萜类-PROTAC协同策略：天然产物药物开发新范式

Terpenoid-PROTAC Synergistic Strategy: A New Paradigm in Natural Product Drug Development

关键词:  萜类  PROTAC技术  药物开发

Key words:  terpenoid  PROTAC technology  drug development

摘要:

摘要：萜类天然产物与蛋白降解靶向嵌合体（PROTAC）技术的交叉融合，为攻克"不可靶向"蛋白难题提供了创新策略。在靶标发现方面，通过PROTAC介导的靶蛋白降解放大效应结合定量蛋白质组学技术，可突破传统多靶点解析的灵敏度瓶颈；在药物开发方面，利用萜类化合物的刚性多环骨架稳定“靶蛋白-E3连接酶-PROTAC”三元复合物，并借助其化学多样性实现组织选择性的优化。基于PROTAC构建的"降解组学-计算模拟-合成生物学"三位一体的技术框架，为系统性解决连接链理性设计、脱靶效应控制等关键问题提供新思路。该策略与萜类化合物相结合，可为萜类化合物的深度开发赋予新维度，更为跨学科融合的精准药物设计提供方法论。

Abstract:

ABSTRACT: The integration of terpenoid natural products with Proteolysis-Targeting Chimera (PROTAC) technology presents an innovative paradigm for addressing undruggable targets. This study proposes a dual-path synergistic strategy: In target discovery, PROTAC-mediated degradation amplifies signal outputs, enabling quantitative proteomics to overcome resolution limitations in multi-target network analysis; In drug development, the rigid polycyclic scaffolds of terpenoids stabilize ternary complexes (target-E3 ligase-PROTAC), while their chemical diversity facilitates tissue-selective optimization. A novel tripartite framework integrating degradomics, computational modeling, and synthetic biology is established to address critical challenges in linker design and off-target control. This strategy not only unlocks the therapeutic potential of natural products but also pioneers an interdisciplinary methodology for precision drug design, offering new possibilities for complex disease intervention.