Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States.
Front Immunol. 2023 Jul 28;14:1184014. doi: 10.3389/fimmu.2023.1184014. eCollection 2023.
Chemokine G-protein coupled receptors are validated drug targets for many diseases, including cancer, neurological, and inflammatory disorders. Despite much time and effort spent on therapeutic development, very few chemokine receptor antagonists are approved for clinical use. Among potential reasons for the slow progress in developing chemokine receptor inhibitors, antagonist tolerance, a progressive reduction in drug efficacy after repeated administration, is likely to play a key role. The mechanisms leading to antagonist tolerance remain poorly understood. In many cases, antagonist tolerance is accompanied by increased receptor concentration on the cell surface after prolonged exposure to chemokine receptor antagonists. This points to a possible role of altered receptor internalization and presentation on the cell surface, as has been shown for agonist (primarily opioid) tolerance. In addition, examples of antagonist tolerance in the context of other G-protein coupled receptors suggest the involvement of noncanonical signal transduction in opposing the effects of the antagonists. In this review, we summarize the available progress and challenges in therapeutic development of chemokine receptor antagonists, describe the available knowledge about antagonist tolerance, and propose new avenues for future investigation of this important phenomenon. Furthermore, we highlight the modern methodologies that have the potential to reveal novel mechanisms leading to antagonist tolerance and to propel the field forward by advancing the development of potent "tolerance-free" antagonists of chemokine receptors.
趋化因子 G 蛋白偶联受体是许多疾病（包括癌症、神经和炎症性疾病）的有效药物靶点。尽管在治疗开发方面投入了大量时间和精力，但只有少数趋化因子受体拮抗剂被批准用于临床使用。在开发趋化因子受体抑制剂进展缓慢的潜在原因中，拮抗剂耐受（反复给予药物后药物疗效逐渐降低）可能起着关键作用。导致拮抗剂耐受的机制仍知之甚少。在许多情况下，拮抗剂耐受伴随着在长期暴露于趋化因子受体拮抗剂后细胞表面上受体浓度的增加。这表明改变的受体内化和在细胞表面上的呈现可能起作用，如激动剂（主要是阿片类药物）耐受所表明的那样。此外，其他 G 蛋白偶联受体中拮抗剂耐受的例子表明，非典型信号转导参与拮抗拮抗剂的作用。在这篇综述中，我们总结了趋化因子受体拮抗剂治疗开发方面的现有进展和挑战，描述了关于拮抗剂耐受的现有知识，并提出了未来研究这一重要现象的新途径。此外，我们强调了具有揭示导致拮抗剂耐受的新机制的潜力的现代方法，并通过推进趋化因子受体的有效“无耐受”拮抗剂的开发来推动该领域向前发展。
