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CCR5 antagonists: from discovery to clinical efficacy

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Chemokine Biology — Basic Research and Clinical Application

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

CCR5 is a prototypically inflammatory chemokine receptor belonging to the seven transmembrane G-protein-coupled receptor (GPCR) family. This family is generally considered druggable and well represented in marketed drugs [1]–[6]. The CCR5 receptor is expressed on numerous host defense cells including monocytes, macrophages, T-lymphocytes, dendritic cells and microglia [4, 5]. Interaction of CCR5 with its ligands MIP-1α, MIP-1β (CCL3/CCL4) or RANTES (CCL5) results in a conformational change in the seven transmembrane domain initiating a signaling cascade through heterotrimeric G-proteins ultimately giving rise to migration of immune cells to sites of inflammation [2, 5]. Due to the well documented role of CCR5 in the immune system, it has been implicated in the pathophysiology of rheumatoid arthritis (RA), multiple sclerosis (MS), transplant rejection, gastric disorders, diabetes and myeloma [7]. Perhaps the biggest driver behind the development of CCR5 receptor antagonists was the discovery that CCR5 plays an important role as a co-receptor for macrophage tropic HIV-1 strains to facilitate viral fusion and entry into host cells [5], [8]–[12]. In addition, individuals with a mutation in the CCR5 gene (CCR5Δ32) lacking expression of CCR5 on the cell surface are resistance to HIV-1 infection without notable immune system effects [13, 14], thus validating pharmaceutical intervention with a CCR5 antagonist.

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Authors and Affiliations

  1. Discovery Chemistry & Research Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Shon R. Pulley

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  1. Lilly Corporate Center, Cancer Inflammation and Cell Survival Eli Lilly and Company, Indianapolis, IN, 46285, USA

    Kuldeep Neote

  2. NitroMed, Inc., 12 Oak Park Drive, Bedford, MA, 01730, USA

    Gordon L. Letts

  3. Theodor Koch Institute, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland

    Bernhard Moser

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Pulley, S.R. (2007). CCR5 antagonists: from discovery to clinical efficacy. In: Neote, K., Letts, G.L., Moser, B. (eds) Chemokine Biology — Basic Research and Clinical Application. Progress in Inflammation Research. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-7437-2_11

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