Synthesis of Structural and Fluorescently Labelled Peptidic Ligands for Optical Imaging of G Protein-Coupled Receptors

Mengjie Liu
2017
Fluorescence imaging is capable of facilitating highly specific and non-invasive investigation of cellular and molecular events both in vitro and in vivo. Fluorescently labelled peptidic ligands are useful in studying the location, distribution, trafficking and functions of G protein-coupled receptors (GPCRs). Although GPCRs are popular targets in modern target-oriented drug design, many of them have not been therapeutically exploited. An effective strategy in preparing such ligands is to
more » ... ate fluorophores to high-affinity and selective peptide analogues that are derived from the endogenous peptides. This thesis describes the synthesis and pharmacological properties of structural and fluorescent peptide analogues that target the GPCRs of interest. Their usefulness as receptor optical imaging agents has been verified in selected analogues. Chapter 1 describes the advantages of using fluorescently labelled peptides as optical imaging agents in studying GPCRs, and provides an overview of the key steps and considerations in designing such peptides. To support our ideas, a table containing representative examples of literature-documented fluorescently labelled peptides that target GPCRs is included. Chapter 2 demonstrates the application of various synthesis strategies in preparing structural and fluorescent peptide analogues derived from the two endogenous neuropeptides: ghrelin and kisspeptin. Specifically, we have verified the effectiveness of standard Fmoc-based solid phase synthesis, use of orthogonal protecting groups and fluorophore conjugation in both solid and solution phase, which have resulted in fluorescently labelled ghrelin and kisspeptin analogues useful in visualising their corresponding receptors. Chapter 3 and 4 describe utility of the verified synthesis strategies in preparing fluorescently labelled peptides that target neuropeptide Y (NPY) receptors. Chapter 3 presents synthesis and pharmacological evaluation of ligands derived from the modified NPY [...]
doi:10.4225/03/58c77bf8b2a95 fatcat:tjrnhtbsjvehhlfuopu22vnypi