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Type: Journal article
Title: Dual targeting of the chemokine receptors CXCR4 and ACKR3 with novel engineered chemokines
Author: Hanes, M.
Salanga, C.
Chowdry, A.
Comerford, I.
McColl, S.
Kufareva, I.
Handel, T.
Citation: Journal of Biological Chemistry, 2015; 290(37):22385-22397
Publisher: American Society for Biochemistry and Molecular Biology
Issue Date: 2015
ISSN: 1083-351X
Statement of
Melinda S. Hanes, Catherina L. Salanga, Arnab B. Chowdry, Iain Comerford, Shaun R. McColl, Irina Kufareva, and Tracy M. Handel
Abstract: The chemokine CXCL12 and its G protein-coupled receptors CXCR4 and ACKR3 are implicated in cancer and inflammatory and autoimmune disorders and are targets of numerous antagonist discovery efforts. Here, we describe a series of novel, high affinity CXCL12-based modulators of CXCR4 and ACKR3 generated by selection of N-terminal CXCL12 phage libraries on live cells expressing the receptors. Twelve of 13 characterized CXCL12 variants are full CXCR4 antagonists, and four have Kd values <5 nm. The new variants also showed high affinity for ACKR3. The variant with the highest affinity for CXCR4, LGGG-CXCL12, showed efficacy in a murine model for multiple sclerosis, demonstrating translational potential. Molecular modeling was used to elucidate the structural basis of binding and antagonism of selected variants and to guide future designs. Together, this work represents an important step toward the development of therapeutics targeting CXCR4 and ACKR3.
Keywords: C-X-C chemokine receptor type 4 (CXCR-4); chemokine; G protein-coupled receptor (GPCR;) phage display; signaling; ACKR3; CXCL12; SDF-1a; chemokine receptors; experimental autoimmune encephalomyelitis (EAE)
Rights: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M115.675108
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Molecular and Biomedical Science publications

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