2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of New 2,6,7-Substituted Purine Derivatives as Toll-like Receptor 7 Agonists for Intranasal Vaccine Adjuvants

Design, Synthesis, and Biological Evaluation of New 2,6,7-Substituted Purine Derivatives as Toll-like Receptor 7 Agonists for Intranasal Vaccine Adjuvants

  • J Med Chem. 2024 Jun 13;67(11):9389-9405. doi: 10.1021/acs.jmedchem.4c00489.
Morgan Kim 1,  Kyungseob Noh 2 3,  Pyeongkeun Kim 1,  Jae Ho Kim 4,  Byeong Wook Choi 1,  Ravi Singh 1,  Jun-Ho Choi 1,  Soo Bong Han 2 5,  Seong Soon Kim 6,  Eun-Young Lee 4,  Myung Ae Bae 6,  Daeho Shin 2,  Meehyein Kim 2 3,  Jin Hee Ahn 1 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 2 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea.
  • 3 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 4 JD Bioscience, 208 Cheomdan-gwagiro, Buk-gu, Gwangju 61005, Republic of Korea.
  • 5 Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Republic of Korea.
  • 6 Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
PMID: 38787938 DOI: 10.1021/acs.jmedchem.4c00489
Abstract

TLR7/8 agonists are versatile immune stimulators capable of treating various diseases such as viral infections, autoimmune, and Cancer. Despite the structural similarity of TLR7/8, their immune stimulation mechanisms and time-course responses significantly differ. In this study, a new series of TLR7-selective agonists was synthesized utilizing the economical building block 2,6-dichloropurine. Compound 27b showed the most potent activity on hTLR7 with an EC50 of 17.53 nM and demonstrated high hTLR7 selectivity (224 folds against TLR8). 27b effectively stimulated the secretion of proinflammatory cytokines in mouse macrophages and enhanced intranasal vaccine efficacy against influenza A virus in vivo. Assessment of humoral and mucosal antibody titers confirmed that 27b elevates IgG and IgA levels, protecting against both homologous and heterologous influenza viral infections. These findings suggest that 27b is a promising candidate as a vaccine Adjuvant to prevent viral infections or as a robust immunomodulator with prolonged activity for treating immune-suppressed diseases.

Figures
Products