Organic‐Platinum Hybrids for Covalent Binding of G‐Quadruplexes: Structural Basis and Application to Cancer Immunotherapy
Liu‐Yi Liu, Tianzhu Ma, You‐Liang Zeng, Wenting Liu, Hang Zhang, Zong‐Wan Mao
Abstract
Abstract 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, L 1 ‐cispt and L 1 ‐transpt , with spatial matching for G4 binding and G4 DNA reactivity for binding site locking. The solution structure of L 1 ‐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, L 1 ‐cispt‐ and L 1 ‐transpt‐ mediated genomic dysfunction could activate the retinoic acid‐induced gene I (RIG‐I) pathway and induce immunogenic cell death (ICD). The use of L 1 ‐cispt/L 1 ‐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.