Organic‐Platinum Hybrids for Covalent Binding of G‐Quadruplexes: Structural Basis and Application to Cancer Immunotherapy

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, 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.