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Abstract <p><b>Objective:</b> The study aimed to investigate the site-specificity of binding to DNA of three series of minor groove ligands – dimeric bisbenzimidazoles DB<sub>2</sub>(<i>n</i>), DB<sub>2</sub>P(<i>n</i>), and DB<sub>2</sub>Py(<i>n</i>) – using DNAase I footprinting. The compounds consist of two bisbenzimidazole units linked by oligomethylene linkers of varying lengths (<i>n</i>), with structural modifications to enhance DNA-binding properties. <b>Methods:</b> The binding specificity of the compounds was determined using DNAase I footprinting. The DB<sub>2</sub>(<i>n</i>) and DB<sub>2</sub>P(<i>n</i>) series are analogs of Hoechst 33342, modified by removing hydrophobic ethoxyphenol cores and introducing hydrophilic aminomethylene groups. The DB<sub>2</sub>Py(<i>n</i>) 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. <b>Results and Discussion:</b> All studied compounds demonstrated specificity for AT-rich DNA sequences. The DB<sub>2</sub>P(<i>n</i>) and DB<sub>2</sub>(<i>n</i>) series exhibited increased affinity for (AATT)<sub>3</sub> and TTTT sequences. The DB<sub>2</sub>Py(<i>n</i>) 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. <b>Conclusions:</b> The study revealed that dimeric bisbenzimidazoles DB<sub>2</sub>(<i>n</i>), DB<sub>2</sub>P(<i>n</i>), and DB<sub>2</sub>Py(<i>n</i>) exhibit distinct binding preferences for AT-rich DNA sequences, with DB<sub>2</sub>Py(<i>n</i>) 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.</p>

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Sequence Specificity of Dimeric Bisbenzimidazoles for DNA AT Sequences of Different Nucleotide Compositions, as Determined by Footprinting

  • 期刊论文

  • 发表日期：

    2025年6月3日

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  • D. S. Naberezhnov,
  • А. F. Arutuynyan,
  • А. D. Beniaminov,
  • N. М. Smirnov,
  • D. N. Kaluzhnyi,
  • A. L. Zhuze,
  • O. Y. Susova

摘要

Abstract

Objective: 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. Methods: 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. Results and Discussion: 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. Conclusions: 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.