免疫疗法
化学
共价键
G-四倍体
DNA
癌症免疫疗法
鸟嘌呤
生物化学
重组DNA
癌症研究
免疫系统
合理设计
基因
生物
免疫学
遗传学
有机化学
核苷酸
作者
Liu‐Yi Liu,Tianzhu Ma,You‐Liang Zeng,Wenting Liu,Hang Zhang,Zong‐Wan Mao
标识
DOI:10.1002/anie.202305645
摘要
G-quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but the G4-mediated immune response remains unclear. We designed a novel class of G4-binding organic-platinum hybrids, L1 -cispt and L1 -transpt, with spatial matching for G4 binding and G4 DNA reactivity for binding site locking. The solution structure of L1 -transpt-MYT1L G4 demonstrated the effectiveness of the covalent binding and revealed the covalent binding-guided dynamic balance, accompanied by the destruction of the A5-T17 base pairs to achieve the covalent binding of the platinum unit to N7 of the G6 residue. Furthermore, L1 -cispt- and L1 -transpt-mediated genomic dysfunction could activate the retinoic acid-induced gene I (RIG-I) pathway and induce immunogenic cell death (ICD). The use of L1 -cispt/L1 -transpt-treated dying cells as therapeutic vaccines stimulated a robust immune response and effectively inhibited tumor growth in vivo. Our findings highlight the importance of the rational combination of specific spatial recognition and covalent locking in G4-trageting drug design and their potential in immunotherapy.
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