Peptide Yy Analogues
1 Assignment
0 Petitions
Accused Products
Abstract
Analogues of the peptide PYY (1-36) are described in which the tertiary structure of the peptide is preserved and stabilised particularly to enhance binding and activation of the Y2 receptor by the use of cross links or rigid bends in the peptide to constrain conformationally the positions of the N-terminal part of the peptide sequence and amino acid 34. The analogues are useful in the control of food intake.
13 Citations
92 Claims
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1-75. -75. (canceled)
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76. A peptide, which is a sequence variant and a functional and/or structural mimic of peptide YY, said peptide comprising at least one modification of the amino acid sequence set forth in SEQ ID NO:
- 2 (h-PYY 3-36), wherein said peptide
includes a modification that conformationally constrains the relative position of the N-terminal amino acid of that part of SEQ ID NO 2 present in the peptide and amino acid 34 of SEQ ID NO;
2 in the peptide; and
/orincludes a branched amino acid sequence resulting in 2 free N-terminal amino acids; and
/orincludes N-terminal and/or C-terminal addition of a net basic amino acid sequence;
optionally further includes deletion of amino acids 1-5 of SEQ ID NO;
2; and
/orincludes deletion of any one or more of amino acid residues 8-15 of SEQ ID NO;
2 without deletion of all of amino acids 1-7 of SEQ ID NO 2; and
/orincludes deletion of amino acids 6 and 7 of SEQ ID NO;
2 without deletion of all of amino acids 1-5 of SEQ ID NO 2; and
/orincludes deletion of amino acids 16-19 of SEQ ID NO;
2 without deletion of all of amino acids 1-15 of SEQ ID NO 2; and
/orincludes two cross linkable protected Cys amino acid substitutions;
wherein said peptide further comprises at most 6 substitutions in the amino acid sequence set forth in SEQ ID NO;
2, each of which is a structure and/or functionality preserving substitution. - View Dependent Claims (77, 79, 80)
- 2 (h-PYY 3-36), wherein said peptide
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78. A peptide of formula I
R1-X-Y-Z-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-R2-
(I)wherein A22 is Ala or a structure and/or functionality preserving substitution thereof;
A23 is Ser or a structure and/or functionality preserving substitution thereof;
A24 is Leu or a structure and/or functionality preserving substitution thereof, His or Cys;
A25 is Arg or a structure and/or functionality preserving substitution thereof;
A26 is Leu or a structure and/or functionality preserving substitution thereof, His or Cys;
A27 is Tyr or a structure and/or functionality preserving substitution thereof;
A28 is Leu or a structure and/or functionality preserving substitution thereof, or Cys;
A29 is Asn or a structure and/or functionality preserving substitution thereof;
or Lys, which is optionally coupled to an amino acid sequence via a peptide bond at the c-amino group;
A30 is Leu or a structure and/or functionality preserving substitution thereof;
A31 is Val or a structure and/or functionality preserving substitution thereof, or Cys;
A32 is Thr or a structure and/or functionality preserving substitution thereof;
A33 is Arg or a structure and/or functionality preserving substitution thereof;
A34 is Gln or a structure and/or functionality preserving substitution thereof;
A35 is Arg or a structure and/or functionality preserving substitution thereof; and
A36 is Tyr or a structure and/or functionality preserving substitution thereof;
Z is a peptide of formula A13-A14-A15-A16-A17-A18-A19-A20-A21 which is absent or wherein, A13 is Ser or a structure and/or functionality preserving substitution thereof or absent;
A14 is Pro or a structure and/or functionality preserving substitution thereof or absent;
A15 is Glu or a structure and/or functionality preserving substitution thereof or absent;
A16 is Glu or a structure and/or functionality preserving substitution thereof or absent;
A17 is Leu or a structure and/or functionality preserving substitution thereof or absent;
A18 is Asn or a structure and/or functionality preserving substitution thereof;
A19 is Arg or a structure and/or functionality preserving substitution thereof;
A20 is Tyr or a structure and/or functionality preserving substitution thereof; and
A21 is Tyr or a structure and/or functionality preserving substitution thereof;
Y is a peptide of formula
A8-A9-A10-A-Bwhich is absent or wherein A8 is Pro or a structure and/or functionality preserving substitution thereof;
A9 is Gly or a structure and/or functionality preserving substitution thereof;
A10 is Glu or a structure and/or functionality preserving substitution thereof, or absent; and
