Analogues of parathyroid hormone (1-34) that function as agonists of the parathyroid hormone receptor-1 and display modified activity profiles
View Patent ↗Described are polypeptide analogs of parathyroid hormone (PTH) that include an unnatural amino acid substitution at positions 7 or 8 from the N-terminus of the polypeptide. Also described are pharmaceutical compositions useful for treating hypoparathyroidism that contain the analogs and methods of using the analogs to treat hypoparathyroidism.
1. An isolated, unnatural peptide analogue comprising:
PTH, a parathyroid hormone receptor (PTHR-1, PTHR-2) agonist-effective fragment of PTH, a parathyroid hormone related protein (PTHrP), a PTHR-1 or PTHR-2 agonist-effective fragment of PTHrP, M-PTH, a PTHR-1 or PTHR-2 agonist-effective fragment of M-PTH, abaloparatide (BA058), or a PTHR-1 or PTHR-2 agonist-effective fragment of abaloparatide, in which at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a β-amino acid residue; and
salts thereof.
2. The peptide analogue of claim 1 , wherein the at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a β 2 -amino acid residue.
3. The peptide analogue of claim 2 , wherein the at least one naturally occurring (L)-α-amino acid residue at 6 or 7 from the N-terminus is replaced with a β 2 -amino acid residue having a side-chain identical to the (L)-α-amino acid residue replaced.
4. The peptide analogue of claim 1 , wherein the at least one naturally occurring (L)-α-amino acid residue at 6 or 7 from the N-terminus is replaced with a β 3 -amino acid residue.
5. The peptide analogue of claim 4 , wherein the at least one naturally occurring (L)-α-amino acid residue at 6 or 7 from the N-terminus is replaced with a β 3 -amino acid residue having a side-chain identical to the (L)-α-amino acid residue replaced.
6. The peptide analogue of claim 1 , wherein the at least one naturally occurring (L)-α-amino acid residue at 6 or 7 from the N-terminus is replaced with a (D)-α-amino acid.
7. The peptide analogue of claim 6 , wherein the at least one naturally occurring (L)-α-amino acid residue at 6 or 7 from the N-terminus is replaced with a (D)-α-amino acid residue having a side-chain identical to the (L)-α-amino acid residue replaced.
8. The peptide analogue of claim 1 , selected from the group consisting of
(SEQ ID NO: 8)
SVSEIQ L MHNLGKHLNSMERVEWLRKKLQDVHNF,
(SEQ ID NO: 14)
S VSEIQ L MHNLGKHLNSMERVEWLRKKLQDVHNF,
and
(SEQ ID NO: 15)
S V SEI LMHNLGKHLNSMERVEWLRKKLQDVHNF;
wherein
L=(R*) β 2 leucine;
Q=(S*) β 2 glutamine;
V=(R*) β 2 valine; and
S=β 2 serine.
9. The peptide analogue of claim 1 , in which at least one additional naturally occurring (L)-α-amino acid residue at position 1 or 2 from the N-terminus is replaced with a β-amino acid residue or a (D)-α-amino acid.
10. An isolated, unnatural peptide analogue selected from the group consisting of:
PTH, a parathyroid hormone receptor (PTHR-1, PTHR-2) agonist-effective fragment of PTH, a parathyroid hormone related protein (PTHrP), a PTHR-1 agonist-effective fragment of PTHrP, a PTHR-2 agonist-effective fragment of PTHrP, M-PTH, a PTHR-1 agonist-effective fragment of M-PTH, a PTHR-2 agonist-effective fragment of M-PTH, abaloparatide (BA058), a PTHR-1 agonist-effective fragment of abaloparatide, and a PTHR-2 agonist-effective fragment of abaloparatide, in which at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a β-amino acid residue; and
salts thereof.
11. The peptide analogue of claim 10 , wherein the at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a β 2 -amino acid residue.
12. The peptide analogue of claim 11 , wherein the at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a β 2 -amino acid residue having a side-chain identical to the (L)-α-amino acid residue replaced.
13. The peptide analogue of claim 10 , wherein the at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a β 3 -amino acid residue.
14. The peptide analogue of claim 13 , wherein the at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a β 3 -amino acid residue having a side-chain identical to the (L)-α-amino acid residue replaced.
15. The peptide analogue of claim 10 , wherein the at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a (D)-α-amino acid.
16. The peptide analogue of claim 15 , wherein the at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a (D)-α-amino acid residue having a side-chain identical to the (L)-α-amino acid residue replaced.
17. The peptide analogue of claim 10 , selected from the group consisting of
(SEQ ID NO: 8)
SVSEIQ L MHNLGKHLNSMERVEWLRKKLQDVHNF,
(SEQ ID NO: 14)
S VSEIQ L MHNLGKHLNSMERVEWLRKKLQDVHNF,
and
(SEQ ID NO: 15)
S V SEI LMHNLGKHLNSMERVEWLRKKLQDVHNF;
wherein L=(R*) β 2 leucine;
Q=(S*) β 2 glutamine;
V=(R*) β 2 valine; and
S=β 2 serine.
18. The peptide analogue of claim 10 , in which at least one additional naturally occurring (L)-α-amino acid residue at position 1 or 2 from the N-terminus is replaced with a β-amino acid residue or a (D)-α-amino acid.
19. A pharmaceutical composition for treating hypoparathyroidism, the composition comprising a parathyroid hormone receptor agonist-effective amount of PTH, a parathyroid hormone receptor (PTHR-1, PTHR-2) agonist-effective fragment of PTH, a parathyroid hormone related protein (PTHrP), a PTHR-1 agonist-effective fragment of PTHrP, a PTHR-2 agonist-effective fragment of PTHrP, M-PTH, a PTHR-1 agonist-effective fragment of M-PTH, a PTHR-2 agonist-effective fragment of M-PTH, abaloparatide (BA058), a PTHR-1 agonist-effective fragment of abaloparatide, and a PTHR-2 agonist-effective fragment of abaloparatide, in which at least one naturally occurring (L)-α-amino acid residue at position 6 or 7 from the N-terminus is replaced with a β-amino acid residue; and pharmaceutically suitable salts thereof, in combination with a pharmaceutically suitable carrier.
20. A method of treating hypoparathyroidism in a mammalian subject, including a human subject, the method comprising administering to the subject a parathyroid hormone receptor agonist-effective amount of a pharmaceutical composition as recited in claim 19 .