Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology
Lun Kelvin Tsou1, Ying-Huey Huang2, Jen-Shin Song1
1Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC.
Abstract:
CXCR4 antagonists (e.g., PlerixaforTM ) 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.
Insights
CXCR4 antagonists are effective stem cell mobilizers for transplantation. Polyamines show promise as preferred ligands for targeting CXCR4 in various diseases and therapies.
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- The chemokine receptor CXCR4 plays a crucial role in diverse cellular signaling pathways.
- CXCR4 is implicated in the progression of various diseases, including cancer, kidney injury, ischemic stroke, and myocardial infarction.
- CXCR4 antagonists, such as Plerixafor™, are validated stem cell mobilizers for transplantation.
Purpose of the Study:
- To review the central role of CXCR4 in cellular signaling and disease.
- To highlight molecular design and optimization strategies for CXCR4-targeting agents.
- To discuss the clinical potential of CXCR4 antagonists in cell-based therapies.
Main Methods:
- Review of literature on CXCR4 signaling and disease involvement.
- Analysis of molecular design and optimization strategies for CXCR4 antagonists.
- Case studies on CXCR4-binding ligands, including polyamines.
- Computer-aided docking into the CXCR4 crystal structure.
Main Results:
- Polyamines emerge as preferred CXCR4-binding ligands, likely mimicking the natural ligand CXCL12.
- Both major and minor subpockets of the CXCR4 binding cavity are functionally important.
- CXCR4 antagonists can mobilize hematopoietic stem/progenitor cells to peripheral blood.
Conclusions:
- CXCR4 antagonists offer a promising therapeutic horizon for unmet medical needs.
- Polyamines represent a promising structural class for developing CXCR4-targeting drugs.
- CXCR4 antagonists may replace bone marrow harvesting for stem cell transplantation.
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