D. N. Kaluzhny

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Moscow, 119991 Russia

A. L. Zhuze

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Moscow, 119991 Russia

O. Y. Susova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health

Email: susovaolga@gmail.com
Moscow, 119991 Russia; Moscow, 115522 Russia

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