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

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    Kokatla_Wiley_2014.pdf (1.494Mb)
    Issue Date
    2014-04
    Author
    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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    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.
    URI
    http://hdl.handle.net/1808/24020
    DOI
    https://doi.org/10.1002/cmdc.201300573
    Collections
    • Medicinal Chemistry Scholarly Works [224]
    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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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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