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Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists
dc.contributor.author | Kokatla, Hari Prasad | |
dc.contributor.author | Sil, Diptesh | |
dc.contributor.author | Tanji, Hiromi | |
dc.contributor.author | Ohto, Umeharu | |
dc.contributor.author | Malladi, Subbalakshmi S. | |
dc.contributor.author | Fox, Lauren M. | |
dc.contributor.author | Shimizu, Toshiyuki | |
dc.contributor.author | David, Sunil A. | |
dc.date.accessioned | 2017-05-08T18:31:17Z | |
dc.date.available | 2017-05-08T18:31:17Z | |
dc.date.issued | 2014-04 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/24020 | |
dc.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. | en_US |
dc.description.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. | en_US |
dc.publisher | Wiley | en_US |
dc.rights | © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim | en_US |
dc.subject | Vaccines | en_US |
dc.subject | Adjuvant | en_US |
dc.subject | Innate immunity | en_US |
dc.subject | TLR8 | en_US |
dc.subject | Aminoquinolines | en_US |
dc.title | Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Kokatla, Hari Prasad | |
kusw.kuauthor | Sil, Diptesh | |
kusw.kuauthor | Malladi, Subbalakshmi S. | |
kusw.kuauthor | Fox, Lauren M. | |
kusw.kuauthor | David, Sunil A. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1002/cmdc.201300573 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-6457-0545 | |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC4105021 | en_US |
dc.rights.accessrights | openAccess |