An evolution-inspired strategy to design disulfide-rich peptides tolerant to extensive sequence manipulation.
An evolution-inspired strategy to design disulfide-rich peptides tolerant to extensive sequence manipulation.
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DOI：
10.1039/d1sc02952e
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发表时间：
2021-09-01
期刊：
影响因子：
8.4
通讯作者：
Wu C
中科院分区：
文献类型：
--
作者：
Zha J;Li J;Fan S;Duan Z;Zhao Y;Wu C
天然富含二硫键的肽（DRP）是开发新生物活性分子和疗法的宝贵支架。然而，自然界中拓扑结构不同的DRP折叠数量有限，并且大多数都存在体外氧化折叠的问题。因此，需要设计具有超出自然折叠范围的新约束拓扑的 DRP 的策略。在此，我们报告了一种受进化启发的通用策略，用于设计具有不同二硫键框架的新DRP，该策略依赖于将两个半胱氨酸残基和随机肽序列合并到前体二硫键稳定的折叠中。这些肽可以在氧化还原缓冲液中自发折叠成预期的三环拓扑结构并具有高产率。此外，我们证明这些 DRP 可以用作构建噬菌体展示肽库的模板，从而能够从完全随机的序列中发现新的 DRP 配体。因此，这项研究为开发新的 DRP 配体和具有非天然 DRP 结构的疗法铺平了道路。开发了一种通用方法来设计具有多种二硫键框架的多环肽，适合随机肽库设计，从而能够开发新的富含二硫键的肽配体和具有非源自天然肽的结构的治疗剂。
Natural disulfide-rich peptides (DRPs) are valuable scaffolds for the development of new bioactive molecules and therapeutics. However, there are only a limited number of topologically distinct DRP folds in nature, and most of them suffer from the problem of in vitro oxidative folding. Thus, strategies to design DRPs with new constrained topologies beyond the scope of natural folds are desired. Herein we report a general evolution-inspired strategy to design new DRPs with diverse disulfide frameworks, which relies on the incorporation of two cysteine residues and a random peptide sequence into a precursor disulfide-stabilized fold. These peptides can spontaneously fold in redox buffers to the expected tricyclic topologies with high yields. Moreover, we demonstrated that these DRPs can be used as templates for the construction of phage-displayed peptide libraries, enabling the discovery of new DRP ligands from fully randomized sequences. This study thus paves the way for the development of new DRP ligands and therapeutics with structures not derived from natural DRPs. A general method was developed to design multicyclic peptides with diverse disulfide frameworks amenable to random peptide library design, enabling the development of new disulfide-rich peptide ligands and therapeutics with structures not derived from natural peptides.
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