Department of Chemistry, College of Chemistry and Chemical Engineering, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, Xiamen University, Xiamen 361005, P.R. China.
J Am Chem Soc. 2020 Sep 23;142(38):16285-16291. doi: 10.1021/jacs.0c06044. Epub 2020 Sep 11.
Disulfide-rich peptides (DRPs) have been an emerging frontier for drug discovery. There have been two DRPs approved as drugs (i.e., Ziconotide and Linaclotide), and many others are undergoing preclinical studies or in clinical trials. All of these DRPs are of nature origin or derived from natural peptides. It is still a challenge to design new DRPs without recourse to natural scaffolds due to the difficulty in handling the disulfide pairing. Here we developed a simple and robust strategy for directing the disulfide pairing and folding of peptides with up to six cysteine residues. Our strategy exploits the dimeric pairing of CPPC (cysteine-proline-proline-cysteine) motifs for directing disulfide formation, and DRPs with different multicyclic topologies were designed and synthesized by regulating the patterns of CPPC motifs and cysteine residues in peptides. As neither sequence manipulations nor unnatural amino acids are involved, the designed DRPs can be used as templates for the de novo development of biosynthetic multicyclic peptide libraries, enabling selection of DRPs with new functions directly from fully randomized sequences. We believe that this work represents as an important step toward the discovery and design of new multicyclic peptide ligands and therapeutics with structures not derived from natural scaffolds.
富含二硫键的肽（DRP）已成为药物发现的一个新兴领域。已有两种 DRP 被批准为药物（即 Ziconotide 和 Linaclotide），还有许多其他药物正在进行临床前研究或临床试验。所有这些 DRP 均源自天然来源或源自天然肽。由于难以处理二硫键配对，因此在不依赖天然支架的情况下设计新的 DRP 仍然是一个挑战。在这里，我们开发了一种简单而强大的策略，用于指导具有多达六个半胱氨酸残基的肽的二硫键配对和折叠。我们的策略利用 CPPC（半胱氨酸-脯氨酸-脯氨酸-半胱氨酸）基序的二聚体配对来指导二硫键形成，并通过调节 CPPC 基序和肽中半胱氨酸残基的模式来设计和合成具有不同多环拓扑结构的 DRP。由于既不涉及序列操作也不涉及非天然氨基酸，因此设计的 DRP 可用作从头开发生物合成多环肽文库的模板，从而可以直接从完全随机化的序列中选择具有新功能的 DRP。我们相信，这项工作代表着在发现和设计结构上不源自天然支架的新型多环肽配体和治疗剂方面迈出了重要一步。
