US-12617831-B2 - Peptide targeting GIP and GLP-2 receptors for treating bone disorders

Abstract

Disclosed is an isolated peptide including the consensus amino acid sequence SEQ ID NO: 1: (SEQ ID NO: 1) HGEGSFX7SDX10 SX12X13LDKLAARDFVNWLLQTK wherein X7 is any amino acid residue, X10 is any amino acid residue, X12 is any amino acid residue and X13 is any amino acid residue. Also disclosed are methods of using such peptide in the treatment of bone disorders.

Inventors

• Guillaume MABILLEAU
• Aleksandra MIECZKOWSKA

Assignees

• UNIVERSITE D'ANGERS
• CENTRE HOSPITALIER UNIVERSITAIRE D'ANGERS

Dates

Publication Date

20260505

Application Date

20200221

Priority Date

20190221

Claims (14)

1. 1 . An isolated peptide comprising the consensus amino acid sequence SEQ ID NO: 1: (SEQ ID NO: 1) HGEGSFX 7 SDX 10 SX 12 X 13 LDKLAARDFVNWLLQTK wherein X 7 is an amino acid selected from the group consisting in glycine, valine, and threonine, X 10 is an amino acid residue selected from the group consisting of methionine, leucine and phenylalanine, X 12 is an amino acid selected from the group consisting in isoleucine and valine and X 13 is an amino acid selected from the group consisting in alanine and valine, provided that when X 12 is isoleucine, then X 13 is alanine, and when X 12 is valine, X 13 is valine.
2. 2 . The peptide according to claim 1 , wherein the C-terminal lysine is amidated.
3. 3 . The peptide according to claim 1 , comprising the consensus amino acid sequence SEQ ID NO: 2: (SEQ ID NO: 2) HGEGSFX 7 SDX 10 SX 12 X 13 LDKLAARDFVNWLLQTKITD, wherein X 7 is an amino acid selected from the group consisting in glycine, valine, and threonine, X 10 is an amino acid residue selected from the group consisting of methionine, leucine and phenylalanine, X 12 is an amino acid selected from the group consisting in isoleucine and valine and X 13 is an amino acid selected from the group consisting in alanine and valine, provided that when X 12 is isoleucine, then X 13 is alanine, and when X 12 is valine, X 13 is valine.
4. 4 . The peptide according to claim 3 , further comprising a peptide tag at its C-terminal end.
5. 5 . An isolated peptide comprising an amino acid sequence selected from the group consisting of the peptides: GL-0001 of sequence (SEQ ID NO: 3) HGEGSFGSDMSIALDKLAARDFVNWLLQTKITD, GL-0007 of sequence (SEQ ID NO: 4) HGEGSFGSDFSIALDKLAARDFVNWLLQTK-NH 2 , GL-0001-Tag of sequence (SEQ ID NO: 5) HGEGSFGSDMSIALDKLAARDFVNWLLQTKITDGAADDDDDD, GL-0004 of sequence (SEQ ID NO: 8) HGEGSFVSDMSVVLDKLAARDFVNWLLQTK-NH 2 , GL-0005 of sequence (SEQ ID NO: 9) HGEGSFVSDLSVVLDKLAARDFVNWLLQTK-NH 2 , GL-0006 of sequence (SEQ ID NO: 10) HGEGSFVSDFSVVLDKLAARDFVNWLLQTK-NH 2 , and GL-0008 of sequence (SEQ ID NO: 11) HGEGSFTSDFSIALDKLAARDFVNWLLQTK-NH 2 .
6. 6 . A pharmaceutical composition comprising a peptide as defined in claim 1 .
7. 7 . An implantable medical device comprising a peptide as defined in claim 1 .
8. 8 . A bone filling biomaterial comprising a peptide as defined in claim 1 .
9. 9 . A method for treating a bone disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide as defined in claim 1 , wherein the bone disorder is selected from osteoporosis, osteopenia, diabetic bone disease, osteomalacia, rickets, and bone dystrophies.
10. 10 . The method according to claim 9 , wherein the bone dystrophies are Paget's disease of bone, osteogenesis imperfecta, and osteomyelitis.
11. 11 . The method according to claim 10 , wherein said bone disorder is osteogenesis imperfecta.
12. 12 . A method for treating a bone disorder in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as defined in claim 6 , wherein the bone disorder is selected from osteoporosis, osteopenia, diabetic bone disease, osteomalacia, rickets, and bone dystrophies.
13. 13 . The method according to claim 12 , wherein the bone dystrophies are Paget's disease of bone, osteogenesis imperfecta, and osteomyelitis.
14. 14 . The method according to claim 13 , wherein said bone disorder is osteogenesis imperfecta.

