Enhanced Sequence-Specific DNA Recognition Using Oligodeoxynucleotide-Benzimidazole Conjugates

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Souvik Sur, Suresh Pujari, Nihar Ranjan, Lidivine Azankia Temgoua, Sarah L. Wicks, Andrea Conner and Dev P. Arya*, 
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引用次数: 0

Abstract

Synthetic modification of oligodeoxynucleotides (ODNs) via conjugation to nucleic acid binding small molecules can improve hybridization and pharmacokinetic properties. In the present study, five Hoechst 33258 derived benzimidazoles were conjugated to T rich ODNs and their hybridization effectiveness was tested. Thermal denaturation studies revealed significant stabilization of complementary duplexes by ODN-benzimidazole conjugates, with the extent of stabilization being highly dependent on the length of the linker between DNA and benzimidazole. The increases in thermal stability were determined to be due to the binding of the benzimidazole moiety to the duplex. Circular dichroism and molecular modeling studies provided insights toward the influence of conjugation on duplex structure and how linker length impacts placement of the benzimidazole moiety in the minor groove. Furthermore, thermal denaturation studies with the complementary strand containing a single base mismatch or being RNA revealed that covalent conjugation of benzimidazoles to an ODN also enhances the sequence specificity. The fundamental studies reported herein provide a strategy to improve the stability and specificity properties of the ODN probes, which can be of use for targeting and diagnostics applications.

Abstract Image

Abstract Image

利用寡聚氧核苷酸-苯并咪唑共轭物增强序列特异性 DNA 识别能力
通过与核酸结合小分子共轭对寡去氧核苷酸(ODN)进行合成修饰,可以改善杂交和药代动力学特性。本研究将五种 Hoechst 33258 衍生的苯并咪唑与富含 T 的 ODN 共轭,并测试了它们的杂交效果。热变性研究表明,ODN-苯并咪唑共轭物能显著稳定互补双链体,其稳定程度与 DNA 和苯并咪唑之间连接体的长度密切相关。热稳定性的增加是由于苯并咪唑分子与双链体结合所致。环二色性和分子建模研究深入揭示了共轭对双链体结构的影响,以及连接体长度如何影响苯并咪唑分子在小沟中的位置。此外,对含有单碱基错配或 RNA 的互补链进行的热变性研究表明,苯并咪唑与 ODN 共价共轭还能增强序列特异性。本文报告的基础研究为提高 ODN 探针的稳定性和特异性提供了一种策略,可用于靶向和诊断应用。
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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
发文量
0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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