A-B designates a dipeptide A11-A12 selected from the group consisting of Gly-Gly, Pro-Gly, Gly-Pro, Sar-Sar, Sar-Hyp, Hyp-Sar, Pro-Sar, Sar-Pro, Pro-Hyp, Pro-Pro, Hyp-Pro, and Hyp-Hyp, where Pro and Hyp independently may be an L or D form, where the ring structure of Pro (III) and Hyp is optionally substituted with halogen, nitro, methyl, amino, or phenyl, Hyp represents 3-hydroxyproline or 4-hydroxyproline, Sar represents sarcosine, or on e or both of the amino acid residues of A-B is a Sar, or an N-cyclohexylglycine residue, or A and B each independently represents a group of the formula II wherein n is an integer having the value 3, 4, or 5, and R represents an optional substituent, preferably selected from the group consisting of halogen, phenyl, hydroxy, NH2, and C(1-6)alkyl optionally substituted with halogen, or A-B designates the formula IIa wherein n is an integer having the value 0, 1, 2, and 3, p is an integer having the value 0, 1, 2, and 3, Z represents 0 or S, and R represents an optional substituent, preferably selected from the group consisting of halogen, phenyl, hydroxy, NH2, and C(1-6)alkyl, or A and B independently represents an amino acid residue having a saturated carbocyclic structure of 4, 5 or 6 members and where in said carbocyclic structure further comprises one or more heteroatoms, X is a peptide of formula
A3-A4-A5-A6-A7which is absent or wherein A3 is Ile or a structure and/or functionality preserving substitution thereof, or Cys;
A4 is Lys or a structure and/or functionality preserving substitution thereof;
A5 is Pro or a structure and/or functionality preserving substitution thereof, or Cys;
A6 is Glu or a structure and/or functionality preserving substitution thereof; and
A7 is Ala or a structure and/or functionality preserving substitution thereof, or Cys;
R1 is absent or an amino acid sequence; and
R2 is absent or an amino acid sequence;
wherein said peptide comprises at most one disulfide bridge selected from Cys3-S—
S-Cys31, Cys3-S—
S-CyS28, CyS5-S—
S-CYS26, and Cys7-S—
S-CYS24or wherein A is absent, Asp or a structure and/or functionality preserving substitution thereof and B is absent, Ala or a structure and/or functionality preserving substitution thereof and said peptide comprises a disulfide bridge selected from Cys3-S—
S-Cys31, Cys3-S—
S-Cys28, Cys5-S—
S-Cys26, and Cys7-S—
S-Cys24;
wherein the number of structure and/or functionality preserving substitutions does not exceed 6;
wherein the C-terminal amino exposes a free carboxylic acid group or an amide group; and
or a multimer and/or pharmaceutically acceptable salt thereof. - View Dependent Claims (81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91)
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92. A method for reducing or enhancing body weight in a subject, the method comprising administering, to the subject, an appropriately effective amount of (i) a peptide, which is a sequence variant and a functional and/or structural mimic of peptide YY, said peptide comprising at least one modification of the amino acid sequence set forth in SEQ ID NO:
- 2 (h-PYY 3-36), wherein said peptide
includes a modification that conformationally constrains the relative position of the N-terminal amino acid of that part of SEQ ID NO 2 present in the peptide and amino acid 34 of SEQ ID NO;
2 in the peptide; and
/orincludes a branched amino acid sequence resulting in 2 free N-terminal amino acids; and
/orincludes N-terminal and/or C-terminal addition of a net basic amino acid sequence;
optionally further includes deletion of amino acids 1-5 of SEQ ID NO;
2; and
/orincludes deletion of any one or more of amino acid residues 8-15 of SEQ ID NO;
2 without deletion of all of amino acids 1-7 of SEQ ID NO 2; and
/orincludes deletion of amino acids 6 and 7 of SEQ ID NO;
2 without deletion of all of amino acids 1-5 of SEQ ID NO 2; and
/orincludes deletion of amino acids 16-19 of SEQ ID NO;
2 without deletion of all of amino acids 1-15 of SEQ ID NO 2; and
/orincludes two cross linkable protected Cys amino acid substitutions;
wherein said peptide further comprises at most 6 substitutions in the amino acid sequence set forth in SEQ ID NO;
2, each of which is a structure and/or functionality preserving substitution;
or of (ii) a peptide of formula I
R1-X-Y-Z-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-R2
(I)Wherein A22 is Ala or a structure and/or functionality preserving substitution thereof;
A23 is Ser or a structure and/or functionality preserving substitution thereof;
A24 is Leu or a structure and/or functionality preserving substitution thereof, His or Cys;
A25 is Arg or a structure and/or functionality preserving substitution thereof;
A26 is Leu or a structure and/or functionality preserving substitution thereof, His or Cys;
