Directed Disulfide Pairing and Folding of Peptides for the De Novo Development of Multicyclic Peptide Libraries
Directed Disulfide Pairing and Folding of Peptides for the De Novo Development of Multicyclic Peptide Libraries
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用于多环肽库从头开发的肽的定向二硫键配对和折叠
DOI：
10.1021/jacs.0c06044
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发表时间：
2020-09-23
影响因子：
15
通讯作者：
Wu, Chuanliu
中科院分区：
文献类型：
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作者：
Lu, Shuaimin;Wu, Yapei;Wu, Chuanliu
富含二硫键的肽（DRPs）已成为药物研发的一个新兴前沿领域。已有两种DRPs被批准作为药物（即齐考诺肽和利那洛肽），还有许多其他的DRPs正在进行临床前研究或临床试验。所有这些DRPs都源于天然或由天然肽衍生而来。由于二硫键配对难以处理，在不借助天然支架的情况下设计新的DRPs仍然是一个挑战。在此，我们开发了一种简单而有效的策略，用于指导含有多达6个半胱氨酸残基的肽的二硫键配对和折叠。我们的策略利用半胱氨酸 - 脯氨酸 - 脯氨酸 - 半胱氨酸（CPPC）基序的二聚体配对来指导二硫键的形成，并且通过调节肽中CPPC基序和半胱氨酸残基的模式，设计并合成了具有不同多环拓扑结构的DRPs。由于既不涉及序列操作也不涉及非天然氨基酸，所设计的DRPs可用作生物合成多环肽文库从头开发的模板，从而能够直接从完全随机的序列中筛选具有新功能的DRPs。我们相信这项工作是朝着发现和设计具有非天然支架衍生结构的新型多环肽配体和治疗药物迈出的重要一步。
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.