Ghrelin splice variant for treating neuronal damage,neurodegenerative disease, parkinsons disease, alzheimers disease, and/or depression

Abstract

The present disclosure relates, in one aspect, to use of ghrelin splice variant or an analogue thereof, or a ghrelin splice variant-like compound for the preparation of a medicament for one or more of: treatment and/or prevention of neuronal damage and/or neurodegeneration and, prophylaxis or treatment of neuronal damage and/or neurodegenerative disease, Parkinson's disease, Alzheimer's disease, depression stimulation of neuronal activity. A further aspect relates to a number of new ghrelin splice variant-like compounds and uses thereof, as well as to pharmaceutical compositions and medical packaging comprising the new ghrelin splice variant-like compounds.

I claim: 
     
         1 . Use of an isolated ghrelin splice variant-like compound having the formula Z1-(X1)m-(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1 in the manufacture of a medicament for the induction of neuron function, protection of neuron function, alteration neuron function, or a combination thereof. 
     
     
         2 . The use of  claim 1 , wherein the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 has at least 98% homology to SEQ ID NO:1. 
     
     
         3 . The use of  claim 1 , wherein the compound is 22-29 amino acids in length. 
     
     
         4 . The use of  claim 1 , wherein the bulky hydrophobic group is an acyl group or a fatty acid group. 
     
     
         5 . The use of  claim 4 , wherein the acyl group is a C.sub.1-C.sub.35 acyl group. 
     
     
         6 . The use of  claim 5 , wherein the acyl group is a C.sub.7-C.sub.12 acyl group. 
     
     
         7 . The use of  claim 1 , wherein the compound has the formula Z1-Gly-(X1)m-(X2)-(X3)n-Z2, Z1-Gly-Ser-(X2)-(X3)n-Z2, or Z1-Gly-(X2)-(X3)n-Z2. 
     
     
         8 . The use of  claim 1 , wherein (X1)m is Gly, Gly-Ser, Gly-Cys, Gly-Lys, Gly-Asp, Gly-Glu, Gly-Arg, Gly-His, Gly-Asn, Gly-Gln, Gly-Thr, or Gly-Tyr. 
     
     
         9 . The use of  claim 1 , wherein (X2) is modified Ser, modified Cys, modified Asp, modified Lys, modified Trp, modified Phe, modified Ile, or modified Leu. 
     
     
         10 . The use of  claim 1 , wherein (X3)n comprises a fragment of SEQ ID NO:6. 
     
     
         11 . The use of  claim 1 , wherein Z1 is selected from the group consisting of C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 substituted alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 substituted alkenyl, aryl, C.sub.1-C.sub.6 alkyl aryl, C(O)—(CH.sub.2)--(C.sub.1-C.sub.6 alkyl)-COOH, C(O)—(C.sub.1-C.sub.6 alkyl), C(O)-aryl, C(O)—O—(C.sub.1-C.sub.6-alkyl), and C(O)—O-aryl. 
     
     
         12 . The use of  claim 1 , wherein Z2 is selected from the group consisting of amide, methylamide, and ethylamide. 
     
     
         13 . The use of  claim 1  which binds to the growth hormone secretagogue (GHS) receptor GHS-R 1a. 
     
     
         14 . The use of  claim 13 , wherein the compound has an EC50 potency on the GHS-R1a of less than 500 nM. 
     
     
         15 . The use of  claim 13 , wherein the compound has a dissociation constant of less than 500 nM. 
     
     
         16 . The use of  claim 1 , wherein the compound has at least about 50% of the functional activity of ghrelin. 
     
     
         17 . The use of  claim 16 , wherein functional activity is activation of Gq/G11, accumulation of inositol phosphate, mobilization of calcium from intracellular stores, activation or deactivation of MAP kinases, NF.kappa.B translocation, CRE driven gene transcription, binding of arrestin to ghrelin receptor, or a combination thereof. 
     
     
         18 . The use of  claim 1 , wherein the compound is conjugated to a polymer molecule. 
     
     
         19 . The use of  claim 18 , wherein the polymer molecule is selected from the group consisting of polyalkylene oxide, polyalkylene glycol, poly-vinyl alcohol, poly-carboxylate, poly-(vinylpyrolidone), polyethylene-co-maleic acid anhydride, polystyrene-co-maleic acid anhydride, and dextran. 
     
     
         20 . The use of  claim 1 , wherein the compound is modified with a chemically reactive group. 
     
     
         21 . The use of  claim 20 , wherein the chemically reactive group is selected from the group consisting of N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide, maleimide-benzoyl-succinimide, gamma-maleimido-butyryloxy succinimide ester, and maleimidopropionic acid. 
     
     
         22 . A method for treating neuronal damage comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of: (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof. 
     
     
         23 . A method for treating neurodegenerative disease comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of: (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof. 
     
     
         24 . A method for preventing neuronal damage and/or neurodegenerative disease comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of: (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof. 
     
     
         25 . A method for treating Parkinson's disease comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of: (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof. 
     
     
         26 . A method for preventing Parkinson's disease comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of: (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof. 
     
     
         27 . A method for treating Alzheimer's disease comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof. 
     
     
         28 . A method for preventing Alzheimer's disease comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of: (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof. 
     
     
         29 . A method for treating depression comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of: (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof. 
     
     
         30 . A method for preventing depression comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of: (a) ghrelin splice variant; (b) a ghrelin splice variant-like compound having the formula Z1-(X1).sub.m--(X2)-(X3)n-Z2, wherein Z1 is an optionally present protecting group; each X1 is independently selected from a naturally occurring amino acid and a synthetic amino acid; X2 is selected from a naturally occurring amino acid and a synthetic amino acid, said amino acid being modified with a bulky hydrophobic group; each X3 is independently selected from a naturally occurring amino acid and a synthetic amino acid, wherein one or more of X1 and X3 optionally may be modified with a bulky hydrophobic group; Z2 is an optionally present protecting group; m is an integer in the range of from 1-10; n is an integer in the range of from 4-92; provided that the compound according to formula Z1-(X1)m-(X2)-(X3)n-Z2 is 15-94 amino acids in length, has at least 95% homology to SEQ ID NO:1, and induce neuron function, protects neuron function, alters neuron function, or a combination thereof of a subject when administered thereto; or (c) a mixture thereof.