Latest update on chemokine receptors as therapeutic targets

Abstract

The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine system has been linked to inflammatory diseases and cancer, which renders chemokine receptors to be considered as therapeutic targets. In the past two decades, around 45 drugs targeting chemokine receptors have been developed, yet only three are clinically approved. The challenging factors include the limited understanding of aberrant chemokine signalling in malignant diseases, high redundancy of the chemokine system, differences between cell types and non-specific binding of the chemokine receptor antagonists due to the broad ligand-binding pockets. In recent years, emerging studies attempt to characterise the chemokine ligand–receptor interactions and the downstream signalling protein–protein interactions, aiming to fine tuning to the promiscuous interplay of the chemokine system for the development of precision medicine. This review will outline the updates on the mechanistic insights in the chemokine system and propose some potential strategies in the future development of targeted therapy.

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

“…Immune mediators may have special importance in neurodevelopmental disorders such as autism and schizophrenia (Deverman and Patterson, 2009), with lifelong effects on cell proliferation, migration, synaptic, and extrasynaptic junctions (Garay and McAllister, 2010;Martineau, 2013). Chemokines ("chemotactic cytokines") govern the movement and localization of cells (Ubogu et al, 2006;Lai and Mueller, 2021;Sawant et al, 2021) and are therefore crucial in the communication between cells of the immune system, neurons and glia. Fractalkine (CX3CL1) has received much interest as it is produced constitutively by neurons and restrains microglial activation.…”

“…Chemokines (“chemotactic cytokines”) govern the movement and localization of cells ( Ubogu et al, 2006 ; Lai and Mueller, 2021 ; Sawant et al, 2021 ) and are therefore crucial in the communication between cells of the immune system, neurons and glia. Fractalkine (CX3CL1) has received much interest as it is produced constitutively by neurons and restrains microglial activation.…”

“…Reinforcing this argument, few cytokine-related drug candidates have reached clinical trials, or those that have done so have proved insufficiently active or selective ( Poeta et al, 2019 ; Lai and Mueller, 2021 ). The difficulty may lie in the potency of many cytokines coupled with the need to target a limited number of immune system cells or a restricted region of CNS.…”

Small molecule-based immunomodulators for cancer therapy

“…While CXCL10 may enhance the antitumor immunity or cytotoxicity of CD8 + T cells. Thus, inhibiting chemokines or their receptors ( e.g., CXCL12/CXCR4) represents an attractive strategy for cancer immunotherapy 58 ( Fig. 3 C).…”

Chemokines and nanomaterials: interaction for useful immune-applications

“…Other molecules can also bind to chemokine receptors and antagonize chemokine interaction. For instance, peptides like [Tyr5,12, Lys7]-polyphemusin II (T22) [24] or small molecules, which are investigated for precision medicine therapies related to viral infection or cancer [25][26][27]. Chemokine-to-chemokine receptor binding is exploited in many ways in immunology and the development of nanotechnologies has increased these opportunities.…”