Modified kisspeptin peptides and uses thereof
The present application provides synthetic modified peptides of five to seven natural or non-natural amino acids as well as pharmaceutical compositions comprising them, for use in the treatment a disease or disorder presenting behavioral abnormalities associated with impairment of sensory gating function, depression or cognitive impairment, particularly schizophrenia and Alzheimer's disease.
1. A synthetic peptide selected from the group consisting of:
(i) a cyclic or linear peptide:
(SEQ ID NOs: 2 and 1)
R 1 -Xaa 1 -Gly-Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -NHR 2
wherein:
Xaa 1 is selected from the group consisting of Phe, Ile, Leu, Val, Nle and analogs thereof;
Xaa 2 is selected from the group consisting of Leu, Ile, Val, Nle, Phe and analogs thereof;
Xaa 3 is selected from the group consisting of Arg, Lys, homo-Arg, homo-Lys, Om and analogs of Arg;
Xaa 4 is selected from the group consisting of Trp and analogs thereof;
Xaa 5 is selected from the group consisting of Tyr, His, O-methyl-Tyr and 2-hydroxy-3-methyl-Phe;
R 1 is selected from the group consisting of para-aminophenylalanine (Pap), NH 2 C 6 H 4 (CH 2 ) 1-3 CO, Fmoc-Pap, FMS-Pap and C 5 -C 20 acyl-Pap, wherein said C 5 -C 20 acyl is derived from a saturated or unsaturated C 5 -C 20 fatty acid linked to the α-amino group of Pap; and
R 2 is H or (CH 2 ) 0-4 CH 3 , and
(ii) pharmaceutically acceptable salts thereof.
2. The synthetic peptide of claim 1 , wherein
said analogs of Arg are selected from the group consisting of L-2-amino-3-guanidino propionic acid and N-ω,ω-dimethyl-L-arginine;
said analogs of Trp are selected from the group consisting of β-(3-benzothienyl)-L-Ala, 6-methyl Trp, 5-methoxy-Trp, 5-hydroxy-Trp, 5-fluoro-Trp, 7-azatryptophpan, 5-bromotryptophan and 5-methyltryptophan;
said analogs of Phe are selected from the group consisting of 2-fluorophenylalanine, 4-fluorophenylalanine, 4-bromophenylalanine, 2-chlorophenylalanine, L-homophenylalanine, 4-nitrophenylalanine and α-methylphenylalanine; and
said analogs of Leu or Val are selected from the group consisting of t-butyl-L-alanine, L-cyclohexylglycine and L-cyclopentylglycine.
3. The synthetic peptide of claim 1 , wherein the peptide is:
a cyclic peptide:
wherein:
Xaa 1 is Tyr or His; and
R 2 is H or (CH 2 ) 0-4 CH 3 .
4. The synthetic peptide of claim 1 , wherein the pepside is:
5. A pharmaceutical composition comprising the synthetic peptide of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5 , formulated for oral administration.
7. A method for the treatment of a disease or disorder presenting behavioral abnormalities associated with impairment of sensory gating function, depression or cognitive impairment, wherein said disease or disorder is selected from the group consisting of schizophrenia, autistic disorder, Huntington's chorea, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), Tourette′s syndrome depression and cognitive impairment, comprising administering to a patient in need thereof a pharmaceutically effective amount of a peptide of claim 1 or a pharmaceutically acceptable salt thereof.
8. The method of claim 7 , wherein said disease or disorder is schizophrenia.
9. The method of claim 7 , wherein said disease or disorder is Alzheimer's disease (AD).
10. The method of claim 7 , wherein said peptide has a sequence as set forth in SEQ ID NO: 6.
11. The method of claim 7 , wherein said disease or disorder is depression or a cognitive impairment.
12. The method of claim 11 , wherein said depression and/or said cognitive impairment are associated with schizophrenia or with Alzheimer's disease.
13. A synthetic peptide, wherein the peptide is
or pharmaceutically acceptable salts thereof.
14. A pharmaceutical composition comprising the synthetic peptide of claim 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 , formulated for oral administration.
16. A method for the treatment of a disease or disorder presenting behavioral abnormalities associated with impairment of sensory gating function, depression or cognitive impairment, wherein said disease or disorder is selected from the group consisting of schizophrenia, autistic disorder, Huntington's chorea, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), Tourette's syndrome, depression and cognitive impairment, comprising administering to a patient in need thereof a pharmaceutically effective amount of a peptide of claim 13 or a pharmaceutically acceptable salt thereof.