Organic-Platinum Hybrids for Covalent Binding of G-Quadruplexes: Structural Basis and Application to Cancer Immunotherapy |
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Authors: | Dr Liu-Yi Liu Tian-Zhu Ma You-Liang Zeng Dr Wenting Liu Dr Hang Zhang Prof Dr Zong-Wan Mao |
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Institution: | MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, Sun Yat-Sen University, Guangzhou, 510275 P. R. China |
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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. |
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Keywords: | Cancer Immunotherapy Covalent Binding G-Quadruplex Organic-Platinum Hybrids Solution Structure |
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