CXCR4 antagonists (e.g., Plerixafor^TM) have been successfully validated as stem cell mobilizers for peripheral blood stem cell transplantation. Applications of the CXCR4 antagonists have heralded the era of cell‐based therapy and opened a potential therapeutic horizon for many unmet medical needs such as kidney injury, ischemic stroke, cancer, and myocardial infarction. In this review, we first introduce the central role of CXCR4 in diverse cellular signaling pathways and discuss its involvement in several disease progressions. We then highlight the molecular design and optimization strategies for targeting CXCR4 from a large number of case studies, concluding that polyamines are the preferred CXCR4‐binding ligands compared to other structural options, presumably by mimicking the highly positively charged natural ligand CXCL12. These results could be further justified with computer‐aided docking into the CXCR4 crystal structure wherein both major and minor subpockets of the binding cavity are considered functionally important. Finally, from the clinical point of view, CXCR4 antagonists could mobilize hematopoietic stem/progenitor cells with long‐term repopulating capacity to the peripheral blood, promising to replace surgically obtained bone marrow cells as a preferred source for stem cell transplantation.

中文翻译：

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在干细胞动员，HIV感染，缺血性疾病和肿瘤学中利用CXCR4拮抗剂

CXCR4拮抗剂（例如Plerixafor ^TM）已被成功验证为用于外周血干细胞移植的干细胞动员剂。CXCR4拮抗剂的应用预示了细胞疗法的时代，并为许多未满足的医疗需求（例如肾脏损伤，缺血性中风，癌症和心肌梗塞）开辟了潜在的治疗前景。在这篇综述中，我们首先介绍CXCR4在多种细胞信号通路中的核心作用，并讨论其在几种疾病进展中的作用。然后，我们从大量案例研究中重点介绍了针对CXCR4的分子设计和优化策略，认为与其他结构选择相比，聚胺是首选的CXCR4结合配体，大概是通过模仿带正电荷的天然配体CXCL12来实现的。通过计算机辅助对接到CXCR4晶体结构中，可以进一步证明这些结果的正确性，其中结合腔的主要和次要子口袋都被认为在功能上很重要。最后，从临床角度来看，CXCR4拮抗剂可以将具有长期繁殖能力的造血干/祖细胞动员到外周血中，有望替代外科手术获得的骨髓细胞作为干细胞移植的首选来源。