Loading...
Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists
Kokatla, Hari Prasad Sil, Diptesh Tanji, Hiromi Ohto, Umeharu Malladi, Subbalakshmi S. Fox, Lauren M. Shimizu, Toshiyuki David, Sunil A.
Kokatla, Hari Prasad
Sil, Diptesh
Tanji, Hiromi
Ohto, Umeharu
Malladi, Subbalakshmi S.
Fox, Lauren M.
Shimizu, Toshiyuki
David, Sunil A.
Citations
Altmetric:
Abstract
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.
Date
2014-04
Journal Title
Journal ISSN
Volume Title
Publisher
Wiley
Collections
Research Projects
Organizational Units
Journal Issue
Keywords
Vaccines, Adjuvant, Innate immunity, TLR8, Aminoquinolines
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