mRNA展示技术高通量筛选环肽药物的研究进展

doi:10.16288/j.yczz.25-186

遗传 ›› 2026, Vol. 48 ›› Issue (4): 345-354.doi: 10.16288/j.yczz.25-186

mRNA展示技术高通量筛选环肽药物的研究进展

王爽¹^,²(), 朱雪¹^,², 方晶¹^,², 薛岩¹^,², 黄志洪¹^,², 王柯¹^,²()

¹ 南京医科大学药学院核药学系，南京 211166
² 国家卫生健康委员会核医学重点实验室，江苏省分子核医学重点实验室，江苏省原子医学研究所，无锡 214063

收稿日期:2025-08-13 修回日期:2025-10-20 出版日期:2026-04-20 发布日期:2025-10-31
通讯作者: 王柯，博士，研究员，研究方向：核药学。E-mail: wangke@jsinm.org
作者简介:王爽，硕士研究生，专业方向：核药学。E-mail: shuangwang@stu.njmu.edu.cn
基金资助:
国家自然科学基金项目(82573711);国家自然科学基金项目(22407052);江苏省自然科学基金(BK20240300);江苏省卫健委科研项目(MQ2024007);江苏省卫健委科研项目(H2023150);江苏省卫健委科研项目(K2024007);无锡市科技发展基金(K20241060);无锡市卫健委重大项目(Z202303);无锡科学技术协会(TJXD-2024-102)

Advances in high-throughput screening of cyclic peptide drugs using mRNA display technology

Shuang Wang¹^,²(), Xue Zhu¹^,², Jing Fang¹^,², Yan Xue¹^,², Zhihong Huang¹^,², Ke Wang¹^,²()

¹ Department of Radio Pharmaceuticais, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
² Jiangsu Institute of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, NHC Key Laboratory of Nuclear Medicine, Wuxi 214063, China

Received:2025-08-13 Revised:2025-10-20 Published:2026-04-20 Online:2025-10-31
Supported by:
National Natural Science Foundation of China(82573711);National Natural Science Foundation of China(22407052);Natural Science Foundation of Jiangsu Province(BK20240300);Scientific Research Projects of Jiangsu Health Commission(MQ2024007);Scientific Research Projects of Jiangsu Health Commission(H2023150);Scientific Research Projects of Jiangsu Health Commission(K2024007);Wuxi Science and Technology Development Fund(K20241060);Major Project of Wuxi Municipal Health Commission(Z202303);Wuxi Association for Science and Technology(TJXD-2024-102)

摘要/Abstract

摘要：

环肽作为突破传统药物开发“难以成药”靶点的重要分子形式，凭借其独特的构象约束特性，成功弥补了小分子药物与生物制剂的治疗间隙。尽管早期环肽的发现依赖于天然产物的挖掘，但是展示技术的出现将库容量提升至10¹⁵，加速了全新环肽药物的研发。mRNA展示技术作为一种基因型(mRNA)与表型(蛋白质)融合的体外多肽/蛋白质筛选技术，可在一次实验中筛选数万亿蛋白质变体以实现所需功能。近年来，随着利用mRNA展示技术筛选出的多肽药物进入临床研发阶段，从头开始的环肽药物发现领域逐渐走向成熟。本文对mRNA展示技术的原理、特点以及其在环肽药物研发过程中的应用展开综述，以期为推动基于mRNA展示技术的原创性环肽药物发现提供新的思路和策略借鉴。

关键词: mRNA展示技术, 体外筛选, 环肽药物, 多肽文库

Abstract:

Cyclic peptides have emerged as a promising therapeutic modality for targeting classically deemed “undruggable” protein that defy conventional small-molecule intervention. Their rigid conformations improve binding affinity, selectivity and proteolytic stability, bridging the gap between low-molecular-weight drugs and large biologics. Early discovery of cyclic peptide relied on natural product isolation. However, display technologies now enable the generation and screening of libraries containing up to 10¹⁵ unique sequences. Among these, mRNA display technology offers a uniquely powerful in vitro platform that covalently links genotype (mRNA) to phenotype (encoded peptide), facilitating the ultrahigh-throughput interrogation of trillions of variants in a single selection cycle. Recent clinical translation of de novo mRNA display-derived cyclic peptides signals the approach’s maturation. In this review, we systematically evaluate mRNA display technology by outlining its methodological framework and highlighting its unique advantages for engineering macrocyclic therapeutics. We critically examine its transformative potential as well as its inherent limitations in identifying bioactive cyclic peptides, with particular attention to library diversity and the precision of on-resin screening. Through this analysis, we aim to provide insightful perspectives and strategic recommendations to guide future efforts in exploiting mRNA display for the development of innovative cyclic peptide-based drugs.

Key words: mRNA display technology, in vitro screening, cyclic peptide drug, peptide library

王爽, 朱雪, 方晶, 薛岩, 黄志洪, 王柯. mRNA展示技术高通量筛选环肽药物的研究进展[J]. 遗传, 2026, 48(4): 345-354.

Shuang Wang, Xue Zhu, Jing Fang, Yan Xue, Zhihong Huang, Ke Wang. Advances in high-throughput screening of cyclic peptide drugs using mRNA display technology[J]. Hereditas(Beijing), 2026, 48(4): 345-354.

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展示技术	文库容量	特点	适用场景	参考文献
噬菌体展示技术	~10⁹	技术成熟、平台稳定；库容量大，多样性高；易扩增和测序	抗体药物发现、肽库筛选、蛋白质-蛋白质相互作用研究	[29]
核糖体展示技术	10¹²~10¹⁴	库容量极大；支持直接且高效的体外进化; 筛选条件灵活可控	抗体片段的筛选与亲和力成熟；肽库和高亲和力配体的筛选	[30]
酵母展示技术	10⁷~10⁹	真核表达系统，适合需糖基化等修饰的蛋白；可直接定量测量亲和力与表达量	抗体亲和力成熟、人源化抗体优化、T细胞受体(TCR)工程	[31]
细胞表面展示技术	~10¹¹	保持蛋白质天然构象与完整功能；提供真实的细胞膜环境；可直接进行功能性筛选	G蛋白偶联受体(GPCR)和离子通道的配体发现、病毒受体研究及抗病毒药物开发	[32]
mRNA展示技术	10¹²~10¹⁵	鉴定蛋白质-蛋白质相互作用；库容量最大；复合物通过共价键连接，稳定性极高；可引入非天然氨基酸	筛选高亲和力环肽、蛋白结合剂；靶向“不可成药”靶点；开发含非天然氨基酸的治疗性肽	[33]

mRNA展示技术高通量筛选环肽药物的研究进展

Advances in high-throughput screening of cyclic peptide drugs using mRNA display technology

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