A27 is Tyr or a structure and/or functionality preserving substitution thereof;
A28 is Leu or a structure and/or functionality preserving substitution thereof, or Cys;
A29 is Asn or a structure and/or functionality preserving substitution thereof, or Lys, which is optionally coupled to an amino acid sequence via a peptide bond at the s-amino group;
A30 is Leu or a structure and/or functionality preserving substitution thereof;
A31 is Val or a structure and/or functionality preserving substitution thereof, or Cys;
A32 is Thr or a structure and/or functionality preserving substitution thereof;
A33 is Arg or a structure and/or functionality preserving substitution thereof;
A34 is Gln or a structure and/or functionality preserving substitution thereof;
A35 is Arg or a structure and/or functionality preserving substitution thereof; and
A36 is Tyr or a structure and/or functionality preserving substitution thereof;
Z is a peptide of formula
A13-A14-A15-A16-A-17-A18-A19-A20-A21which is absent or wherein, A13 is Ser or a structure and/or functionality preserving substitution thereof or absent;
A14 is Pro or a structure and/or functionality preserving substitution thereof or absent;
A15 is Glu or a structure and/or functionality preserving substitution thereof or absent;
A16 is Glu or a structure and/or functionality preserving substitution thereof or absent;
A17 is Leu or a structure and/or functionality preserving substitution thereof or absent;
A18 is Asn or a structure and/or functionality preserving substitution thereof;
A19 is Arg or a structure and/or functionality preserving substitution thereof;
A20 is Tyr or a structure and/or functionality preserving substitution thereof; and
A21 is Tyr or a structure and/or functionality preserving substitution thereof;
Y is a peptide of formula
A8-A9-A10-A-Bwhich is absent or wherein A8 is Pro or a structure and/or functionality preserving substitution thereof;
A9 is Gly or a structure and/or functionality preserving substitution thereof, A10 is Glu or a structure and/or functionality preserving substitution thereof, or absent; and
A-B designates a dipeptide A11-A12 selected from the group consisting of Gly-Gly, Pro-Gly, Gly-Pro, Sar-Sar, Sar-Hyp, Hyp-Sar, Pro-Sar, Sar-Pro, Pro-Hyp, Pro-Pro, Hyp-Pro, and Hyp-Hyp, where Pro and Hyp independently may be an L or D form, where the ring structure of Pro and Hyp is optionally substituted with halogen, nitro, methyl, amino, or phenyl, Hyp represents 3-hydroxyproline or 4-hydroxyproline, Sar represents sarcosine, or one or both of the amino acid residues of A-B is a Sar, or an N-cyclohexylglycine residue, or A and B each independently represents a group of the formula II wherein n is an integer having the value 3, 4, or 5, and R represents an optional substituent, preferably selected from the group consisting of halogen, phenyl, hydroxy, NH2, and C(1-6)alkyl optionally substituted with halogen, or A-B designates the formula IIa wherein n is an integer having the value 0, 1, 2, and 3, p is an integer having the value 0, 1, 2, and 3, Z represents O or S, and R represents an optional substituent, preferably selected from the group consisting of halogen, phenyl, hydroxy, NH2, and C(1-6)alkyl, or A and B independently represents an amino acid residue having a saturated carbocyclic structure of 4, 5 or 6 members and where in said carbocyclic structure further comprises one or more heteroatoms, X is a peptide of formula
A3-A4-A5-A6-A7which is absent or wherein A3 is Ile or a structure and/or functionality preserving substitution thereof, or Cys;
A4 is Lys or a structure and/or functionality preserving substitution thereof;
A5 is Pro or a structure and/or functionality preserving substitution thereof, or Cys;
A6 is Glu or a structure and/or functionality preserving substitution thereof; and
A7 is Ala or a structure and/or functionality preserving substitution thereof, or Cys;
R1 is absent or an amino acid sequence; and
R2 is absent or an amino acid sequence;
wherein said peptide comprises at most one disulfide bridge selected from Cys3-S—
S-Cys31, Cys3-S—
S-CyS28, Cys5-S—
S-Cys26, and Cys7-S—
S-Cys24;
or wherein A is absent, Asp or a structure and/or functionality preserving substitution thereof and B is absent, Ala or a structure and/or functionality preserving substitution thereof and said peptide comprises a disulfide bridge selected from Cys3-S—
S-cys31, Cys3-S—
S-Cys28, Cys5-S—
S-Cys26, and Cys7-S—
S-Cys24;
wherein the number of structure and/or functionality preserving substitutions does not exceed 6;
wherein the C-terminal amino exposes a free carboxylic acid group or an amide group; and
or a multimer and/or pharmaceutically acceptable salt thereof.
- 2 (h-PYY 3-36), wherein said peptide
Specification