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从“会环化”到“可筛选”：环肽化学生物学的新工具与新边界

已有 516 次阅读 2026-9-28 20:51 |个人分类:分享|系统分类:科研笔记

环肽兼具高亲和力、代谢稳定性与靶向“难成药”位点的独特能力，已成为多肽药物与化学生物学的重要分子骨架。然而传统基因编码肽库受限于天然氨基酸组成，如何在保持基因型—表型关联的同时，用温和、选择性的化学反应拓展化学空间，仍是该领域的关键命题。

国内进展为此提供了新路径。兰州大学雷新响团队以天然酪氨酸为反应位点，发展酪氨酸酶催化的Tyr–Aniline偶联，在水相温和条件下实现多肽后期编辑、肽–肽偶联与宏环化，并首次在噬菌体表面原位构建双酪氨酸环肽文库，经酶切结合高分辨质谱直接验证环化产物，针对Keap1与EphA4筛选出高亲和配体，其中CM1结合亲和力达211±60 nM、血浆稳定性显著优于线性前体^[1]。该团队同期又将巯基–烯烃光点击化学用于无保护肽的双环化与噬菌体展示双环肽文库构建，针对CypA筛得亲和力（364±70 nM）与半衰期（463分钟）均大幅提升的双环肽^[2]。环肽的“序列编码结构”思路甚至延伸至材料：Nature新近报道九肽DILT可借二聚体与三链连接规则自组装呈蜂窝状多通道纳米纤维，提示序列编程具有超越药物的普适性^[3]。

这些工作与国际前沿相互呼应。围绕酪氨酸位点，SuFEx诱导的水相大环化提供了化学选择性互补方案^[4]；mRNA展示被拓展至结构化RNA靶标与细胞裂解液环境，使共价环肽、RNA结合配体的发现成为可能^[5,6]；酵母展示与亲和选择—质谱联用让筛选过程更可控、更贴近序列可线性化需求^[7,8]；RaPID系统更催生了靶向GBA1的纳摩尔环肽酶稳定剂，为戈谢病等罕见病治疗提供新选项^[9]。

不难看出，环肽化学生物学的竞争已从“能否成环”转向“如何在保留骨架的同时编辑侧链、控制环数与引入亲电弹头”。天然位点的选择性化学、正交点击环化与多元展示平台相互叠加，正把“可环化的多肽”变成“可筛选、可成药、可设计”的功能分子。

参考文献

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