Fracture targeted bone regeneration through parathyroid hormone receptor stimulation

Abstract

Disclosed herein includes a drug delivery system comprising at least one peptide and a targeting ligand for bone fracture and/or for bone healing. Some embodiments include a peptide delivery system comprising at least an acidic, basic, hydrophilic, hydrophobic or neutral peptide linked to an acidic peptide or nonpeptidic polyanion for use in targeting the aforementioned attached peptide to a bone fracture surface. In some embodiments, a conjugated peptide expresses an anabolic function that acts through PTH receptor 1, and various formats of targeting ligands guide the drug to raw hydroxyapatite. This system offsets some side effects caused by free anabolic drug, such as high blood calcium concentration

1 . A compound comprising:
 a compound of the formula X—Y—Z;   wherein:   X is at least one agent that modulates activity of parathyroid hormone receptor;   Z is at least one bone-targeting molecule; and   Y is a linker that joins and/or links X and Z;   or a pharmaceutically acceptable salt thereof, or a metabolite thereof.   
     
     
         2 . The compound according to  claim 1 , wherein:
 X is at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone related peptide (SEQ ID NO: 12), at least 80% sequence identity to a full length parathyroid hormone (SEQ ID NO: 13), and/or at least 80% identity to a full length abaloparatide or analogs thereof;   Y is at least one polypeptide comprising at least 80% sequence identity to amino acid residues 35-40, 35-41, 35-42, 35-43, 35-44, 35-45, 35-46, and/or 35-84 of a full length parathyroid hormone related peptide or parathyroid hormone, and/or at least one Cathepsin K sensitive polypeptide; and   Z is at least one polypeptide comprising 4 or more acidic amino acid residues, polyphosphate, aminohexanedioic acid or derivatives thereof, and/or alendronate or derivatives thereof.   
     
     
         3 . The compound according to  claim 1 , wherein:
 X is at least one polypeptide having at least 80% sequence identity to SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, and 9;   Y is at least one polypeptide comprising at least 80% sequence identity to amino acid residues 35-46 and/or 41-46 of a full length parathyroid hormone related peptide; and   Z is at least one polypeptide comprising 4 or more acidic amino acid residues, polyphosphate, and/or alendronate or derivatives thereof.   
     
     
         4 . The compound according to  claim 1 , wherein:
 X is at least one polypeptide having 80% identity to a full length abaloparatide or analogs thereof;   Y is at least one polypeptide comprising at least 80% sequence identity to amino acid residues 35-46 of a full length parathyroid hormone related peptide; and   Z is at least one polypeptide comprising 4 or more acidic amino acid residues, polyphosphate, and/or alendronate or derivatives thereof.   
     
     
         5 . The compound according to  claim 1 , wherein:
 Z is at least one polypeptide comprising 6, 7, 8, 9, and/or 10 acidic amino acid residues.   
     
     
         6 . The compound according to  claim 1 , wherein the acidic amino acid residues comprise L- or D-aspartic acid, L- or D-glutamic acid, or a combination thereof. 
     
     
         7 . The compound according to  claim 1 , wherein the acidic amino acid residues further comprises branched amino acid, and/or branched chains of amino acids. 
     
     
         8 . The compound according to  claim 1 , wherein:
 Y is at least one polypeptide comprising the formula of Gly-Gly-Pro-Nle, wherein Nle comprises norleucine, leucine, isoleucine, and/or an equivalent thereof.   
     
     
         9 . The compound according to  claim 1 , wherein the compound of the formula X—Y—Z is at least one polypeptide having at least 80%, 90%, and/or 95% sequence identity to SEQ ID NO: 10 and/or SEQ ID NO: 11. 
     
     
         10 . The compound according to  claim 1 , wherein the compound of the formula X—Y—Z is at least one polypeptide having SEQ ID NO: 10 and/or SEQ ID NO: 11. 
     
     
         11 . The compound according to  claim 1 , wherein X is at least one agonist of parathyroid hormone receptor 1. 
     
     
         12 . The compound according to  claim 1 , wherein X is at least one polypeptide having at least 80% sequence homology to the first 13 amino acids of a full length parathyroid hormone related peptide (SEQ ID NO: 12), at least 80% sequence homology to the first 13 amino acids of a full length parathyroid hormone (SEQ ID NO: 13), and/or at least 80% homology to the first 13 amino acids of SEQ ID NO:3. 
     
     
         13 . A method of treating a bone-related disease, the method comprising the steps of:
 providing a subject at least one therapeutically effective dose of a compound of  claim 1  or a pharmaceutically acceptable salt or metabolite thereof.   
     
     
         14 . The method according to  claim 13 , wherein the subject comprises a human, an animal, a cell, and/or a tissue. 
     
     
         15 . The method according to  claim 13 , wherein the bone-related disease comprises osteopenia, osteoporosis, rheumatoid arthritis, hematologic, autoimmunity, transplant rejection, and/or bone fracture. 
     
     
         16 . The method according to  claim 13 , the effective dose of the compound of any one of  claims 1 - 10  comprises from 0.001 nmol/kg/day to 1000 nmol/kg/day, from 0.01 nmol/kg/day to 1000 nmol/kg/day, from 0.1 nmol/kg/day to 1000 nmol/kg/day, from 1 nmol/kg/day to 500 nmol/kg/day, from 1 nmol/kg/day to 250 nmol/kg/day, from 1 nmol/kg/day to 100 nmol/kg/day, from 10 nmol/kg/day to 75 nmol/kg/day, and/or from 20 nmol/kg/day to 50 nmol/kg/day. 
     
     
         17 . The method according to  claim 13 , wherein the compound is administered orally, parenterally, rectally, and/or transdermally. 
     
     
         18 . A compound comprising:
 a compound of the formula X—Z;   wherein:   X is at least one peptide; and   Z is at least one bone-targeting molecule;   or a pharmaceutically acceptable salt thereof, or a metabolite thereof.   
     
     
         19 . The compound according to  claim 18 , wherein Z is at least one molecule that preferentially and/or selectively targets fractured bone. 
     
     
         20 . The compound according to  claim 18 , wherein X is at least one peptide having fewer than 60, 50, 40, 30, 20, and/or 10 amino acid residues. 
     
     
         21 - 36 . (canceled)