Departments of Chemistry and Division of Advanced Material Science , Pohang University of Science and Technology (POSTECH) , Pohang 37673 , South Korea.
Bioconjug Chem. 2019 Nov 20;30(11):2931-2938. doi: 10.1021/acs.bioconjchem.9b00628. Epub 2019 Nov 8.
We report the design and synthesis of a DNA-encoded one-bead one-compound library of cyclic peptoids composed of more than 11 million molecules. We show that affinity-based screening of this large library can identify cyclic peptoid ligands for a target protein. In this work, we developed a simple method for amplifying the PCR product from DNA tags on a single bead, thereby enabling determination of the structures of hit cyclic peptoids with no need for high-throughput sequencing and complicated data analysis. We also developed a sublibrary screening strategy to minimize false positives caused by the interference of coding DNA tags before starting laborious and impractical hit confirmation. Given the simplicity and robustness of the synthesis and screening, along with the desirable features of macrocyclic peptoids including improved conformational rigidity, our method will be highly useful for discovering biologically active molecules modulating challenging targets such as protein-protein interactions that are not easily targeted by typical peptidomimetics and small-molecules.
我们报告了一种由超过 1100 万个分子组成的环状缩肽的 DNA 编码单珠单化合物文库的设计和合成。我们表明，对这个大型文库进行基于亲和力的筛选可以鉴定出靶蛋白的环状缩肽配体。在这项工作中，我们开发了一种简单的方法来扩增单个珠子上 DNA 标签的 PCR 产物，从而无需高通量测序和复杂的数据分析即可确定命中环状缩肽的结构。我们还开发了一种亚文库筛选策略，以最小化编码 DNA 标签干扰引起的假阳性，然后再开始进行费力且不切实际的命中确认。鉴于合成和筛选的简单性和稳健性，以及大环缩肽的理想特性，包括改善构象刚性，我们的方法对于发现生物活性分子调节具有挑战性的靶标（如蛋白质-蛋白质相互作用）将非常有用，这些靶标不易被典型的肽模拟物和小分子靶向。
