title: An antedrug of the CXCL12 neutraligand blocks experimental allergic asthma without systemic effect in mice.
abstract: 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.
authors: Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS/Université de Strasbourg, Faculté de Pharmacie, 74 Route du Rhin, 67401 Illkirch, France.
authors: François
authors: F
authors: Daubeuf
authors: Muriel
authors: M
authors: Hachet-Haas
authors: Patrick
authors: P
authors: Gizzi
authors: Vincent
authors: V
authors: Gasparik
authors: Dominique
authors: D
authors: Bonnet
authors: Valérie
authors: V
authors: Utard
authors: Marcel
authors: M
authors: Hibert
authors: Nelly
authors: N
authors: Frossard
authors: Jean-Luc
authors: JL
authors: Galzi
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019718:Receptors, CXCR4 / Q000378:metabolism
chemical_list: D018927:Anti-Asthmatic Agents; C514936:CXCR4 protein, mouse; D047188:Chalcones; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4