Investigating the mechanism of action of small-molecule modulators at the human CXCR2 receptor

Lead Research Organisation: University of Nottingham
Department Name: School of Life Sciences

Abstract

The CXCR2 chemokine receptor has emerged as a target of such a class of inhibitors but it is currently unknown whether these drugs truly affect the binding of the orthosteric ligand via an allosteric mechanism or they compete for binding with arrestins and G proteins. As the interface between the receptor and effectors such as G proteins, beta arrestins and GRKs is different, it would also be of importance to investigate whether the CXCR2 small-molecule antagonists differentially affect the coupling of the different effectors acting as 'biased' ligands. The kinetics of binding of the modulators and its effect on CXCR2 signalling is another area open for investigation. Using the CXCR2 receptor with a range of structurally distinct small-molecule allosteric modulators available, these concepts will be explored in whole cell pharmacological assays (including novel split luciferase based assays for protein-protein interactions). In due course, the project would further develop an assay to directly probe the modulators and G protein competition in an isolated purified CXCR2 system.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M008770/1 01/10/2015 30/09/2023
1944745 Studentship BB/M008770/1 01/10/2017 25/11/2021 Desislava Nesheva
 
Description Small molecules acting as antagonists of the human CXCR2 receptor were investigated in their ability to inhibit receptor activation and fluorescent endogenous agonist binding to the receptor. All molecules tested inhibited CXCR2 activation but they displayed different pharmacological profiles which may be underlined by differences in their receptor residence time.
Exploitation Route Extention of funding to complete the project
Sectors Pharmaceuticals and Medical Biotechnology