Open AccessAgonists for the Chemokine Receptor CXCR4
Author(s) -
Marilou Lefrançois,
MarieReine Lefebvre,
Geneviève Saint-Onge,
Philip E. Boulais,
Simon Lamothe,
Richard Leduc,
Pierre Lavigne,
Nikolaus Heveker,
Emanuel Escher
Publication year - 2011
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml200084n
Subject(s) - agonist , chimera (genetics) , chemokine receptor , receptor , chemokine , cxcr4 , chemistry , partial agonist , peptide , chemotaxis , g protein coupled receptor , microbiology and biotechnology , pharmacology , biology , biochemistry , gene
The development of agonists for the chemokine receptor CXCR4 could provide promising therapeutic candidates. On the basis of previously forwarded two site model of chemokine-receptor interactions, we hypothesized that linking the agonistic N-terminus of SDF-1 to the T140 backbone would yield new high-affinity agonists of CXCR4. We developed chimeras with the agonistic SDF-1 N-terminus grafted to a T140 side chain and tested their binding affinity and chemotactic agonist activity. While chimeras with the peptide grafted onto position 12 of T140 remained high-affinity antagonists, those bearing the peptide on position 14 were in part agonists. One chimera was a full CXCR4 agonist with 25 nM affinity, and several chimeras showed low nanomolar affinities with partial agonist activity. Our results confirmed that we have developed high-affinity agonists of CXCR4.
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