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Biased antagonism of CXCR4 avoids antagonist tolerance. Sci Signal 2018 10 16;11(552)



Pubmed ID


Pubmed Central ID




Scopus ID

2-s2.0-85055022783   6 Citations


Repeated dosing of drugs targeting G protein-coupled receptors can stimulate antagonist tolerance, which reduces their efficacy; thus, strategies to avoid tolerance are needed. The efficacy of AMD3100, a competitive antagonist of the chemokine receptor CXCR4 that mobilizes leukemic blasts from the bone marrow into the blood to sensitize them to chemotherapy, is reduced after prolonged treatment. Tolerance to AMD3100 increases the abundance of CXCR4 on the surface of leukemic blasts, which promotes their rehoming to the bone marrow. AMD3100 inhibits both G protein signaling by CXCR4 and β-arrestin1/2-dependent receptor endocytosis. We demonstrated that biased antagonists of G protein-dependent chemotaxis but not β-arrestin1/2 recruitment and subsequent receptor endocytosis avoided tolerance. The peptide antagonist X4-2-6, which is derived from transmembrane helix 2 and extracellular loop 1 of CXCR4, limited chemotaxis and signaling but did not promote CXCR4 accumulation on the cell surface or cause tolerance. The activity of X4-2-6 was due to its distinct mechanism of inhibition of CXCR4. The peptide formed a ternary complex with the receptor and its ligand, the chemokine CXCL12. Within this complex, X4-2-6 released the portion of CXCL12 critical for receptor-mediated activation of G proteins but enabled the rest of the chemokine to recruit β-arrestins to the receptor. In contrast, AMD3100 displaced all components of the chemokine responsible for CXCR4 activation. We further identified a small molecule with similar biased antagonist properties to those of X4-2-6, which may provide a viable alternative to patients when antagonist tolerance prevents drugs from reaching efficacy.

Author List

Hitchinson B, Eby JM, Gao X, Guite-Vinet F, Ziarek JJ, Abdelkarim H, Lee Y, Okamoto Y, Shikano S, Majetschak M, Heveker N, Volkman BF, Tarasova NI, Gaponenko V


Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

CHO Cells
Chemokine CXCL12
Drug Tolerance
GTP-Binding Proteins
Heterocyclic Compounds
Jurkat Cells
Protein Domains
Receptors, CXCR4
Signal Transduction
THP-1 Cells
beta-Arrestin 1
beta-Arrestin 2
jenkins-FCD Prod-444 eb4ebd1a08581aba961d3befd3b851a3c3ec6b46