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G4 ligands, which are small molecules that bind to G4 ODNs with high affinity, were reported to improve the stability of G4. In this study, we propose to increase the stability and function of G4 CpG ODNs using G4 ligands. We show the effects of two G4 ligands, named L2H2-6OTD (L2H2) and L2G2-2M2EG-6OTD (L2G2), on the topology, stability, and immunostimulatory properties of a monomeric hybrid-type G4 CpG ODN containing CpG motifs in the central loop, named GD3. We found that L2H2 helps maintain the hybrid G4 topology of GD3 whereas L2G2 induces parallel G4 formation. Both G4 ligands increase the thermodynamic and nuclease stability of GD3. However, only GD3 associated with L2H2 binds efficiently to TLR9 and evokes a higher immune response from mouse macrophage-like RAW264 cells. GD3 associated with L2G2 does not bind efficiently to TLR9 and elicits lower cytokine production. Our results demonstrate that the potential to enhance immunostimulatory properties depends on the ability of G4 ligands to maintain and stabilize the hybrid G4 of GD3. We anticipate that our findings will facilitate the development of more effective G4 CpG ODN-based vaccine adjuvants against infectious diseases.

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• In Copyright
  This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Biology, copyright © 2022 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acschembio.1c00904

Keyword: guanine quadruplex, CpG oligodeoxynucleotide, toll-like receptor 9, phosphodiester backbone, G-quadruplex ligand

Date published: 2022-07-15

Publisher: American Chemical Society (ACS)

Journal:

• ACS Chemical Biology (ISSN: 15548929) vol. 17 issue. 7 p. 1703-1713

Funding:

• Ministry of Education, Culture, Sports, Science and Technology
• Japan Society for the Promotion of Science 17KK0122
• Japan Society for the Promotion of Science 18K04858
• Japan Society for the Promotion of Science 21K19057

Manuscript type: Author's version (Accepted manuscript)

MDR DOI: https://doi.org/10.48505/nims.4796

First published URL: https://doi.org/10.1021/acschembio.1c00904

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Updated at: 2024-10-03 16:30:22 +0900

Published on MDR: 2024-10-03 16:30:22 +0900