Synthesis of modulators of TLR2, TLR4, and TLR7 functionalized for conjugation to biomolecules.
| dc.contributor.advisor | Kane, Robert R. | |
| dc.creator | Akinbobuyi, Babatope, 1979- | |
| dc.date.accessioned | 2017-01-19T16:37:38Z | |
| dc.date.available | 2017-01-19T16:37:38Z | |
| dc.date.created | 2016-12 | |
| dc.date.issued | 2016-11-09 | |
| dc.date.submitted | December 2016 | |
| dc.date.updated | 2017-01-19T16:37:38Z | |
| dc.description.abstract | A wide range of pathogen-associated molecules including acylated lipopeptides, lipopolysaccharides (LPS), and single-stranded viral RNAs initiate an innate immune response via binding to members of a protein family called Toll-like receptors (TLRs). Toll-like receptors recognize general molecular patterns associated with various pathogens. Recognition of pathogen-associated molecular patterns (PAMPs) by TLRs results in specific signaling pathways which initiates an immune defense against the pathogen. Herein is described the synthesis of small-molecule modulators that can activate or inhibit Toll-like receptors in order to modulate immune responses. Our strategy to avoid systemic activation is to conjugate the synthetic compounds to biomolecules which allow targeted delivery. A variety of compounds have been designed and characterized as agonists of TLR7, an endosomal receptor recognizing viral ligands. Among these compounds are imidazoquinolines and adenine derivatives. A significant part of the synthetic work presented herein is focused on the synthesis of adenine derivatives which can be developed as vaccine adjuvants (to achieve improved immunogenicity). In the first part of the work, concise and efficient synthesis of adenine derivatives, several of which were functionalized for antibody conjugation is presented. The second part of this project was directed towards the chemical modification of a TLR4 inhibitor TAK-242. The anti-inflammatory potential of TAK-242 led us to explore its potential for the control of the blood-mediated inflammatory response which occurs subsequent to islet transplants. We describe our efforts to synthesize TAK-242 and attach it to a β-eliminative bifunctional linker, which is expected to facilitate an in vivo slow release of active drug. Finally, an analog of the TLR2 agonistic lipopeptide Pam3CSK4 was also synthesized for bioconjugation. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/2104/9891 | |
| dc.language.iso | en | |
| dc.rights.accessrights | Worldwide access. | |
| dc.rights.accessrights | Access changed 6/7/19. | |
| dc.subject | Toll-like receptors. Adenine compounds. Bioconjugation. | |
| dc.title | Synthesis of modulators of TLR2, TLR4, and TLR7 functionalized for conjugation to biomolecules. | |
| dc.type | Thesis | |
| dc.type.material | text | |
| local.embargo.lift | 2018-12-01 | |
| local.embargo.terms | 2018-12-01 | |
| thesis.degree.department | Baylor University. Dept. of Chemistry & Biochemistry. | |
| thesis.degree.grantor | Baylor University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Ph.D. |
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