An Antedrug of the CXCL12 Neutraligand Blocks Experimental Allergic Asthma without Systemic Effect in Mice

• Published in: The Journal of biological chemistry 2013-04, Vol.288 (17), p.11865-11876
• Main Authors: Daubeuf, François, Hachet-Haas, Muriel, Gizzi, Patrick, Gasparik, Vincent, Bonnet, Dominique, Utard, Valérie, Hibert, Marcel, Frossard, Nelly, Galzi, Jean-Luc
• Format: Article
• Language: English
• Subjects: Animals; Anti-Asthmatic Agents - chemistry; Anti-Asthmatic Agents - pharmacology; Asthma - drug therapy; Asthma - metabolism; Asthma - pathology; Chalcones - chemistry; Chalcones - pharmacology; Chemical Sciences; Chemokine CXCL12 - antagonists & inhibitors; Chemokine CXCL12 - metabolism; Chemokines; Drug Evaluation, Preclinical; Eosinophils - metabolism; Eosinophils - pathology; HEK293 Cells; Humans; Inflammation; Life Sciences; Male; Medicinal Chemistry; Mice; Mice, Inbred BALB C; Pharmaceutical sciences; Pharmacology; Receptors, CXCR4 - metabolism; Signal Transduction; Soft Drugs
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.449348

The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in normal tissue patterning but also in tumor cell growth and survival as well as in the recruitment of immune and inflammatory cells, as successfully demonstrated using agents that block either CXCL12 or CXCR4. In order to achieve selectivity in drug action on the CXCR4/CXCL12 pair, in particular in the airways, drugs should be delivered as selectively as possible in the treated tissue and should not diffuse in the systemic circulation, where it may reach undesired organs. To this end, we used a previously unexploited Knoevenagel reaction to create a short lived drug, or soft drug, based on the CXCL12-neutralizing small molecule, chalcone 4, which blocks binding of CXCL12 to CXCR4. We show that the compound, carbonitrile-chalcone 4, blocks the recruitment of eosinophils to the airways in ovalbumin-sensitized and challenged mice in vivo when administered directly to the airways by the intranasal route, but not when administered systemically by the intraperitoneal route. We show that the lack of effect at a distant site is due to the rapid degradation of the molecule to inactive fragments. This approach allows selective action of the CXCL12 neutraligands although the target protein is widely distributed in the organism. Background: The chemokine CXCL12 and its receptor CXCR4 are widely distributed and contribute to the physiopathology of inflammation. Results: Recruitment of eosinophils in the inflamed airway is selectively attenuated by short lived antagonists that block CXCL12-mediated activation of CXCR4. Conclusion: CXCL12/CXCR4 signaling regulates local leukocyte-mediated inflammation. Significance: Antedrugs of neutraligands allow dissecting the physiological role of chemokines, especially when expression occurs in multiple tissues.