Description

BACKGROUND OF THE INVENTION Field of the Invention The present invention concerns the treatment of bone disorders. Description of the Related Art Today, bone fragilities represent an important public health issue. Indeed, with the population ageing, the number of bone fractures is constantly increasing (377 000 fractures in France in 2013) with serious socio-economical consequences. Bone tissue is a tissue which is permanently remodeled in order to adapt to mechanical stress (gravity, movements, etc.) but also to metabolic stress (release or storage of calcium, phosphate, proteins, etc.) and represents a system balanced between bone formation and bone resorption. Bone remodeling depends on several factors such as calcium phosphate metabolism hormones, mechanical load or local factors. Bone fragilities happen when an imbalance of bone formation and bone resorption activities, during bone remodeling, occurs, or when bone cells activity is disturbed. This leads either to a decrease in the amount of bone tissue or to an alteration of the bone matrix quality, or to both of them, and results in an increased bone fragility and a high risk of fracture. Several therapeutic solutions to treat bone fragilities exist (vitamin D, bisphosphonates, anti-RANKL, recombinant calcitonin, intermittent injection of recombinant parathormone, modulators of estrogens receptor) or are about to be marketed (anti-cathepsin K, anti-sclerostin, PTHrP analog). However, these molecules display use restrictions and cannot be administered to all the patients suffering from bone fragility. Additionally, some of these molecules have side effects (mandibular osteonecrosis, atypical fracture of the femur, risk of cancer), which demand strict monitoring and regular follow-up of the patients. Furthermore, the efficiency of these molecules remains moderate, and despite their use, it is estimated that only 50% of bone fragility fractures are prevented in case of ongoing treatment, confirming the need to find new therapeutic pathways. SUMMARY OF THE INVENTION The present invention meets this need. It was recently shown that intestinal hormones, released after the entry of the food bowl in the intestine, acted on bone remodeling. Among the plethora of bioactive peptides that the gastrointestinal tract secretes, a class of peptides called incretins has emerged as important modulators of energy metabolism. Incretins are hormones that are secreted from the intestine in response to glucose and stimulate insulin release in a glucose-dependent manner. Although several hormones with insulinotropic action are secreted by the gut, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the only two physiological incretins identified so far. Recently, based on knockout preclinical animal models, potential beneficial effects of both GIP and GLP-1 have been highlighted on diabetes-induced bone fragility. The present invention arises from the unexpected finding by the inventors that a peptide bearing a specifically designed consensus sequence was capable to bind to and activate both glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide 2 (GLP-2) receptor similarly to respective GIP and GLP-2 native peptides, and thereby to control bone remodeling. In particular, the inventors show that this dual-target peptide increased enzymatic cross-linking of collagen matrix produced by osteoblasts at a higher level than each native peptide and reduced the number of generated osteoclasts in a more important way than each native peptide. The present invention thus concerns an isolated peptide comprising the consensus amino acid sequence SEQ ID NO: 1: (SEQ ID NO: 1)HGEGSFX7SDX10 SX12X13LDKLAARDFVNWLLQTK wherein X7 is any amino acid residue, X10 is any amino acid residue, X12 is any amino acid residue and X13 is any amino acid residue. The present invention also concerns a pharmaceutical composition comprising a peptide of the invention. The present invention further concerns an implantable medical device comprising, in particular coated with, the peptide of the invention. Another object of the invention is the in vitro use of a peptide of the invention for coating an implantable medical device. A further object of the invention concerns a peptide of the invention or a pharmaceutical composition of the invention for use in a method for treating and/or preventing a bone disorder in a subject. In a particular embodiment, said bone disorder is a manifestation, in bones, of a metabolic or hormonal disorder. The present invention also concerns a bone filling biomaterial comprising the peptide of the invention. The present invention further concerns a bone filling biomaterial comprising the peptide of the invention for use for bone regeneration. DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions In the context of the invention, the term “peptide” refers to native peptides (either proteolysis products or syntheticall