Methods and compositions related to improving properties of pharmacological agents targeting nervous system

Abstract

Disclosed are compositions and methods related to improving pharmacological properties of bioactive compounds targeting nervous system.

1 . A method of increasing permeability of the blood-brain barrier for a peptide, the method comprising modifying the peptide to have increased lipophilic character and increased basicity of the peptide compared to the unmodified form of the peptide. 
     
     
         2 . The method of  claim 1 , wherein the lipophilic character is increased by conjugating the peptide to a hydrophobic moiety. 
     
     
         3 . The method of  claim 2 , wherein the hydrophobic moiety is polyaliphatic chains. 
     
     
         4 . The method of  claim 1 , wherein the lipophilic character is increased by the substitution of one or more aromatic residues with a halogenated aromatic amino acid residue. 
     
     
         5 . The method of  claim 1 , wherein the basicity is increased by introducing homo- and heterooligomers of positively charged amino acid residues, including, but not limited to Lysine, Arginine, homo-Lysine, homo-Arginine, Ornitine in L- or D-isomer configuration; 2,3-Diaminopropioic acid; 2,4-Diaminobutyric acid. 
     
     
         6 . The method of  claim 1 , wherein the basicity is increased by conjugation to polyamine-based moieties, such as spermine, spermidine, polyamidoamine dendrimers or polyamine toxins and derivatives thereof. 
     
     
         7 . The method of  claim 1 , wherein the peptide can cross the blood-brain barrier with 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% more efficiency compared to the unmodified peptide. 
     
     
         8 . The method of  claim 1 , further comprising increasing glycosylation of the peptide compared to the unmodified form of the peptide. 
     
     
         9 . The method of  claim 1 , comprising a first modification relative to the unmodified peptide that increases the lipophilic character of the modified neuropeptide when compared to the unmodified peptide; with the first modification being selected from at least one of:
 (a) a hydrophobic moiety conjugated to one or more amino acid residues of the modified neuropeptide; and   (b) substitution of one or more aromatic amino acid residues with a halogenated aromatic amino acid residue, and   a second modification relative to the unmodified peptide that increases the basicity of the modified neuropeptide when compared to the unmodified peptide, with the second modification being selected from at least one of:   (a) an oligomer of positively charged amino acid residues introduced into the amino acid sequence of the unmodified peptide, wherein the oligomer is selected from the group consisting of homooligomers and heterooligomers comprising Lysine, Arginine, homo-Lysine, homo-Arginine, L-Ornithine, D-Ornithine, 2,3-Diaminopropioic acid, and 2,4-Diaminobutyric acid, and   (b) a polyamine-based moiety conjugated to the modified neuropeptide, wherein the polyamine-based moiety is selected from the group consisting of spermine, spermidine, polyamidoamine, dendrimers, and polyamine toxins.   
     
     
         10 . An isolated polypeptide modified to have increased permeability of the blood-brain barrier according to the method of  claim 1 . 
     
     
         11 . The isolated polypeptide of  claim 10 , wherein the modified polypeptide is derived from an unmodified peptide selected from galanin, somatostatin, delta-sleep inducing peptide, neuropeptide Y, and neurotensin. 
     
     
         12 . The isolated polypeptide of  claim 10  comprising SEQ ID NO:3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 29, SEQ ID NO: 50, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 101, SEQ ID NO: 105, and SEQ ID NO: 142. 
     
     
         13 . A method of treating, preventing, or ameliorating pain or other neurological disorders comprising administering to a subject in need thereof an effective amount of a polypeptide modified to have increased permeability of the blood-brain barrier according to the method of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the modified polypeptide is derived from an unmodified peptide selected from galanin, somatostatin, delta-sleep inducing peptide, neuropeptide Y, and neurotensin. 
     
     
         15 . The method of  claim 13 , wherein the modified polypeptide is a galanin analog. 
     
     
         16 . The method of  claim 13 , wherein the modified polypeptide is a galanin analog selected from at least one of SEQ ID NO: 56, SEQ ID NO: 66, and SEQ ID NO: 67. 
     
     
         17 . The method of  claim 13 , wherein the pain is caused by one or more of the following, or the neurological disorder is selected from one or more of the following: chronic back pain, cancer, fibromyalgia, postherpetic neuralgia, multiple sclerosis, diabetic neuropathy, peripheral nerve injury, traumatic mononeuropathy, complex regional pain syndrome, and spinal cord injury. 
     
     
         18 . A method of treating epilepsy, comprising administering to a subject in need thereof an effective amount of a polypeptide modified to have increased permeability of the blood-brain barrier according to the method of  claim 1 . 
     
     
         19 . A method of treating spinal cord injury in a subject, comprising administering to the subject a polypeptide modified to have increased permeability of the blood-brain barrier according to the method of  claim 1 . 
     
     
         20 . A method of treating multiple sclerosis in a subject, comprising administering to the subject a polypeptide modified to have increased permeability of the blood-brain barrier according to the method of  claim 1 .