Pth analogs for the treatment of hypoparathyroidism
AssigneeIndiana University Research and Technology Corporation
InventorsRichard D. DIMARCHI, Fa ZHANG
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Abstract
A novel derivative of parathyroid hormone is provided that has an extended time of action relative to known native parathyroid hormone agonist peptides, while minimizing excessive action shortly after administration. Compositions comprising the novel parathyroid hormone conjugates can be used to treat hypoparathyroidism and osteoporosis.
Claims20
A conjugate comprising a PTH peptide, and a non-enzymatic self-cleaving dipeptide covalently linked to the N-terminal alpha amine of said PTH peptide via an amide bond, wherein said PTH peptide comprises the amino acid sequence of
- (SEQ ID NO:
- 16)
- SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHX33,
- wherein
- X33 is an amino acid comprising a side chain comprising -{gamma glutamic acid-[COCH2(OCH2CH2)k—NH]q-gamma glutamic acid}-CO(CH2)14-20COOH;
- and
- said self-cleaving dipeptide comprises the general structure:
- wherein
- R1 comprises —NH—CO(CH2)14-20COOH, —NH-[spacer]-CO(CH2)14-20COOH, —NH—CO(CH2)14-20CH3, or —NH-[spacer]-CO(CH2)14-20CH3;
- R2, R4 and R8 are each H;
- R3 is CH3;
- R5 is NH2;
- q is 2 or 4 and
- k is 2.
A conjugate comprising a PTH peptide and a non-enzymatic self-cleaving dipeptide covalently bound to said PTH peptide via an amide bond,
- said PTH peptide comprising an amino acid sequence selected from the group consisting of
- (SEQ ID NO:
- 16)
- SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHX33,
- wherein said non-enzymatic self-cleaving dipeptide comprising the general structure A-B—;
- wherein
- A is an amino acid or an acylated amino acid;
- B is an N-alkylated amino acid;
- wherein said acylated amino acid of each of X33 and A is independently selected from an amino acid comprising a C16-C30 fatty acid or C16-C30 diacid covalently linked to the amino acid side chain, optionally via a spacer, and said non-enzymatic self-cleaving dipeptide is linked to said PTH peptide through formation of an amide bond between B and the N-terminal alpha amine of said PTH peptide, further wherein said optional spacer of each of X33 and A comprises one or more linker moieties independently selected from the group consisting of a gamma glutamic acid, and COCH2(OCH2CH2)kNH, wherein k is an integer selected from the range of 1-8;
- with the proviso that when A is a non-acylated amino acid, then A is an amino acid in the D-stereochemical configuration.
Dependencies are inferred from the claim text.