Biased Action of the CXCR4-targeting Drug Plerixafor is Essential for Its Superior Hematopoietic Stem Cell Mobilization

Overview

Journal Commun Biol

Specialty Biology

Date 2021 May 13

PMID 33980979

Citations 19

Authors

Astrid S Jorgensen

Viktorija Daugvilaite

Katia De Filippo

Christian Berg

Masa Mavri

Tau Benned-Jensen

Goda Juzenaite

Gertrud Hjorto

Sara Rankin

Jon Vabeno

Mette M Rosenkilde

Affiliations

Soon will be listed here.

Abstract

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.

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References

Berg C, Daugvilaite V, Steen A, Jorgensen A, Vabeno J, Rosenkilde M . Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4. ACS Chem Biol. 2018; 13(4):881-886. DOI: 10.1021/acschembio.8b00061. View

Roed S, Wismann P, Underwood C, Kulahin N, Iversen H, Cappelen K . Real-time trafficking and signaling of the glucagon-like peptide-1 receptor. Mol Cell Endocrinol. 2013; 382(2):938-49. DOI: 10.1016/j.mce.2013.11.010. View

McGrath K, Koniski A, Maltby K, McGann J, Palis J . Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4. Dev Biol. 1999; 213(2):442-56. DOI: 10.1006/dbio.1999.9405. View

Dar A, Schajnovitz A, Lapid K, Kalinkovich A, Itkin T, Ludin A . Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells. Leukemia. 2011; 25(8):1286-1296. PMC: 4175714. DOI: 10.1038/leu.2011.62. View

Hitchinson B, Eby J, Gao X, Guite-Vinet F, Ziarek J, Abdelkarim H . Biased antagonism of CXCR4 avoids antagonist tolerance. Sci Signal. 2018; 11(552). PMC: 6422681. DOI: 10.1126/scisignal.aat2214. View

Haribabu B, Richardson R, Fisher I, Sozzani S, Peiper S, Horuk R . Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and internalization. J Biol Chem. 1997; 272(45):28726-31. DOI: 10.1074/jbc.272.45.28726. View

Zhou X, He Y, de Waal P, Gao X, Kang Y, Van Eps N . Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors. Cell. 2017; 170(3):457-469.e13. PMC: 5567868. DOI: 10.1016/j.cell.2017.07.002. View

Rosenkilde M, Andersen M, Nygaard R, Frimurer T, Schwartz T . Activation of the CXCR3 chemokine receptor through anchoring of a small molecule chelator ligand between TM-III, -IV, and -VI. Mol Pharmacol. 2006; 71(3):930-41. DOI: 10.1124/mol.106.030031. View

Signoret N, Rosenkilde M, Klasse P, Schwartz T, Malim M, Hoxie J . Differential regulation of CXCR4 and CCR5 endocytosis. J Cell Sci. 1998; 111 ( Pt 18):2819-30. DOI: 10.1242/jcs.111.18.2819. View

10.

Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Shieh J . Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood. 2001; 97(11):3354-60. DOI: 10.1182/blood.v97.11.3354. View

11.

Fraile-Ramos A, Kledal T, Pelchen-Matthews A, Bowers K, Schwartz T, Marsh M . The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling. Mol Biol Cell. 2001; 12(6):1737-49. PMC: 37337. DOI: 10.1091/mbc.12.6.1737. View

12.

Dar A, Goichberg P, Shinder V, Kalinkovich A, Kollet O, Netzer N . Chemokine receptor CXCR4-dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells. Nat Immunol. 2005; 6(10):1038-46. DOI: 10.1038/ni1251. View

13.

Mosi R, Anastassova V, Cox J, Darkes M, Idzan S, Labrecque J . The molecular pharmacology of AMD11070: an orally bioavailable CXCR4 HIV entry inhibitor. Biochem Pharmacol. 2011; 83(4):472-9. DOI: 10.1016/j.bcp.2011.11.020. View

14.

De Clercq E . Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration. Antivir Chem Chemother. 2019; 27:2040206619829382. PMC: 6379795. DOI: 10.1177/2040206619829382. View

15.

Jensen P, Nygaard R, Thiele S, Elder A, Zhu G, Kolbeck R . Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8. Mol Pharmacol. 2007; 72(2):327-40. DOI: 10.1124/mol.106.035543. View

16.

Alkhatib G . The biology of CCR5 and CXCR4. Curr Opin HIV AIDS. 2009; 4(2):96-103. PMC: 2718543. DOI: 10.1097/COH.0b013e328324bbec. View

17.

Marchese A, Raiborg C, Santini F, Keen J, Stenmark H, Benovic J . The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev Cell. 2003; 5(5):709-22. DOI: 10.1016/s1534-5807(03)00321-6. View

18.

Hatse S, Princen K, Bridger G, De Clercq E, Schols D . Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett. 2002; 527(1-3):255-62. DOI: 10.1016/s0014-5793(02)03143-5. View

19.

Murphy P, Baggiolini M, Charo I, Hebert C, Horuk R, Matsushima K . International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev. 2000; 52(1):145-76. View

20.

Foster S, Brauner-Osborne H . Investigating Internalization and Intracellular Trafficking of GPCRs: New Techniques and Real-Time Experimental Approaches. Handb Exp Pharmacol. 2017; 245:41-61. DOI: 10.1007/164_2017_57. View