IL-8小分子调节剂的研究进展、挑战与未来展望
Research Progress, Challenges, and Future Perspectives of Small-Molecule Modulators Targeting IL-8
DOI: 10.12677/hjmce.2026.142011, PDF,    科研立项经费支持
作者: 朱怡萍, 卢 帅：中国药科大学理学院，江苏 南京；陆 涛*：中国药科大学理学院，江苏 南京；中国药科大学多靶标天然药物全国重点实验室，江苏 南京
关键词: 白介素8；G蛋白偶联受体1/2；小分子调节剂；变构抑制剂；免疫调节；Interleukin-8； G Protein-Coupled Receptor 1/2； Small-Molecule Modulators； Allosteric Inhibitors； Immune Regulation
摘要: 白介素(Interleukin, IL)家族是一类在免疫系统中发挥关键作用的细胞因子家族，其中IL-8 (CXCL8)作为核心ELR+ CXC趋化因子，不仅参与调节中性粒细胞趋化与活化，还广泛参与炎症性疾病进展与肿瘤微环境塑造，现有靶向IL-8及其受体CXCR1/CXCR2的生物大分子药物已展现出一定的治疗潜力。尽管CXCR1与CXCR2具有高度序列同源性，且其与IL-8的蛋白相互作用界面复杂，开发选择性小分子调节剂面临较大挑战，但近年来基于变构机制的多种小分子抑制剂已取得重要突破。越来越多的成功案例表明，靶向趋化因子受体胞内变构位点的小分子策略是可行的。因此，CXCR1/2小分子调节剂的研发已引起广泛关注。在本篇文章中，我们系统讨论了IL-8/CXCR1/2信号轴的结构基础与生物学功能，并列举了代表性的选择性CXCR2抑制剂和CXCR1/2双受体抑制剂，总结其发现历程、结构优化策略及临床试验进展，同时还展望了下一代抑制剂的开发方向与临床应用潜力。
Abstract: The interleukin (IL) family comprises a group of cytokines that play pivotal roles in the immune system. Among them, IL-8 (CXCL8), a prototypical ELR⁺ CXC chemokine, not only regulates neutrophil chemotaxis and activation but is also extensively involved in the progression of inflammatory diseases and the shaping of the tumor microenvironment. Existing biologics targeting IL-8 and its receptors CXCR1/CXCR2 have demonstrated certain therapeutic potential. Although the high sequence homology between CXCR1 and CXCR2, together with the complex protein-protein interaction interface with IL-8, poses significant challenges for the development of selective small-molecule modulators. Recent years have witnessed important breakthroughs in the discovery of various small-molecule inhibitors exploiting allosteric mechanisms. Accumulating successful cases indicate that small-molecule strategies targeting the intracellular allosteric sites of chemokine receptors are feasible. Consequently, the research and development of small-molecule modulators of CXCR1/2 have attracted considerable attention. In this review, we systematically discuss the structural basis and biological functions of the IL-8/CXCR1/2 signaling axis, highlight representative selective CXCR2 inhibitors and dual CXCR1/2 inhibitors, summarize their discovery history, structural optimization strategies, and clinical trial progress, and also provide perspectives on the future development directions and clinical application potential of next-generation inhibitors.
文章引用：朱怡萍, 卢帅, 陆涛. IL-8小分子调节剂的研究进展、挑战与未来展望[J]. 药物化学, 2026, 14(2): 107-118. https://doi.org/10.12677/hjmce.2026.142011

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