Novel antagonists of cxcr3-binding cxc chemokines

Details Novel antagonists of cxcr3-binding cxc chemokines Novel antagonists of cxcr3-binding cxc chemokines

C - Chemistry, Metallurgy

07

K

C07K 14/52 (2006.01) A61K 38/19 (2006.01) C12N 15/19 (2006.01)

Patent

CA 2489298

Novel antagonists of CXCR3 -binding CXC chemokines, and in particular of human CXCL11, can be obtained by generating mutants of such chemokines in which the binding to glycosaminoglycans (GAGs) is impaired due to non-conservative substitutions of amino acids involved in this interaction. Compounds prepared in accordance with the present invention can be used to block the activity of CXCR3-binding CXC chemokines on CXCR3 -expressing cells, thereby providing therapeutic compositions for use in the treatment or prevention of diseases related to excessive activated T cells migration, such as graft rejection and autoimmune diseases, and of diseases needing an increase of vascularization, such as ischemic heart disease.

L'invention concerne de nouveaux antagonistes de chimiokines CXC à liaison CXCR3, et plus particulièrement de CXCL11 humaines, que l'on peut obtenir en générant des mutants de ces chimiokines dans lesquelles la liaison à des glycosaminoglycanes (GAG) est diminuée en raison des substitutions non conservatrices d'acides aminés impliqués dans cette interaction. Les composés préparés selon la présente invention peuvent être utilisés pour bloquer l'activité des chimiokines CXC à liaison CXCR3 sur des cellules exprimant CXCR3, ce qui permet d'obtenir des compositions thérapeutiques que l'on utilise dans le traitement ou la prévention de maladies associées à une migration de lymphocytes T activés en excès, notamment le rejet d'une greffe et les maladies auto-immunes, et de maladies nécessitant une augmentation de vascularisation, notamment la cardiopathie ischémique.

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