Development of Small Molecule as Toll-like Receptor 1/2 Agonist

Grover, Alexander

Undergraduate Honors Thesis

Development of Small Molecule as Toll-like Receptor 1/2 Agonist Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/wh246s50p

Abstract

Toll-like receptors (TLRs) are a specific class of cell membrane spanning proteins that recognize and bind foreign microbes. Over time, these receptors have evolved to recognize wellconserved features commonly expressed by foreign pathogens including: flagellin proteins, lipopolysaccharides (LPS), lipoproteins, and even unmethylated CpG islands found within bacterial and viral DNA. Traditionally, non-covalent interactions between these microbes and the TLR invoke a signaling cascade within the cell to ultimately elicit an inflammatory response through the recruitment of cytokines and chemokines. The exact TLR signaling mechanism is quite similar to that of receptor tyrosine kinases, in which a specific ligand binds and facilitates a cell-specific response through the heterodimerization of the TLR. Specifically the interaction and dimerization of TLR 1 and 2 induces the expression of genes involved with inflammation and innate immunity. Although in vivo TLRs are typically activated solely by microbial ligands, recent literature and discoveries have demonstrated synthetic small-molecule compounds are similarly capable of eliciting a powerful physiological response in vitro. Investigations into these synthetic agonists have given greater insight into how/why these receptors govern such a dramatic change within the cell. The specific role of this project has sought to investigate and explore various TLR 1/2 agonist derivatives building off of previous research to ultimately synthesize and test in vitro small molecule agonists capable of regulating the TLR complex at the molecular level.

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