Neuroprotection using nap-like and sal-like peptide mimetics

Abstract

This invention relates to NAP-like and SAL-like peptide mimetics, polypeptides, or small molecules derived from them, and their use in the treatment of neuronal dysfunction, neurodegenerative disorders cognitive deficits, neuropsychiatric disorders, and autoimmune disease.

What is claimed is: 
     
         1 . A NAP-like peptide mimetic or SAL-like peptide mimetic, wherein the NAP-like or SAL-like peptide mimetic has the formula (R 1 ) a —(R 2 )—(R 3 ) b  (SEQ ID NO:X) wherein:
 R 1  is an amino acid sequence comprising from 1 to about 40 amino acids wherein each amino acid is independently selected from the group consisting of naturally occurring amino acids and amino acid analogs; 
 R 2  is a member selected from the group consisting of 
 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   NATLSIHQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   STPTAIPQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 2) 
                 
                     
                   NAVLSIHQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 3) 
                 
                     
                   NATLSVHQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   NATLSIVHQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   NTPVSIPQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 8) 
                 
                     
                   APVSIPQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                   NTPISIPQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 10) 
                 
                     
                   NAPVSIP, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 11) 
                 
                     
                   NAPVAVPQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 12) 
                 
                     
                   NARVSIPQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 13) 
                 
                     
                   DAPVSVPQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 20) 
                 
                     
                   ALLRSIPA, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 21) 
                 
                     
                   ALLRSIP, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 22) 
                 
                     
                   AMLRSIPA, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 23) 
                 
                     
                   ALLRAIPA, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 24) 
                 
                     
                   SALLRSIP, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 25) 
                 
                     
                   SALLRAIP, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 26) 
                 
                     
                   ALLRTIPA, 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 27) 
                 
                     
                   ALLRSVPA; 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         R 3  is an amino acid sequence comprising from 1 to about 40 amino acids wherein each amino acid is independently selected from the group consisting of naturally occurring amino acids and amino acid analogs; and 
         a and b are independently selected and are equal to zero or one, with the proviso that the NAP-like or SAL-like peptide mimetic does not comprise the sequence NAPVSIPQ (SEQ ID NO:1) or SALLRSIPA (SEQ ID NO:19). 
       
     
     
         2 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 , wherein R 2  is a member selected from the group consisting of NATLSIHQ (SEQ ID NO:4) and STPTAIPQ (SEQ ID NO:6). 
     
     
         3 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 , wherein a and b are equal to zero. 
     
     
         4 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 , wherein at least one amino acid of R 2  is a D-amino acid. 
     
     
         5 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 , wherein each amino acid of R 2  is a D-amino acid. 
     
     
         6 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 , wherein the NAP-like peptide mimetic or SAL-like peptide mimetic further comprises at least one protecting group. 
     
     
         7 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 , wherein the peptide mimetic is NATLSIHQ (SEQ ID NO:4). 
     
     
         8 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 , wherein the peptide mimetic is STPTAIPQ (SEQ ID NO:6). 
     
     
         9 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 7  or  8 , wherein at least one amino acid is a D-amino acid. 
     
     
         10 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 7  or  8 , wherein each amino acid is a D-amino acid. 
     
     
         11 . The NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 7  or  8 , wherein the NAP-like peptide mimetic or SAL-like peptide mimetic further comprises at least one protecting group. 
     
     
         12 . A pharmaceutical composition comprising the NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 . 
     
     
         13 . The pharmaceutical composition of  claim 12 , further comprising a neuroprotective polypeptide comprising an amino acid sequence selected from the group consisting of NAPVSIPQ (SEQ ID NO:1) and SALLRSIPA (SEQ ID NO:19). 
     
     
         14 . A method of treating or preventing a neurodegenerative disorder, a cognitive deficit, an autoimmune disorder, peripheral neurotoxicity, motor dysfunction, sensory dysfunction, anxiety, depression, schizophrenia, psychosis, a condition related to fetal alcohol syndrome, a condition involving retinal degeneration, a disorder affecting learning and memory, or a neuropsychiatric disorder in a subject, the method comprising the step of administering a therapeutically effective amount of a NAP-like peptide mimetic or SAL-like peptide mimetic of  claim 1 , to a subject in need thereof, thereby treating or preventing the neurodegenerative disorder, the cognitive deficit, the autoimmune disorder, peripheral neurotoxicity, motor dysfunction, sensory dysfunction, anxiety, depression, schizophrenia, psychosis, the condition related to fetal alcohol syndrome, the condition involving retinal degeneration, the disorder affecting learning and memory, or the neuropsychiatric disorder in the subject. 
     
     
         15 . The method of  claim 14 , wherein the NAP-like peptide mimetic is NATLSIHQ (SEQ ID NO:4). 
     
     
         16 . The method of  claim 14 , wherein the NAP-like peptide mimetic is STPTAIPQ (SEQ ID NO:6). 
     
     
         17 . The method of  claim 14 , wherein the NAP-like peptide mimetic or SAL-like peptide mimetic is administered intranasally. 
     
     
         18 . The method of  claim 14 , wherein the NAP-like peptide mimetic or SAL-like peptide mimetic is administered orally. 
     
     
         19 . The method of  claim 14 , wherein the NAP-like peptide mimetic or SAL-like peptide mimetic is administered intravenously or subcutaneously.