Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC.
Senhwa Biosciences, San Diego, California.
Med Res Rev. 2018 Jul;38(4):1188-1234. doi: 10.1002/med.21464. Epub 2017 Aug 2.
CXCR4 antagonists (e.g., Plerixafor ) 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.
CXCR4 拮抗剂（例如，plerixafor）已被成功验证为外周血造血干细胞移植的干细胞动员剂。CXCR4 拮抗剂的应用开创了细胞治疗的时代，为许多未满足的医疗需求（如肾损伤、缺血性中风、癌症和心肌梗死）开辟了潜在的治疗前景。在这篇综述中，我们首先介绍了 CXCR4 在多种细胞信号通路中的核心作用，并讨论了它在几种疾病进展中的参与。然后，我们从大量案例研究中突出了针对 CXCR4 的分子设计和优化策略，得出结论，多胺是首选的 CXCR4 结合配体，而不是其他结构选择，可能是通过模拟高度带正电荷的天然配体 CXCL12。这些结果可以通过计算机辅助对接进入 CXCR4 晶体结构进一步证明，其中结合腔的主要和次要亚口袋都被认为具有重要的功能。最后，从临床角度来看，CXCR4 拮抗剂可以将具有长期造血重建能力的造血干/祖细胞动员到外周血中，有望替代手术获得的骨髓细胞成为干细胞移植的首选来源。
