Peptides for suppressing inflammation

Abstract

Provided herein are peptides that exhibit ApoE biological activity, as well as compositions and pharmaceutical formulations that include the peptides. The peptides, compositions, and methods disclosed herein have broad applications as they can be used to treat a broad spectrum of injury, diseases, disorders, and clinical indications.

We claim: 
     
         1 . An isolated peptide of Formula I: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   X1-X2-X3-X4-X5 
                 
             
                
                
               
            
           
         
         or a salt thereof, wherein 
         X1 is selected from an amino acid having a hydrophobic side chain or an amino acid having a positively charged side chain; 
         X2 is selected from an amino acid having a hydrophobic side chain, an amino acid having a positively charged side chain, or an amino acid having a polar uncharged side chain; 
         X3 is selected from an amino acid having a positively charged side chain; 
         X4 is selected from an amino acid having a positively charged side chain; and 
         X5 is selected from an amino acid having a hydrophobic side chain or an amino acid having a positively charged side chain. 
       
     
     
         2 . The isolated peptide of  claim 1 , wherein:
 X1 is V or R;   X2 is S, A, or H;   X3 is K or R;   X4 is K or R; and   X5 is R, L, or K.   
     
     
         3 . The peptide of  claim 2 , wherein Formula I comprises VSRKR (SEQ ID NO:2), VSKRR (SEQ ID NO:3), VSRRR (SEQ ID NO:4), VARKL (SEQ ID NO:5), RHKKL (SEQ ID NO:6), RARRL (SEQ ID NO:7), RSKKL (SEQ ID NO:8), RHKRR (SEQ ID NO:9), VARRL (SEQ ID NO:10), VARRK (SEQ ID NO:11), or RSKRR (SEQ ID NO:12). 
     
     
         4 . The peptide of  claim 1 , wherein the peptide does not have primary polypeptide sequence identity with any region of 5 consecutive amino acids of human ApoE protein (SEQ ID NO:14). 
     
     
         5 . The peptide of  claim 4 , wherein the peptide does not have primary polypeptide sequence identity with any 5 consecutive amino acids from residue 130 to residue 150 of human ApoE protein (SEQ ID NO:14). 
     
     
         6 . The peptide of  claim 1 , wherein the peptide suppresses activation of microglial cells. 
     
     
         7 . The peptide of  claim 6 , wherein the peptide suppresses secretion of TNF-α by cultured microglial cells exposed to lipopolysaccharide. 
     
     
         8 . The peptide of  claim 6 , wherein the peptide suppresses secretion of nitric oxide by cultured microglial cells exposed to lipopolysaccharide. 
     
     
         9 . The peptide of  claim 1 , wherein the peptide binds a cell-surface ApoE receptor. 
     
     
         10 . The peptide of  claim 1 , wherein the peptide blocks NMDA receptor mediated excitotoxicity. 
     
     
         11 . A method of reducing inflammation in a subject in need thereof, the method comprising administering to the subject an effective amount of a peptide of Formula I: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   X1-X2-X3-X4-X5 
                 
             
                
                
               
            
           
         
         or a salt thereof, wherein 
         X1 is selected from an amino acid having a hydrophobic side chain or an amino acid having a positively charged side chain; 
         X2 is selected from an amino acid having a hydrophobic side chain, an amino acid having a positively charged side chain, or an amino acid having a polar uncharged side chain; 
         X3 is selected from an amino acid having a positively charged side chain; 
         X4 is selected from an amino acid having a positively charged side chain; and 
         X5 is selected from an amino acid having a hydrophobic side chain or an amino acid having a positively charged side chain. 
       
     
     
         12 . The method of  claim 11 , wherein the peptide comprising administering the peptide by an injection, inhalation, transdermal, intravenous, intranasal, intracranial, and/or intrathecal route. 
     
     
         13 . A method of treating a neurological condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an effective amount of a peptide of Formula I: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   X1-X2-X3-X4-X5 
                 
             
                
                
               
            
           
         
         or a salt thereof, wherein 
         X1 is selected from an amino acid having a hydrophobic side chain or an amino acid having a positively charged side chain; 
         X2 is selected from an amino acid having a hydrophobic side chain, an amino acid having a positively charged side chain, or an amino acid having a polar uncharged side chain; 
         X3 is selected from an amino acid having a positively charged side chain; 
         X4 is selected from an amino acid having a positively charged side chain; and 
         X5 is selected from an amino acid having a hydrophobic side chain or an amino acid having a positively charged side chain. 
       
     
     
         14 . The method of  claim 13 , wherein the neurological condition is selected from at least one of traumatic CNS injury, subarachnoid hemorrhage, intracranial hemorrhage, stroke, experimental allergic encephalomyelitis, multiple sclerosis, neuroinflammation, chronic neurological disease, ALS, dementia, neuropathy, epilepsy, Parkinson's disease, and Alzheimer's disease. 
     
     
         15 . The isolated peptide according to  claim 1 , wherein the peptide comprises Formula II: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 17) 
                 
                     
                   X1-X2-X3-X4-X5-X6-X7-X8-X9; 
                 
             
                
                
               
            
           
         
       
       or a salt thereof, wherein X1 is selected from an amino acid having a hydrophobic side chain or an amino acid having a positively charged side chain; X2 is selected from an amino acid having a hydrophobic side chain, an amino acid having a positively charged side chain, or an amino acid having a polar uncharged side chain; X3 is selected from an amino acid having a positively charged side chain; X4 is selected from an amino acid having a positively charged side chain; X5 is selected from an amino acid having a hydrophobic side chain or an amino acid having a positively charged side chain; and each of X6, X7, X8, and X9 are independently selected from any amino acid, and are optionally absent. 
     
     
         16 . A composition comprising the peptide of  claim 15  and a pharmaceutically acceptable carrier, vehicle, diluent, or adjuvant. 
     
     
         17 . A composition comprising the peptide of  claim 1  and a pharmaceutically acceptable carrier, vehicle, diluent, or adjuvant. 
     
     
         18 . A method of reducing inflammation in a subject in need thereof, the method comprising administering to the subject an effective amount of a peptide of  claim 15 . 
     
     
         19 . A method of treating a neurological condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a peptide of  claim 15 . 
     
     
         20 . The method of  claim 19 , wherein the neurological condition is selected from at least one of traumatic CNS injury, subarachnoid hemorrhage, intracranial hemorrhage, stroke, experimental allergic encephalomyelitis, multiple sclerosis, neuroinflammation, chronic neurological disease, ALS, dementia, neuropathy, epilepsy, Parkinson's disease, and Alzheimer's disease.