Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists

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Issue Date
2014-04Author
Kokatla, Hari Prasad
Sil, Diptesh
Tanji, Hiromi
Ohto, Umeharu
Malladi, Subbalakshmi S.
Fox, Lauren M.
Shimizu, Toshiyuki
David, Sunil A.
Publisher
Wiley
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Show full item recordAbstract
Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We recently reported pure TLR8 agonistic activity in a C2-butyl furo[2,3-c]quinoline. We have obtained the structure of human TLR8 ectodomain co-crystallized with the furoquinoline compound, which indicates ligand-induced reorganization of the binding pocket of TLR8. The loss of a key H-bond between the oxygen atom of the furanyl ring of the agonist and Thr574 in TLR8 suggested that the furan ring was dispensable. We employed a disconnection strategy and examined 3- and 4-substituted aminoquinolines. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist.
Description
This is the peer reviewed version of the following article: Kokatla, H. P., Sil, D., Tanji, H., Ohto, U., Malladi, S. S., Fox, L. M., … David, S. A. (2014). Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists. ChemMedChem, 9(4), 719–723. http://doi.org/10.1002/cmdc.201300573, which has been published in final form at doi.org/10.1002/cmdc.201300573. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
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Citation
Kokatla, H. P., Sil, D., Tanji, H., Ohto, U., Malladi, S. S., Fox, L. M., … David, S. A. (2014). Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists. ChemMedChem, 9(4), 719–723. http://doi.org/10.1002/cmdc.201300573
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