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首页> 外文期刊>Nucleic Acid Therapeutics >Pyrene-Modified DNA Aptamers with High Affinity to Wild-Type EGFR and EGFRvIII
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Pyrene-Modified DNA Aptamers with High Affinity to Wild-Type EGFR and EGFRvIII

机译：芘改性的DNA适体，具有高亲和力的野生型EGFR和EGFRVIII

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摘要

Nucleic acid aptamers have been proven to be a useful tool in many applications. Particularly, aptamers to epidermal growth factor receptor (EGFR) have been successfully used for the recognition of EGFR-expressing cells, the inhibition of EGFR-dependent pathways, and targeted drug delivery into EGFR-positive cells. Several aptamers are able to discriminate wild-type EGFR from its mutant form, EGFRvIII. Aptamers to EGFR have hairpin-like secondary structures with several possible folding variations. Here, an aptamer, previously selected to EGFRvIII, was chosen as a lead compound for extensive post-SELEX maturation. The aptamer was 1.5-fold truncated, the ends of the hairpin stem were appended with GC-pairs to increase thermal stability, and single pyrene modification was introduced into the aptamer to increase affinity to the target protein. Pyrene modification was selected from extensive computer docking studies of a library of thousands of chemicals to EGFR near the EGF-binding interface. The resulting aptamers bound extracellular domains of both variants of EGFR: EGFRwt and EGFRvIII with subnanomolar apparent dissociation constants. Compared with the initial aptamer, affinity to EGFRwt was increased up to 7.5-fold, whereas affinity to EGFRvIII was increased up to 4-fold.
机译：已被证明是许多应用中的有用工具的核酸适体。特别地，对表皮生长因子受体（EGFR）的适体已成功地用于识别EGFR表达的细胞，抑制EGFR依赖性途径，并将靶向药物输送到EGFR-阳性细胞中。几种适体能够从其突变形式区分野生型EGFR，例如，EGFRVIII。 EGFR的适体具有类似折叠变化的发夹式二级结构。这里，选自先前选择于EGFRVIII的适体作为铅化合物，以进行广泛的SELEX成熟。 Aptamer截短1.5倍，发夹茎的末端伴有GC对以增加热稳定性，并将单醇改性引入适体中以增加对靶蛋白的亲和力。选自芘改性，从egf结合界面附近的egfr提供了千分之一化学品的大量计算机对接研究。得到的Aptamers与亚诺莫氨基醇表观解离常数结合了EGFR：EGFRWT和EGFRVIII的变体的细胞外结构域。与初始适体相比，对EGFRWT的亲和力升高至7.5倍，而对EGFRVIII的亲和力增加至4倍。

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