Molecules often take advantage of cyclic topology to enable enhancement of their properties such as thermal stability, binding affinity to targets, and self‐assembly profiles. Despite the advantages of cyclization, peptide‐oligonucleotide conjugates (POCs) have not fully utilized the cyclic topology, presumably due to a dearth of generalized synthetic methods. Here, we report a feasible way to synthesize self‐assembling cyclic POCs using a thiol‐maleimide reaction and copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) in the solution phase and evaluate the properties of cyclic POCs such as molecular conformation, Watson‐Crick base pairing, and self‐assembly profile in comparison to those of linear POCs. Although there is a marginal difference between cyclic POCs and linear POCs in terms of their overall conformation, the self‐assembly profile is greatly affected. The cyclic POCs form homogeneous spherical aggregates, while the linear POCs form a heterogeneous population of fibrous and spherical aggregates. On the other hand, these cyclic POCs show less efficiency in Watson‐Crick base pairing to complementary cyclic POCs than linear POCs, which subsequently affects the self‐assembly of each duplex POC. Our study provides a synthetic method for self‐assembling cyclic POCs as well as a better understanding of the effect of cyclic topology on the overall conformation, self‐assembly, and Watson‐Crick base pairing of POCs.

中文翻译：

---

自组装环肽-寡核苷酸共轭物：合成策略和环状拓扑对自组装和碱基配对的影响

分子通常利用循环拓扑来增强其特性，例如热稳定性，与靶标的结合亲和力和自组装特性。尽管具有环化的优势，但肽-寡核苷酸共轭物（POC）尚未充分利用环状拓扑结构，这可能是由于缺乏通用的合成方法所致。在这里，我们报告了在溶液相中使用硫醇-马来酰亚胺反应和铜催化的叠氮化物-炔烃环加成（CuAAC）合成自组装环状POC的可行方法，并评估了环状POC的性质，例如分子构象，沃森克里克（Watson-Crick）与线性POC的碱基配对和自组装曲线相比。尽管环状POC和线性POC在总体构象方面存在边际差异，自组装配置文件受到很大影响。环状POC形成均质的球形聚集体，而线性POC形成异质的纤维状和球形聚集体。另一方面，这些循环POC在Watson-Crick碱基与互补循环POC配对中显示出比线性POC更低的效率，随后会影响每个双工POC的自组装。我们的研究为自组装环状POC提供了一种综合方法，并更好地了解了环状拓扑对POC整体构象，自组装和Watson-Crick碱基配对的影响。与线性POC相比，这些循环POC在Watson-Crick碱基与互补循环POC配对中显示出较低的效率，这随后会影响每个双工POC的自组装。我们的研究为自组装环状POC提供了一种综合方法，并更好地了解了环状拓扑对POC整体构象，自组装和Watson-Crick碱基配对的影响。与线性POC相比，这些循环POC在Watson-Crick碱基与互补循环POC配对中显示出较低的效率，这随后会影响每个双工POC的自组装。我们的研究为自组装环状POC提供了一种综合方法，并更好地了解了环状拓扑对POC整体构象，自组装和Watson-Crick碱基配对的影响。