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https://hdl.handle.net/2440/99802
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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 1083-351X |
Statement of Responsibility: | 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 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1066781 |
Published version: | http://dx.doi.org/10.1074/jbc.m115.675108 |
Appears in Collections: | Aurora harvest 3 Molecular and Biomedical Science publications |
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