2. Academic Validation
  3. Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity

Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity

  • Bioorg Med Chem Lett. 2020 Mar 15;30(6):126984. doi: 10.1016/j.bmcl.2020.126984.
Hélène G Bazin 1,  Laura S Bess 2,  Mark T Livesay 2,  Yufeng Li 3,  Van Cybulski 4,  Shannon M Miller 5,  David A Johnson 3,  Jay T Evans 4
Affiliations

Affiliations

  • 1 Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, United States; GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States. Electronic address: helene.bazin-lee@mso.umt.edu.
  • 2 Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, United States; GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States.
  • 3 GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States.
  • 4 Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Division of Biological Sciences, University of Montana, Missoula, MT 59812, United States; GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States.
  • 5 Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Division of Biological Sciences, University of Montana, Missoula, MT 59812, United States.
PMID: 32001135 DOI: 10.1016/j.bmcl.2020.126984
Abstract

Toll-like receptors 7 and 8 (TLR7/8) agonists are potent immunostimulants that are attracting considerable interest as vaccine adjuvants. We recently reported the synthesis of a new series of 2-O-butyl-8-oxoadenines substituted at the 9-position with various linkers and N-heterocycles, and showed that TLR7/8 selectivity, potency and cytokine induction could be modulated by varying the alkyl linker length and the N-heterocyclic ring. In the present study, we further optimized the oxoadenine scaffold by investigating the effect of different substituents at the 2-position of the oxoadenine on TLR7/8 potency/selectivity, cytokine induction and DC maturation in human PBMCs. The results show that introducing a 1-(S)-methylbutoxy group at the 2-position of the oxoadenine significantly increased potency for TLR7/8 activity, cytokine induction and DC maturation.

Keywords

Oxoadenine; TLR7; TLR8; Toll-like-receptor.

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