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    Modulators of Toll-like Receptors -7 and -8

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    Issue Date
    2011-05-31
    Author
    Shukla, Nikunj M.
    Publisher
    University of Kansas
    Format
    202 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Medicinal Chemistry
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    Toll-like receptors (TLR)-7/-8 are innate immune receptors present in the endosomal compartment that are activated by single-stranded RNA (ssRNA) molecules of viral as well as nonviral origin, inducing the production of inflammatory cytokines necessary for the development of adaptive immunity, and are thus useful as vaccine adjuvants. A general introduction to TLRs, with an emphasis on the role of TLR7 activation in mobilizing innate and adaptive immune responses is presented in Chapter 1. Synthetic small molecule agonists of TLR7 include the imidazoquinoline class of compounds such as Gardiquimod [1-(4-amino-2-((ethylamino)methyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol]. En route to the synthesis of gardiquimod, its des-amino 3H regioisomer was found to be antagonistic at TLR7 (Chapter 2). Using the 3H imidazoquinoline as a lead, the syntheses, characterization, and biological evaluation of a pilot library of 3H imidazoquinolines was undertaken, which led to the identification of a dual TLR7/TLR8 antagonist (Chapter 3). With the goal of developing more potent TLR7 agonists as adjuvants, derivatives of gardiquimod were synthesized and a detailed SAR study on the imidazoquinoline chemotype was performed, which led to the discovery of a highly potent, lipophilic, human TLR7 agonist (Chapter 4). Further exploration on the imidazoquinoline chemotype led us to a highly active TLR7/8 dual agonistic molecule bearing a free primary amine on the N1 substituent. This molecule was utilized to synthesize fluorescent imidazoquinoline analogues that retained TLR7/8-agonistic activity, and were used to study the distribution of TLR7 and also to examine its differential uptake in lymphocytic subsets (Chapter 5). Homodimers of imidazoquinolines were synthesized in order to test whether such constructs would behave as modulators of TLR3 (Chapter 6). The TLR7/8 dual agonistic molecule was also used as a convenient precursor for the synthesis of isothiocyanate and maleimide derivatives, enabling its direct conjugation to protein and polysaccharide antigens to make self adjuvanting vaccine constructs. The isothiocyanate derivative was covalently coupled to a model antigen, alpha-lactalbumin, and this self-adjuvanting alpha-lactalbumin construct induced robust, high-affinity immunoglobulin titers in murine models of vaccination (Chapter 7).
    URI
    http://hdl.handle.net/1808/8186
    Collections
    • Dissertations [3958]
    • Medicinal Chemistry Dissertations and Theses [58]

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    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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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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