Alpha-/beta-polypeptide analogs of parathyroid hormone (PTH) and method of using same
Described are polypeptide analogs of parathyroid hormone (PTH) that include at least two non-adjacent β-amino acid residues in place of a naturally occurring α-amino acid residues. 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 analog comprising:
PTH, a parathyroid hormone receptor (PTHR-1, PTHR-2) agonist- or inverse agonist effective fragment of PTH, a parathyroid hormone related protein (PTHrP), a PTHR-1 or PTHR-2 agonist-, or inverse agonist-effective fragment of PTHrP, M-PTH, a PTHR-1 or PTHR-2 agonist- or inverse agonist-effective fragment of M-PTH, BA058, or a PTHR-1 or PTHR-2 agonist-, or inverse agonist-effective fragment of BA058, in which at least five non-adjacent α-amino acid residues are replaced with β-amino acid residues; and
salts thereof.
2. The peptide analog of claim 1 , in which the at least five α-amino acid residues are replaced with five β-amino acid residues having the same side-chain as the α-amino acid residues they replace.
3. The peptide analog of claim 1 , in which at least one of the at least five non-adjacent α-amino acid residues is replaced with a cyclically constrained β-amino acid residue.
4. The peptide analog of claim 1 , in which the at least five β-amino acid residues appear in a pattern comprising αβαβαβαβαβ, ααβααβααβααβααβ, αααβαααβαααβαααβαααβ, and ααβαααβααβαααβααβ.
5. The peptide analog of claim 1 , comprising thirty four (34) N-terminal residues of a mammalian parathyroid hormone, PTH(1-34), in which at least five non-adjacent α-amino acid residues are replaced with a β-amino acid residues.
6. The peptide analog of claim 5 , in which the at least five α-amino acid residues are replaced with three β-amino acid residues having the same side-chain as the α-amino acid residues they replace.
7. The peptide analog of claim 5 , in which at least one of the at least five non-adjacent α-amino acid residues is replaced with a cyclically constrained β-amino acid residue.
8. The peptide analog of claim 5 , in which the at least three β-amino acid residues appear in a pattern comprising αβαβαβαβαβ, ααβααβααβααβααβ, αααβαααβαααβαααβαααβ, and ααβαααβααβαααβααβ.
9. The peptide analog of claim 1 , selected from the group consisting of
(SEQ. ID. NO: 5)
A5: SVSEIQLMHNLGKH L NSM E RVE W LRK K LQD V HNF-NH 2 ,
(SEQ. ID. NO: 6)
B5: SVSEIQLMHNLGKHL N SME R VEW L RKK L QDV Q NF-NH 2 ,
(SEQ. ID. NO: 7)
C5: SVSEIQLMHNLGKHLN S MER V EWL R KKL Q DVH N F-NH 2 ,
(SEQ. ID. NO: 8)
D5: SVSEIQLMHNLGKHLNS M ERV E WLR K KLQ D VHN F -NH 2 ,
(SEQ. ID. NO: 9)
D6: SVSEIQLMHNLGK W LNS M ERV E WLR K KLQ D VHN F -NH 2 ,
and
(SEQ. ID. NO: 10)
D7: SVSEIQLMH N LGK W LNS M ERV E WLR K KLQ D VHN F -NH 2
wherein bold, underlined residues designate β3 residues having a side chain of the α residue indicated by the letter, and salts thereof.
10. The peptide analog of claim 1 , which is an agonist of parathyroid hormone receptor-1.
11. 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 or PTHR-2 agonist-effective fragment of PTHrP, M-PTH, a PTHR-1 or PTHR-2 agonist-effective fragment of M-PTH, BA058, or a PTHR-1 or PTHR-2 agonist-effective fragment of BA058, in which at least five non-adjacent α-amino acid residues are replaced with β-amino acid residues, in combination with a pharmaceutically suitable carrier.
12. 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 11 .