Investigation of the Melanocortin Receptor Biased Signaling and the Peptide Drug Design for Melanocortin and Opioid Receptor Systems

Abstract

Melanocortin receptors are important GPCRs controlling different biological functions. As cell membrane integrated receptors, melanocortin receptors have complicated 7-transmembrane domains and delicate internal structures. As membrane protein, melanocortin receptors are highly mobile and their conformations are subjected to change upon ligands binding and induction. The phenomenon of GPCRs’ potential to have different states/conformations is the functional basis of multiple signaling pathways. Ligand types determines the GPCR conformations when they bind and GPCR conformations determine which signaling protein can be recruited, further determining which pathway to initiate. This is the simple accepted mechanism of GPCR biased signaling. In the previous decades, we achieved tremendous milestones in making ligands receptor selective, for example, making MC1R selective agonists, making MC4R selective agonists and so on. However, the receptor subtype selectivity does not mean the ligand is necessary to inflict a single biological signaling outcome: The ligand can be a balanced ligand on this GPCR subtype and activate multiple pathways that this receptor controls. In this respect, making the GPCR ligand go biased signaling is important for the ligand’s anticipated drug effect and for the avoidance of side effects as well. In this dissertation, the author Zekun Liu first uses melanocortin receptor 4(MC4R) as an example to elucidate the mechanism of biased signaling and its influence in MCR peptide drug development. Meanwhile, to test the hypothesis of the relation between receptor structure and function, plasmon waveguide resonance (PWR) research was done. Apart from the biased signaling study, this dissertation also involves the peptide drug development for MC4R and MC5R in introduction of halogenation, beta homo amino acids and N-methylations. Besides the traditional single MCR ligand design, there is also the development of novel conjugation of MC1R agonist and melanoma killing drug as a novel macromolecule to target and kill melanoma. And the thinking of pharmacophore conjugation is also applied to opioid receptor research where Mu and Delta opioid receptors can form a dimer and control specific feedback regulation. In conclusion, this dissertation describes GPCR biased signaling (using MC4R as an example), a couple cases of MCR drug developments, opioid drug developments and DM1 drug development, with the application of multiple scientific approaches including molecular docking, molecular dynamics simulation, solid phase peptide synthesis, PWR, NMR, radiation based cAMP and binding assay for GPCR signaling, and so on. Hopefully, the thinking of the author can produce some inspiration for future peptide research.