Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization

Jørgensen, Astrid S. (avtor), Daugvilaite, Viktorija (avtor), De Filippo, Katia (avtor), Berg, Christian (avtor), Mavri, Maša (avtor), Benned-Jensen, Tau (avtor), Juzenaite, Goda (avtor), Hjortø, Gertrud Malene (avtor), Rankin, Sara (avtor), Våbenø, Jon (avtor), Rosenkilde, Mette Marie (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: stem cells, hematopoietic stem cells, GTP-binding proteins, molecular medicine, receptor pharmacology
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: VF - Veterinarska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: 12 str.
• Številčenje: Vol. 4, art. 569
• PID: 20.500.12556/RUL-137259
• UDK: 577
• ISSN pri članku: 2399-3642
• DOI: 10.1038/s42003-021-02070-9
• COBISS.SI-ID: 110393859
• Datum objave v RUL: 08.06.2022

Gradivo je del revije

• Naslov: Communications biology
• Skrajšan naslov: Commun. biolog.
• Založnik: Springer Nature
• ISSN: 2399-3642
• COBISS.SI-ID: 5134671

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 12.05.2021