News Release

Metallo-supramolecular complexes enantioselectively target monkeypox virus mRNA G-quadruplex and inhibit monkeypox virus replication by increasing the immune response

Peer-Reviewed Publication

Science China Press

Schematic representation of the MH3 Λ upregulating A5L protein by interacting with G4 to inhibit viral replication

image: 

A highly conservative and stable G4 in MPXV, which acts as a positive regulatory element for viral immunodominant protein expression. RNA G4-specific helicase DHX36 inhibits A5L protein expression by unwinding G4. In contrast, MH3 Λ enhanced mRNA stability by specifically targeting G4 structures and subsequently increased protein expression.

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Credit: ©Science China Press

This study is led by Dr. Xiaogang Qu (Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences). Dr. Xiaogang Qu and Dr. Jinsong Ren designed the research. Jie Yang, Geng Qin and Chuanqi Zhao predicted and identified the presence of G4 in MPXV, and determined that metallo-supramolecular complex MH3 Λ could up-regulate MPXV A5L gene expression by targeting mRNA G-quadruplex. Hualong Song, Miles Postings and Peter Scott synthesized the complexes for screening. Chunyu Wang involved the validation of G4 formation. Dr. Wenjie Tan, Dr. Baoying Huang and Jiewei Sun designed and performed viral experiments to verify the inhibition of MH3 Λ against MPXV.

Employing an integrated approach encompassing bioinformatics, biophysical, and biological techniques, the team have successfully found a highly conserved RNA G4 structure within the MPXV A5L mRNA (encoding 39-kDa virion core protein) and elucidated its pivotal role as a positive regulatory element in viral immunodominant protein expression.

By screening 42 optically pure chiral metal complexes, MH3Λ was found to exhibit selectively binding to MPXV mRNA G4, but not to the numerous DNA G4s found in the human genome, thus indicating the potential use of metal supramolecular complexes for mpox therapy. The researchers also underscore the impact on A5L protein expression resulting from modulating the stability of this G4 through either chiral metallo-supramolecular complexes or RNA G4-specific helicase DHX36 (see below image). 

Considering the pivotal role played by the A5L gene in immune response activation and virion maturation, the team found that the targeted interaction of MH3 Λ with A5L mRNA G4 demonstrated remarkable antiviral effects through immune enhancement (see below image).

These findings underscore the significance of G4s in viral mRNA as crucial regulatory signals for viral immunodominant protein expression and immune evasion. The insights gained from this research provide novel perspectives on the biological function of G4s in the lifecycle of MPXV and offer potential avenues for developing antiviral therapeutics targeting mpox prevention and treatment.

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See the article:

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

https://doi.org/10.1093/nsr/nwae388


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