The evolution of sequence-defined synthetic polymers made of building blocks beyond those compatible with polymerase enzymes or the ribosome has the potential to generate new classes of receptors, catalysts and materials. Here we describe a ligase-mediated DNA-templated polymerization and in vitro selection system to evolve highly functionalized nucleic acid polymers (HFNAPs) made from 32 building blocks that contain eight chemically diverse side chains on a DNA backbone. Through iterated cycles of polymer translation, selection and reverse translation, we discovered HFNAPs that bind proprotein convertase subtilisin/kexin type 9 (PCSK9) and interleukin-6, two protein targets implicated in human diseases. Mutation and reselection of an active PCSK9-binding polymer yielded evolved polymers with high affinity (K_D = 3 nM). This evolved polymer potently inhibited the binding between PCSK9 and the low-density lipoprotein receptor. Structure–activity relationship studies revealed that specific side chains at defined positions in the polymers are required for binding to their respective targets. Our findings expand the chemical space of evolvable polymers to include densely functionalized nucleic acids with diverse, researcher-defined chemical repertoires.

由与聚合酶或核糖体相容的构件组成的序列定义的合成聚合物的发展有可能产生新类别的受体、催化剂和材料。在这里，我们描述了一种连接酶介导的 DNA 模板聚合和体外选择系统，以进化由 32 个构建块制成的高度功能化的核酸聚合物 (HFNAP)，这些构建块在 DNA 主链上包含八个化学不同的侧链。通过聚合物翻译、选择和反向翻译的反复循环，我们发现了结合前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 和白细胞介素 6 的 HFNAP，这两种蛋白质靶标与人类疾病有关。活性 PCSK9 结合聚合物的突变和重新选择产生了具有高亲和力的进化聚合物（K _D = 3纳米）。这种进化的聚合物有效地抑制了 PCSK9 和低密度脂蛋白受体之间的结合。结构-活性关系研究表明，聚合物中特定位置的特定侧链是与其各自靶标结合所必需的。我们的研究结果扩展了可进化聚合物的化学空间，包括具有多种、研究人员定义的化学库的密集功能化核酸。