Ccr2 antagonist peptides

Abstract

The invention relates to a peptide comprising the following amino acid sequence Thr-Phe-Leu-Lys or Thr-Phe-Leu-Lys-Cys, useful as a CCR2 non competitive antagonist peptide.

1 .- 17  (canceled) 
     
     
         18 . A peptide of no more than 18 amino acids, comprising:
 amino acid sequence Thr-Phe-Leu-Lys (SEQ ID NO:17).   a sequence deriving from SEQ ID NO:17 by one or more chemical modifications that confer resistance to proteolysis;   or a sequence deriving from SEQ ID NO:17 by one or more conservative substitutions.   
     
     
         19 . The peptide of  claim 18  comprising:
 amino acid sequence Thr-Phe-Leu-Lys-Cys (SEQ ID NO:1). 
 a sequence deriving from SEQ ID NO:1 by one or more chemical modifications that confer resistance to proteolysis; 
 or a sequence deriving from SEQ ID NO:1 by one or more conservative substitutions. 
 
     
     
         20 . The peptide of  claim 19 , consisting of
 X1-TFLKC-X2 (SEQ ID NO:2),   wherein X1 is absent, is glycine or represents an amino acid sequence selected from the group consisting of AG, LG, YLG, and HYLG;   and X2 independently is absent, is methionine, or represents an aminoacid sequence selected from the group consisting of MA, MAN, MANG, MANGF, MANGFV, MANGFVW, MANGFVWE, and MANGFVWEN;   or a sequence deriving from SEQ ID NO:2 by one or more chemical modifications that confer resistance to proteolysis;   or a sequence deriving from SEQ ID NO:2 by one or more conservative substitutions.   
     
     
         21 . The peptide of  claim 18 , consisting of
 X1-TFLK-X3 (SEQ ID NO:18),   wherein X1 is absent, is glycine or represents an aminoacid sequence selected from the group consisting of AG, LG, YLG, and HYLG;   and X3 independently is absent, or is alanine   or a sequence deriving from SEQ ID NO:18 by one or more chemical modifications that confer resistance to proteolysis;   or a sequence deriving from SEQ ID NO:18 by one or more conservative substitutions.   
     
     
         22 . The peptide of  claim 18 , selected from the group consisting of 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                     
                   LGTFLKC; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 4) 
                 
                     
                   HYLGTFLKCMA; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   LGTFLKCMA; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   HYLGTFLKC; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   GTFLKCMANGF; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 8) 
                 
                     
                   TFLKCMANGFV; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                   HYLGTFLKCMANGFVWEN; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 19) 
                 
                     
                   LGTFLK 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 20) 
                 
                     
                   AGTFLKC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 21) 
                 
                     
                   LGTFLKA 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 22) 
                 
                     
                   GTFLK 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 23) 
                 
                     
                   AGTFLKA 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         a sequence deriving from any of SEQ ID NO:3 to 10, or 19 to 23 by one or more chemical modifications that confer resistance to proteolysis; 
         and a sequence deriving from any of SEQ ID NO:3 to 9 or 19 to 23 by one or more conservative substitutions. 
       
     
     
         23 . The peptide of  claim 22  that consists of LGTFLKC (SEQ ID NO:3). 
     
     
         24 . The peptide of  claim 18 , wherein all or part of the amino acids are in D configuration. 
     
     
         25 . The peptide of  claim 18 , wherein all or part of the amino acids are in L configuration. 
     
     
         26 . The peptide of  claim 18 , that consists of a peptide of no more than 15 amino acids, preferably no more than 10 amino acids. 
     
     
         27 . A compound that comprises a peptide as defined in  claim 18  linked to at least one non-peptide moiety. 
     
     
         28 . The compound of  claim 27 , wherein the non-peptide moiety is polyethylene gycol. 
     
     
         29 . A pharmaceutical composition, comprising the peptide as defined in  claim 18 , in association with a pharmaceutically acceptable carrier. 
     
     
         30 . A method of treating a CCR2 mediated syndrome, disorder or disease in a patient, which method comprises administering the patient with the pharmaceutical composition of  claim 29 . 
     
     
         31 . The method according to  claim 30 , wherein the CCR2 mediated syndrome, disorder or disease is selected from the group consisting of ophthalmic disorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphyloccocia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, asthma, allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, and carcinomas of the bladder, breast, cervix, colon, lung, prostate, or stomach. 
     
     
         32 . The method according to  claim 31 , wherein the syndrome, disorder or disease is age-related macular degeneration or retinal degeneration. 
     
     
         33 . The method according to  claim 31 , wherein the syndrome, disorder or disease is a cardiovascular disease, especially ischemia of lower members or of the heart, or preventing or treating atherogenesis. 
     
     
         34 . The method according to  claim 31 , wherein the syndrome, disorder or disease is pain, in particular peripheral pain, such as pain from the sciatic nerve. 
     
     
         35 . A pharmaceutical composition, comprising the compound as defined in  claim 27 , in association with a pharmaceutically acceptable carrier. 
     
     
         36 . A method of treating a CCR2 mediated syndrome, disorder or disease in a patient, which method comprises administering the patient with the pharmaceutical composition of  claim 35 . 
     
     
         37 . The method according to  claim 36 , wherein the CCR2 mediated syndrome, disorder or disease is selected from the group consisting of ophthalmic disorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphyloccocia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, asthma, allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, and carcinomas of the bladder, breast, cervix, colon, lung, prostate, or stomach. 
     
     
         38 . The method according to  claim 37 , wherein the syndrome, disorder or disease is age-related macular degeneration or retinal degeneration. 
     
     
         39 . The method according to  claim 37 , wherein the syndrome, disorder or disease is a cardiovascular disease, especially ischemia of lower members or of the heart, or preventing or treating atherogenesis. 
     
     
         40 . The method according to  claim 37 , wherein the syndrome, disorder or disease is pain, in particular peripheral pain, such as pain from the sciatic nerve.