Hélène G Bazin1, Laura S Bess2, Mark T Livesay2, Yufeng Li3, Van Cybulski4, Shannon M Miller5, David A Johnson3, Jay T Evans4. 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.
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.
Toll-like receptors 7 and 8 (n class="Gene">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 andN-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.
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