Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Department of Medicine, National Heart and Lung Institute (NHLI), Imperial College, London, United Kingdom.
Commun Biol. 2021 May 12;4(1):569. doi: 10.1038/s42003-021-02070-9.
Following the FDA-approval of the hematopoietic stem cell (HSC) mobilizer plerixafor, orally available and potent CXCR4 antagonists were pursued. One such proposition was AMD11070, which was orally active and had superior antagonism in vitro; however, it did not appear as effective for HSC mobilization in vivo. Here we show that while AMD11070 acts as a full antagonist, plerixafor acts biased by stimulating β-arrestin recruitment while fully antagonizing G protein. Consequently, while AMD11070 prevents the constitutive receptor internalization, plerixafor allows it and thereby decreases receptor expression. These findings are confirmed by the successful transfer of both ligands' binding sites and action to the related CXCR3 receptor. In vivo, plerixafor exhibits superior HSC mobilization associated with a dramatic reversal of the CXCL12 gradient across the bone marrow endothelium, which is not seen for AMD11070. We propose that the biased action of plerixafor is central for its superior therapeutic effect in HSC mobilization.
继 FDA 批准造血干细胞 (HSC) 动员剂培利西林后，人们开始研究口服有效的、强效的 CXCR4 拮抗剂。其中一个提案是 AMD11070，它具有口服活性，体外拮抗作用更强；然而，它在体内对 HSC 动员的效果似乎并不理想。在这里，我们证明尽管 AMD11070 作为完全拮抗剂发挥作用，但培利西林通过刺激β-arrestin 募集而表现出偏向性，同时完全拮抗 G 蛋白。因此，尽管 AMD11070 阻止了受体的组成性内化，但培利西林允许其内化，从而降低了受体表达。这些发现得到了成功转移两种配体的结合位点和作用到相关的 CXCR3 受体的证实。在体内，培利西林表现出优越的 HSC 动员作用，同时显著逆转了骨髓内皮细胞上的 CXCL12 梯度，而 AMD11070 则没有这种作用。我们提出，培利西林的偏向性作用是其在 HSC 动员治疗中优越疗效的核心。
