Metallo-supramolecular complexes enantioselectively target monkeypox virus RNA G-quadruplex and bolster immune responses against MPXV  

作　　者：Jie Yang Geng Qin Baoying Huang Hualong Song Jiewei Sun Miles Postings Peter Scott Chuanqi Zhao Chunyu Wang Wenjie Tan Jinsong Ren Xiaogang Qu 

机构地区：[1]Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China [2]School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China [3]NHC Key Laboratory of Biosafety,National Institute for Viral Disease Control and Prevention,Chinese Center for Disease Control and Prevention,National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases(NITFID),Beijing 102206,China [4]Department of Chemistry,University of Warwick,Coventry CV47AL,UK [5]School of Pharmacy,Xinxiang Medical University,Xinxiang 453003,China [6]State Key Laboratory of Supramolecular Structure and Materials,Jilin University,Changchun 130012,China

出　　处：《National Science Review》2025年第1期161-170,共10页国家科学评论(英文版)

基　　金：supported by the National Key R&D Program of China(2019YFA0709202,2021YFF1200700,2022YFC2304100,2021YFA1201003);the National Natural Science Foundation of China(22437006,22237006,22122704,22107098,82241066);the Jilin Innovation Project(2023DJ02).

摘　　要：The Mpox virus(MPXV)has emerged as a formidable orthopoxvirus,posing an immense challenge to global public health.An understanding of the regulatory mechanisms of MPXV infection,replication and immune evasion wi l l benefit the development of novel antiviral strategies.Despite the involvement of G-quadruplexes(G4s)in modulating the infection and replication processes of multiple viruses,their roles in the MPXV life cycle remain largely unknown.Here,we found a highly conservative and stable G4 in MPXV that acts as a positive regulatory element for viral immunodominant protein expression.Furthermore,by screening 42 optically pure chiral metal complexes,we identified theenantiomer of a pair of chiral helical compounds that can selectively target mRNA G4 and enhance expression of the 39-kDa core protein encoded by the MPXV A5L gene.Mechanistically,RNA G4-specific helicase DHX36 inhibits A5L protein expression by unwinding G4s.In contrast,MH3enhanced mRNA stability by specifically targeting G4 structures and subsequently increased protein expression.Furthermore,given the pivotal role of the 39-kDa core protein in activating immune responses and facilitating virion maturation,modulation of MPXV G4 folding by MH3exhibited inhibitory effects on MPXV replication through enhancing the immune response.Our findings underscore the critical involvement of G4 in the MPXV life cycle and offer potential avenues for developing antiviral drugs that target G4.

关 键 词：G-QUADRUPLEX ligand binding Mpox virus CHIRALITY supramolecular chemistry 

分 类 号：O62[理学—有机化学]