US2014249091A1PendingUtilityA1

Delta-Opioid Receptor Selective Analgesics

Assignee: BIOUSIAN BIOSYSTEMS INCPriority: Dec 8, 2008Filed: Oct 8, 2013Published: Sep 4, 2014
Est. expiryDec 8, 2028(~2.4 yrs left)· nominal 20-yr term from priority
C07K 9/001A61P 25/00C07K 7/06A61P 29/02
53
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Claims

Abstract

Methods and materials are provided for the production of glycosylated peptides that exhibit high affinity and specificity for delta opioid receptors. The methods and materials of the present invention may be used for treatment of conditions involving pain, such as acute pain and nociceptic pain, neuralgia and myalgia.

Claims

exact text as granted — not AI-modified
1 . A glycosylated peptide comprising the following amino acid sequence: 
       
         
           
                 
                 
               
                     
                   SEQ ID NO 1 
                 
                     
                   X1-X2-X3-X4-X5-X6-X7-W 
                 
             
                
                
               
            
           
         
       
       wherein:
 W is selected from NH2 and OH; 
 X1 is Y; 
 X2 is selected from dAla and dMet; 
 X3 is F; 
 X4 is selected from H, E, D and Q; 
 X5 is selected from L, V, I, C and Y; 
 X6 is selected from M, A, V, I, D, L, C, P and H; 
 X7 is selected from S, T, D, G, N, A and K; 
 
       and wherein at least one of X3, X6 and X7 is glycosylated. 
     
     
         2 . A glycosylated peptide according to  claim 1 , wherein at least one of X3, X6 and X7 is glycosylated with a sugar residue selected from the group consisting of glucose; galactose; xylose; fructose; mannose; fucose; ribose; deoxyribose; arabinose; rhamnose; sucrose; trehalose; saccharose; maltose; and lactose. 
     
     
         3 . A glycosylated peptide according to  claim 1 , comprising an amino acid sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   SEQ ID NO 2 
                 
                     
                   Y-dMet-F-H-L-M-Ser(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 3 
                 
                     
                   Y-dAla-F-H-L-A-Ser(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 4 
                 
                     
                   Y-dMet-F-H-L-M-Thr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 5 
                 
                     
                   Y-dAla-F-H-L-A-Thr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 6 
                 
                     
                   Y-dMet-F-H-L-M-dSer(beta-D-Glc)NH2; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   SEQ ID NO 7 
                 
                     
                   Y-dAla-F-H-L-A-dSer(beta-D-Glc)NH2. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         4 . A glycosylated peptide comprising the following amino acid sequence: 
       
         
           
                 
                 
               
                     
                   SEQ ID NO 8 
                 
                     
                   X1-X2-X3-X4-X5-X6-X7-W 
                 
             
                
                
               
            
           
         
       
       wherein:
 W is selected from NH2 and OH; 
 X1 is Y; 
 X2 is selected from dAla and dMet; 
 X3 is selected from F and A; 
 X4 is selected from H, E, D and Q; 
 X5 is selected from Nva, Nle, L, V, I, C and Y; 
 X6 is selected from Nva, Nle, L, V, I, M, A, D, C, P and H; 
 X7 is selected from S, dSer, T, dThr, D, G, N, A and K; 
 
       and wherein at least one of X3, X6 and X7 is glycosylated. 
     
     
         5 . A glycosylated peptide according to  claim 4 , wherein at least one of X3, X6 and X7 is glycosylated with a sugar residue selected from the group consisting of glucose, galactose, xylose, fructose, mannose, fucose, ribose, deoxyribose, arabinose, rhamnose, sucrose, trehalose, saccharose, maltose, and lactose. 
     
     
         6 . A glycosylated peptide according to  claim 4 , comprising an amino acid sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   SEQ ID NO 9 
                 
                     
                   Y-dAla-F-E-Nva-Nva-Ser(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 10 
                 
                     
                   Y-dAla-F-E-Nle-Nle-Ser(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 11 
                 
                     
                   Y-dAla-F-E-Nva-Nva-Thr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 12 
                 
                     
                   Y-dAla-F-H-Nle-Nle-Thr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 13 
                 
                     
                   Y-dAla-F-H-Nva-Nva-dSer(beta-D-Glc)NH2; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   SEQ ID NO 14 
                 
                     
                   Y-dAla-F-H-Nle-Nle-dSer(beta-D-Glc)NH2. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         7 . A glycosylated peptide comprising the following amino acid sequence: 
       
         
           
                 
                 
               
                     
                   SEQ ID NO 15 
                 
                     
                   X1-X2-X3-X4-X5-X6-X7-Z-W 
                 
             
                
                
               
            
           
         
       
       wherein:
 X1 is Y; 
 X2 is selected from dAla and dMet; 
 X3 is F; 
 X4 is selected from H, E, D and Q; 
 X5 is selected from L, V, Nva, Nle, I, C and Y; 
 X6 is selected from L, V, Nva, Nle, I, M, A, D, L, C, P and H; 
 X7 is selected from S, dSer, T, dThr, D, G, N, A and K; 
 Z is selected from a sequence of 0 to 5 amino acids; 
 W is selected from NH2 and OH; 
 
       and wherein at least one of X3, X6 and X7 is glycosylated. 
     
