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Agonists for the Chemokine Receptor CXCR4
Authors:Lefrançois Marilou  Lefebvre Marie-Reine  Saint-Onge Geneviève  Boulais Philip E  Lamothe Simon  Leduc Richard  Lavigne Pierre  Heveker Nikolaus  Escher Emanuel
Affiliation:Département de Pharmacologie, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada;Centre de Recherche, Hôpital Sainte-Justine, Montréal, Québec H3T 1C5, Canada;§Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada
Abstract:
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.
Keywords:CXCR4   agonist   CXCL12   T140   chemotaxis
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