Functional Modulation of the Pattern Recognition Formyl Peptide Receptors in Neutrophils - Lipopeptides - allosteric modulators of G-protein coupled receptors

Abstract

G-protein-coupled receptors (GPCRs), which are the largest class of cell-surface receptors, are involved in a range of physiologic processes and pathologies, making this a highly interesting group of proteins as targets for drug development. Studies of these receptors have uncovered novel receptor biology concepts, including biased signaling, functional selectivity, and allosteric modulation. “Tailor-made” lipopeptides (pepducins and lipopeptoids) represent novel and promising classes of receptor-specific allosteric modulators. In this thesis, immunomodulating lipopeptides that interact with a group of pattern recognition receptors, formyl peptide receptors (FPRs), which play key roles in host defense against microbial infections, tissue homeostasis, and the initiation and resolution of inflammation, are generated and functionally characterized. The FPRs are expressed in both human and murine white blood cells, and novel allosteric lipopeptide modulators that selectively interact with human and murine receptors are described. We show that the targeted receptor is not always the one that might be expected. This receptor hijacking process raises questions about the precise mechanisms of action of these lipopeptides and of these types of molecules acting as a molecular pattern that is recognized by the receptor group studied. Fundamental differences are also revealed by the receptor-ligand recognition profiles, between mice and men. This represents important knowledge needed for the development and use of animal models for human diseases. In summary, the results presented in this thesis not only highlight the value of the different lipopeptides as tools for modulating receptor activities in human and murine immune cells, but also provide new insights into the allosteric modulation concept.