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dc.contributor.advisorDavid, Sunil A
dc.contributor.authorYoo, Euna
dc.date.accessioned2017-05-07T16:30:29Z
dc.date.available2017-05-07T16:30:29Z
dc.date.issued2015-05-31
dc.date.submitted2015
dc.identifier.otherhttp://dissertations.umi.com/ku:13902
dc.identifier.urihttp://hdl.handle.net/1808/23923
dc.description.abstractToll-like receptors (TLRs)-7/-8 are among pathogen recognition receptors (PRRs) present in the endosomal compartment that are activated by viral single-stranded RNA (ssRNA) as well as synthetic small molecules. TLR7/8 agonists hold promise as potential vaccine adjuvants, since they directly activate antigen-presenting cells and enhance T helper 1-driven immune responses. A general introduction to TLRs, with an emphasis on the role of TLR7/8 activation in innate and adaptive immune responses is presented in Chapter 1. Structure-activity relationship (SAR) studies in small molecule TLR8/7-agonistic ligands showed that thiazolo[4,5-c]quinolines display mixed TLR8/7 agonistic activities with the optimal C2-alkyl chain length being butyl (Chapter 2). In an ongoing search toward exploring alternative chemotypes, furo[2,3-c]pyridines with pyridoxal as the aldehyde component in a one-pot multicomponent Groebke-Blackburn-Bienaymé reaction were obtained and found to exhibit TLR8-dependent NF-kB activation and strong adjuvanticity without proinflammatory cytokine induction (Chapter 3). Combinatorial libraries using the Groebke-Blackburn-Bienaymé reaction have also yielded TLR7/8-inactive, but antibacterial imidazo[1,2-a]pyridines (Chapter 4). Based on the previously reported SARs on imidazoquinolines, the syntheses and biological evaluation of novel imidazo[4,5-c]pyridine analogues were undertaken, with modifications at the N4- and C6 positions, which afforded strong Type I IFN inducers in conjunction with attenuated proinflammatory profiles (Chapter 5). With the goal of defining structural requisites governing activity and selectivity at TLR7 and/or TLR8, we undertook scaffold-hopping approach, quantum chemical calculations followed by linear discriminant analyses that permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity (Chapter 6). Molecular conjugation of TLR7/8 agonists to hyaluronic acid (HA) was evaluated to enhance selective and targeted delivery of vaccine construct to draining lymph nodes while limiting systemic exposure. The superior adjuvanticity evoking affinity-matured high-avidity immunoglobulins after a single boost was observed with HA conjugate bearing dual TLR7/8 agonist (Chapter 7). Extensive SAR investigations in several TLR7/8 agonistic scaffolds and exploration as vaccine adjuvant candidates have incrementally improved our understanding of how these molecules activate innate and adaptive immune responses and also catalyzed novel approaches to vaccine design and development.
dc.format.extent281 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectPharmaceutical sciences
dc.subjectImmunology
dc.subject
dc.titleExploration of Toll-like Receptor 7 and 8 Agonists as Potential Vaccine Adjuvants
dc.typeDissertation
dc.contributor.cmtememberPeterson, Blake R
dc.contributor.cmtememberRafferty, Michael F
dc.contributor.cmtememberLaurence, Jennifer S
dc.contributor.cmtememberRivera, Mario
dc.thesis.degreeDisciplineMedicinal Chemistry
dc.thesis.degreeLevelPh.D.
dc.rights.accessrightsopenAccess


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