Amylin aggregation inhibitors and use thereof
Short peptides and derivatives or analogs thereof for the treatment or prevention of IAAP related disorders, in particular amyloid deposits associated with Type I or Type II diabetes are herein described. These peptides and/or their derivatives have been designed to inhibit the formation of amylin fibrils which are implicated in the pathogenesis of diabetes Type II as well as to dissolve the fibrillar deposits already formed
1 . A peptide having an amino acid sequence of Formula I (SEQ ID NO: 1):
X 1 FGAPX 2 X 3 in which
X 1 , is selected from Aspartic acid and a derivative thereof selected from acylated and alkylated Aspartic acid;
X 2 is Leucine or when X 3 is absent, X 2 is selected from Leucine and amidated Leucine;
X 3 is absent or selected from Aspartic acid and amidated Aspartic acid;
as well as salt and any derivative or analogue thereof.
2 . A peptide according to claim 1 wherein X 1 and X 3 are Aspartic acid.
3 . A peptide according to claim 1 wherein X 3 is absent.
4 . A peptide according to claim 1 of the Formula II below:
wherein R 1 is selected from H, C 2 -C 6 acyl and C 1 -C 6 alkyl; R 2 is selected from OH and NR 3 R 4 , wherein R 3 and R 4 are independently selected from H and C 1 -C 6 alkyl and R 5 , R 6 R 7 , R 8 and R 9 are independently selected from H and C 1 -C 6 alkyl.
5 . A peptide according to claim 4 wherein R 1 is selected from H and C 2 -C 6 acyl and R 2 is selected from OH and NH 2 .
6 . A peptide according to claim 4 wherein R 1 is H and R 2 is OH.
7 . A peptide according to claim 1 of the Formula III below:
wherein R′ is selected from H, C 2 -C 6 acyl and C 1 -C 6 alkyl; R 2 is selected from OH and NR 3 R 4 , wherein R 3 and R 4 are independently selected from H and C 1 -C 6 alkyl and R 5 , R 6 , R 7 and R8 are independently selected from H and C 1 -C 6 alkyl.
8 . A peptide according to claim 7 wherein R 1 is selected from H and C 2 -C 6 acyl and R 2 is selected from OH and NH 2 .
9 . A peptide according to claim 7 wherein R 1 is acetyl and R 2 is NH 2 .
10 . A peptide according claim 4 wherein R 5 , R 6 , R 7 and R 8 are H.
11 . A peptide according claim 1 selected from the following group:
SEQ ID NO. 2, SEQ ID NO. 3 and SEQ ID NO. 4.
12 . A compound comprising the peptide according to claim 1 for use as a medicament.
13 . A method for the preparation of a medicament for the treatment or prevention of an amyloidosis disorder related to IAPP comprising adding a peptide according to claim 1 to the medicament formulation.
14 . The method according to claim 13 wherein the amyloidosis disorder is a diabetic disorder.
15 . The method according to claim 14 wherein the diabetic condition is Type II diabetes.
16 . The method according to claim 14 wherein the diabetic condition is post-transplantation Type I diabetes.
17 . A pharmaceutical composition comprising a the peptide according to claim 1 as active ingredient and a pharmaceutically acceptable excipient or carrier.
18 . A method of treating or preventing diabetic disorders by administering an effective amount of the peptide according to claim 1 to a subject in the need thereof.
19 . A method according to claim 18 , in which the subject is human.
20 . A peptide according to claim 7 wherein R 5 , R 6 , R 7 and R 8 are H.