Directed Disulfide Pairing and Folding of Peptides for the De Novo Development of Multicyclic Peptide Libraries,Journal of the American Chemical Society

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Directed Disulfide Pairing and Folding of Peptides for the De Novo Development of Multicyclic Peptide Libraries
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-09-11 , DOI: 10.1021/jacs.0c06044
Shuaimin Lu ₁ , Yapei Wu ₁ , Jinjing Li ₁ , Xiaoting Meng ₁ , Chenliang Hu ₁ , Yibing Zhao ₁ , Chuanliu Wu ₁

Affiliation

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.

中文翻译：

用于多环肽文库从头开发的肽的定向二硫键配对和折叠

富含二硫化物的肽 (DRP) 已成为药物发现的新兴前沿。已经有两种 DRP 获批作为药物（即齐考诺肽和利那洛肽），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 都是天然来源或源自天然肽。由于难以处理二硫键配对，在不求助于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，用于指导最多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的形成，通过调节肽中 CPPC 基序和半胱氨酸残基的模式，设计和合成了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，设计的 DRP 可用作生物合成多环肽库从头开发的模板，从而能够直接从完全随机的序列中选择具有新功能的 DRP。我们相信，这项工作代表着发现和设计具有非天然支架结构的新型多环肽配体和治疗剂的重要一步。能够直接从完全随机的序列中选择具有新功能的 DRP。我们相信，这项工作代表着发现和设计具有非天然支架结构的新型多环肽配体和治疗剂的重要一步。能够直接从完全随机的序列中选择具有新功能的 DRP。我们相信，这项工作代表着发现和设计具有非天然支架结构的新型多环肽配体和治疗剂的重要一步。

更新日期：2020-09-11

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