     
         8 . A glycopeptide of  claim 7 , wherein at least one of X3, X6 and X7 is glycosylated with a sugar residue selected from the group consisting of glucose; galactose; xylose; fructose; mannose; fucose; ribose; deoxyribose; arabinose; rhamnose; sucrose; trehalose; saccharose; maltose; and lactose. 
     
     
         9 . A glycosylated peptide comprising the following amino acid sequence: 
       
         
           
                 
                 
               
                     
                   SEQ ID NO 16 
                 
                     
                   X1-X2-X3-X4-X5-X6-X7-Z-W 
                 
             
                
                
               
            
           
         
       
       wherein:
 X1 is selected from Y; Dmt and Tmt; 
 X2 is selected from dAla; dMet; dVal; and B; 
 X3 is selected from F; Tic and Nmf; 
 X4 is selected from H, E, D; Q and F; 
 X5 is selected from L, V, I, C, Y, A, Nva and Nle; 
 X6 is selected from M, V, I, D, L, C, P, H, A, T, Nva and Nle; 
 X7 is selected from D, G, N, S, A, K, T, dSer, and dThr; 
 Z is selected from a sequence of 0 to 5 amino acids; 
 W is selected from NH2 and OH; 
 
       and wherein at least one of X3, X6 and X7 is glycosylated, each of A, C, D, F, G, H, I, K, L, M, N, P, Q, S, T, V and Y are understood to represent commonly known amino acids, and wherein: 
       Dmt=2,5-dimethyltyrosine 
       Tic=tetrahydroisoquinoline-3-carboxylic acid 
       B=alpha-aminoisobutyric acid 
       Tmt=2,5,beta-trimethyltyrosine (R,S isomer) 
       Nmf=N-methylphenylalanine 
       Nva=L-norvaline 
       Nle=L-norleucine 
     
     
         10 . A glycosylated peptide according to  claim 9 , wherein at least one of X3, X6 and X7 is glycosylated with a sugar residue selected from the group consisting of glucose; galactose; xylose; fructose; mannose; fucose; ribose; deoxyribose; arabinose; rhamnose; sucrose; trehalose; saccharose; maltose; and lactose. 
     
     
         11 . A glycosylated peptide according to  claim 9 , wherein, comprising an amino acid sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   SEQ ID NO 17 
                 
                     
                   Y-dAla-F-E-Nle-Nle-dThr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 18 
                 
                     
                   Y-dAla-F-E-Nle-Nle-dSer(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 19 
                 
                     
                   Y-dAla-F-E-Nle-Nle-Thr(beta-D-Rhamnoside)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 20 
                 
                     
                   Y-dAla-F-E-Nle-Nle-Thr(beta-Lactoside)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 21 
                 
                     
                   Y-dAla-F-E-I-I-Thr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 22 
                 
                     
                   Y-dAla-F-E-V-V-Ser(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 23 
                 
                     
                   Dmt-dAla-F-E-Nle-Nle-Thr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 24 
                 
                     
                   Y-dAla-Tic-E-Nle-Nle-Thr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 25 
                 
                     
                   Y-B-F-E-Nle-Nle-Thr(beta-D-Glc)NH2; 
                 
                     
                     
                 
                     
                   SEQ ID NO 26 
                 
                     
                   Tmt-dAla-F-E-Nle-Nle-Thr(beta-D-Glc)NH2; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   SEQ ID NO 27 
                 
                     
                   Y-dAla-Nmf-E-Nle-Nle-Thr(beta-D-Glc)NH2. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . A method of treating a subject suffering from a neurological disease or disorder, comprising administering the glycosylated peptide of  claim 1  to the subject. 
     
     
         13 . The method of  claim 12 , wherein the neurological disease or disorder involves acute or nociceptic pain. 
     
     
         14 . A method of treating a subject suffering from a neurological disease or disorder, comprising administering the glycosylated peptide of  claim 4  to the subject. 
     
     
         15 . The method of  claim 14 , wherein the neurological disease or disorder involves acute or nociceptic pain. 
     
     
         16 . A method of treating a subject suffering from a neurological disease or disorder, comprising administering the glycosylated peptide of  claim 9  to the subject. 
     
     
         17 . The method of  claim 16 , wherein the neurological disease or disorder involves acute or nociceptic pain.

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