双靶E3连接酶配体：克服耐药新出路
Dual Target E3 Ligase Ligands: A New Way to Overcome Drug Resistance
摘要: 由与E3泛素连接酶配体连接的蛋白质靶向配体组成的蛋白水解靶向嵌合体(PROTAC)的靶向蛋白质降解已成为一种通过蛋白酶体介导的降解致病蛋白质的强大治疗方式。目前对于PROTAC的研究如火如荼，但在应用方面PROTAC仍具有较大限制，例如肿瘤细胞的耐药性。联合用药是目前最广泛使用的规避耐药性方式，但是联合用药带来了新的问题。相较之下，双靶药物则具有巨大前景。双靶药物通过同时抑制多个靶标蛋白并产生协同抗病毒作用来对抗病毒感染。肿瘤的耐药性突变改变的是E3连接酶，如果能够设计合成双靶E3连接酶配体的PROTAC，哪怕其中一端的E3连接酶失活，另一端对应的E3连接酶仍能发挥作用。
Abstract: Targeted protein degradation by proteolytic targeting chimera (protac), which consists of protein targeting ligands linked to E3 ubiquitin ligase ligands, has become a powerful therapeutic modality to degrade pathogenic proteins through proteasome-mediated degradation. At present, the research on protac is in full swing, but there are still great limitations in the application of protac, such as the drug resistance of tumor cells. Drug combination is the most widely used way to avoid drug resistance, but it has brought new problems. In contrast, dual-target drugs have great prospects. Dual target drugs fight against viral infection by simultaneously inhibiting multiple target proteins and producing synergistic antiviral effects. The drug resistance mutation of tumor is targeted at the E3 ligase. If protacs with dual target E3 ligase ligands can be designed and synthesized, even if the E3 ligase at one end is inactivated, the corresponding E3 ligase at the other end can still play a role.
文章引用：潘相奕. 双靶E3连接酶配体：克服耐药新出路[J]. 药物化学, 2026, 14(1): 53-63. https://doi.org/10.12677/hjmce.2026.141006

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