受ChemBioChem编辑部邀请，我们课题组和波士顿学院Jianmin Gao课题组合作撰写了主题为“Strategies for the Construction of Multicyclic Phage Display Libraries”的综述。在该综述中，我们回顾了环状噬菌体展示文库的发展历程，总结了多环肽库的构建方法，并介绍了这些环肽库在多肽抑制剂等环肽药物高通量筛选中的应用。

      原文链接：F.-J. Chen, N. Pinnette, J. Gao, ChemBioChem, 2024, e202400072.

      摘要：肽类药物受到人们广泛关注，因为它们比起小分子药物和抗体药物有很多优势。首先，合成起来比较容易；其次，有可能口服后能够被人体有效吸收利用；而且它们的大小正好适中，可以精准地作用于蛋白质之间的相互作用，这是小分子药物所做不到的。但是，要开发不是从天然产物提取的全新肽类药物却存在两个主要挑战：一是肽的代谢不稳定，容易被身体内的酶降解；二是要达到类似抗体那样的效果和特异性很难。多环肽相对于线性的或者只有一个二硫键环的肽来说，具有更加稳定的构象、更强的代谢稳定性和更高的蛋白质相互作用抑制效能。但是，要找到新型的多环肽结合物并不容易。然而，最近在构建多环肽噬菌体文库方面的进展大大推动了针对不同蛋白质靶点的新型多环肽结合物的识别过程。这篇综述将介绍目前用于创建多环肽文库的方法，着重介绍了新型环化反应的开发以及验证这些文库对不同蛋白质靶点的潜在应用。

      Abstract: Peptide therapeutics have gained great interest due to their multiple advantages over small molecule and antibody-based drugs. Peptide drugs are easier to synthesize, have the potential for oral bioavailability, and are large enough to target protein-protein interactions that are undruggable by small molecules. However, two major limitations have made it difficult to develop novel peptide therapeutics not derived from natural products, including the metabolic instability of peptides and the difficulty of reaching antibody-like potencies and specificities. Compared to linear and disulfide-monocyclized peptides, multicyclic peptides can provide increased conformational rigidity, enhanced metabolic stability, and higher potency in inhibiting protein-protein interactions. The identification of novel multicyclic peptide binders can be difficult, however, recent advancements in the construction of multicyclic phage libraries have greatly advanced the process of identifying novel multicyclic peptide binders for therapeutically relevant protein targets. This review will describe the current approaches used to create multicyclic peptide libraries, highlighting the novel chemistries developed and the proof-of-concept work done on validating these libraries against different protein targets.

      We gratefully acknowledge the financial support from the National Science Foundation (CHE-2204078 to JG) and the National Institute of General Medical Sciences (R35GM152005 to JG). FJC acknowledges the support of Fuzhou University (No. 511264).