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Evans JT, Bess LS, Mwakwari SC, et al. Synthetic Toll-like Receptors 7 and 8 Agonists: Structure-Activity Relationship in the Oxoadenine Series. ACS Omega. 2019;4(13):15665-15677doi: 10.1021/acsomega.9b02138.
Evans, J. T., Bess, L. S., Mwakwari, S. C., Livesay, M. T., Li, Y., Cybulski, V., Johnson, D. A., & Bazin, H. G. (2019). Synthetic Toll-like Receptors 7 and 8 Agonists: Structure-Activity Relationship in the Oxoadenine Series. ACS omega, 4(13), 15665-15677. https://doi.org/10.1021/acsomega.9b02138
Evans, Jay T, et al. "Synthetic Toll-like Receptors 7 and 8 Agonists: Structure-Activity Relationship in the Oxoadenine Series." ACS omega vol. 4,13 (2019): 15665-15677. doi: https://doi.org/10.1021/acsomega.9b02138
Evans JT, Bess LS, Mwakwari SC, Livesay MT, Li Y, Cybulski V, Johnson DA, Bazin HG. Synthetic Toll-like Receptors 7 and 8 Agonists: Structure-Activity Relationship in the Oxoadenine Series. ACS Omega. 2019 Sep 10;4(13):15665-15677. doi: 10.1021/acsomega.9b02138. eCollection 2019 Sep 24. PMID: 31572869; PMCID: PMC6761749.
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ACS Omega. 2019 Sep 10;4(13):15665-15677. doi: 10.1021/acsomega.9b02138. eCollection 2019 Sep 24.

Synthetic Toll-like Receptors 7 and 8 Agonists: Structure-Activity Relationship in the Oxoadenine Series.

ACS omega

Jay T Evans, Laura S Bess, Sandra C Mwakwari, Mark T Livesay, Yufeng Li, Van Cybulski, David A Johnson, Hélène G Bazin

Affiliations

  1. GSK Vaccines, 553 Old Corvallis Road, Hamilton, Montana 59840, United States.
  2. Division of Biological Sciences and Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana 59802, United States.

PMID: 31572869 PMCID: PMC6761749 DOI: 10.1021/acsomega.9b02138

Abstract

Toll-like receptors 7 and 8 (TLR7/8) are broadly expressed on antigen-presenting cells, making TLR7/8 agonists likely candidates for the development of new vaccine adjuvants. We previously reported the synthesis of a new series of 8-oxoadenines substituted at the 9-position with a 4-piperidinylalkyl moiety and demonstrated that TLR7/8 selectivity and potency could be modulated by varying the length of the alkyl linker. In the present study, we broadened our initial structure-activity relationship study to further evaluate the effects of N-heterocycle ring size, chirality, and substitution on TLR7/8 potency, receptor selectivity, and cytokine (IFNα and TNFα) induction from human peripheral blood mononuclear cells (PBMCs). TLR7/8 activity correlated primarily to linker length and to a lesser extent to ring size, while ring chirality had little effect on TLR7/8 potency or selectivity. Substitution of the heterocyclic ring with an aminoalkyl or hydroxyalkyl group for subsequent conjugation to phospholipids or antigens was well tolerated with the retention of both TLR7/8 activity and cytokine induction from human PBMCs.

Copyright © 2019 American Chemical Society.

Conflict of interest statement

The authors declare the following competing financial interest(s): All authors were employees of the GSK group of companies at the time when the TLR7/8 agonists described here were first prepared and

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