Allosteric Modulation of Chemokine Receptors

Abstract

A central role of chemokines and their receptors in inflammatory processes has spurred numerous screening campaigns dedicated to the search for chemokine-receptor antagonists, which largely failed to deliver drugs for the treatment of inflammatory diseases. The quest for effective chemokine-receptor drug candidates thus continues, and the concept of allosteric targeting of the receptors may be the way forward. In this review, the complex allosteric mechanisms by which the functions of chemokines and their receptors are fine-tuned will be discussed and their impact on preclinical drug discovery presented. The opportunities and challenges of bench-to-clinic approaches are elucidated. We propose that while allosteric modulation of chemokine receptors adds a level of complexity to analyses and approaches to drug discovery, it also introduces a tremendous capacity for pharmacologic control of this physiological system for therapeutic advantage.

What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

“…As detailed above, GPCRs are fundamentally allosteric machines, because their intracellular action (G protein coupling) is controlled by binding of ligands on the extracellular side (132) (Fig. 4a).…”

Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

“…1−3 In the case of the human chemokine receptor CXCR3, which binds three endogenous chemokines CXCL9, CXCL10, and CXCL11, biased signaling is used by nature to fine-tune the responses of CXCR3 + cells upon physiological insult. 4 CXCR3 expression is rapidly induced on naive T cells following activation and preferentially remains highly expressed on type 1 helper (Th1) CD4 + T cells, effector CD8 + T cells, and innate-type lymphocytes, such as natural killer (NK) and natural killer T (NKT) cells. 5,6 Depending on the endogenous chemokine bound, the activation of CXCR3 leads to distinct functional outcomes, which considerably influence the course of inflammation and healing processes.…”

“…Biased signaling is a now well recognized phenomenon observed in the G protein coupled receptors (GPCRs) that describes the ability of different ligands acting at the same GPCR to stabilize distinct receptor conformations that, in turn, are linked to different functional outcomes. − In the case of the human chemokine receptor CXCR3, which binds three endogenous chemokines CXCL9, CXCL10, and CXCL11, biased signaling is used by nature to fine-tune the responses of CXCR3 + cells upon physiological insult . CXCR3 expression is rapidly induced on naive T cells following activation and preferentially remains highly expressed on type 1 helper (Th1) CD4 + T cells, effector CD8 + T cells, and innate-type lymphocytes, such as natural killer (NK) and natural killer T (NKT) cells. , Depending on the endogenous chemokine bound, the activation of CXCR3 leads to distinct functional outcomes, which considerably influence the course of inflammation and healing processes. , The opportunity to mimic this mechanism by small molecule allosteric ligands has remained largely unexploited, even though CXCR3 has been deemed as a promising therapeutic target in pathologies like autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis), cancer, and metastasis. − To inhibit the inflammatory response driven by the CXCR3 + cells, published research was focused solely on the development of small molecules with inhibitory effects on the CXCR3, which ultimately failed to deliver therapeutics. − A single study used metal-ion site engineering to probe the molecular mechanism of CXCR3 activation and identified high-potency allosteric agonists based on complexes containing Cu or Zn and phenantroline or bipyridine .…”

“…The general focus of our group is the understanding of the structure–activity relationships (SARs) of allosteric modulators of CXCR3 with probe-dependent behavior and biased signaling. − The unique nature of allosteric ligands (reflected in permissivity, saturability of effect, probe dependence, and biased signaling) offers great potential to extend therapeutic effects compared to orthosteric ligands , and is still a poorly explored opportunity. In this work we focused our research on the allosteric agonists of CXCR3.…”

“…13 C NMR (150 MHz, CDCl 3 ): δ (ppm) 176 4. (CO), 156.8 (CO), 156.0 (CO), 136.6 (C q ), 128.7 (2 × CH), 128.3 (2 × CH), 128.1 (CH), 80.4 (C q ), 66.9 (CH 2 ), 53.3 (CH), 40.7 (CH 2 ), 32.0 (CH 2 ), 29.3 (CH 2 ), 29.5 (3 × CH 3 ), 22.1 (CH 2 ).…”