Synthesis and bioconjugation of small organic molecules for immunomodulation.

Abstract

Over the past two decades, a number of immunological pathways have been identified which recognize a wide range of pathogen-associated molecular patterns including lipopolysaccharide and single-stranded viral RNAs. These receptors, known as Toll-like receptors, initiate innate immune responses and the subsequent signaling pathways which lead to an immune response toward a pathogen. This dissertation describes the synthesis and characterization of several small, organic molecules which either elicited or suppressed immune responses through Toll-like receptor pathways. Linkers for bioconjugation were then installed and used to conjugate the compounds to a variety of biological substrates. Conjugated fluorophores were also developed for the purpose of determining the molecular loading and release kinetics of conjugates to single cells and cell clusters, to solid tissue, and to the vasculature of intact limbs. These experiments successfully demonstrated multiple bioconjugation methods in diverse systems, providing information about the conditions needed for future in vivo applications.