Design and synthesis of immunomodulatory peptide conjugates

Abstract

This dissertation explores new chemical strategies for the synthesis of self-adjuvanting peptide conjugates and immunomodulatory ligands aimed at targeted activation of the immune system. Particular focus is given to the optimization of Toll-like receptor (TLR) ligands, including TLR2/1 targeting UPam-conjugates as potential SARS-CoV-2 vaccine candidates and mono-palmitoyl-N-alkylurea derivatives as selective activators of TLR2/6 heterodimers. Furthermore, intracellular receptors are addressed through cathepsin B-sensitive peptide conjugates for TLR7/8 and through phosphorylated muramyl dipeptides as NOD2 ligands. Finally, multivalent peptide clusters targeting the mannose-6-phosphate receptor are developed as an alternative strategy for cellular uptake in the absence of pattern recognition receptor ligands. Together, these studies provide insight into the relationship between chemical structure and immune activation, and establish design principles for the rational development of next-generation vaccine and therapeutic platforms.