Peptide antagonists of the vasopressin-2 receptor

Patent metadata

Field	Value
Publication number	US-9631001-B2
Application number	US-201314427733-A
Country	US
Kind code	B2
Filing date	Sep 17, 2013
Priority date	Sep 17, 2012
Publication date	Apr 25, 2017
Grant date	Apr 25, 2017

Abstract

The invention relates to a new group of snake venom basic protease inhibitors having vasopressin-2 receptor antagonist activity that can be used in therapy, diagnosis, medical imaging, drug screening and research.

First claim

The invention claimed is:

1. A method of inhibiting the vasopressin-2 receptor (V2R) pathway in a subject in need thereof comprising administering a V2R antagonist to the subject, wherein said V2R antagonist comprises a isolated protein, comprising an amino acid sequence which is at least 65% identical to residues 1 to 57 of SEQ ID NO: 1, and which comprises:
(i) a motif X 1 X 2 X 3 X 4 in positions 15 to 18 of SEQ ID NO: 1, wherein X 1 is an asparagine (N), X 2 is a glycine (G), X 3 and X 4 are hydrophobic amino acids or X 1 is a methionine (M), X 2 and X 3 are phenylalanines (F), and X 4 is an Isoleucine (I), and
(ii) one to three disulfide bonds between two cysteine residues,
and wherein said V2R antagonist is administered to the subject in an amount sufficient to inhibit the V2R pathway.

2. The method according to claim 1 , wherein said protein comprises or consists of a sequence selected from the group consisting of: the amino acid sequences of SEQ ID NO: 1 to 5, a variant of any one of SEQ ID NO: 1 to 3 comprising an N-terminal deletion of one to four amino acid residues and/or a C-terminal deletion of one or two amino acid residues, and a variant of SEQ ID NO: 5 or 6 comprising an N-terminal deletion of one to thirty amino acid residues and/or a C-terminal deletion of one or two amino acid residues.

3. The method according to claim 1 , wherein said subject suffers from a disease selected from the group consisting of pathological conditions characterized by euvolemic or hypovolemic hyponatremia, Nephrogenic Syndrome of Inappropriate Antidiuresis, Congenital Nephrogenic Diabetes Insipidus, Polycystic kidney disease, cancers, thrombosis, and Menière disease.

4. An isolated protein, comprising an amino acid sequence which is at least 70% identical to residues 1 to 57 of SEQ ID NO: 1, and which comprises:
(i) a motif X 1 X 2 X 3 X 4 in positions 15 to 18 of SEQ ID NO: 1, wherein X 1 is an asparagine (N), X 2 is a glycine (G), X 3 and X 4 are hydrophobic amino acids, and
(ii) one to three disulfide bonds between two cysteine residues, and wherein said protein has V2R antagonist activity.

5. The protein according to claim 4 , wherein said sequence comprises an N-terminal deletion of one to four amino acid residues of SEQ ID NO: 1 and/or a C-terminal deletion of one or two amino acid residues of SEQ ID NO: 1.

6. The protein according to claim 4 , wherein said sequence comprises one to three disulfide bonds chosen from disulfide bonds between C1 and C6, C2 and C4, and C3 and C5, wherein C1 to C6 are each a cysteine residue, numbered, respectively from the N-terminus to the C-terminus of said sequence.

7. The protein according to claim 6 , wherein C1 to C6 are in positions 5, 14, 30, 38, 51 and 55, respectively of SEQ ID NO: 1.

8. The protein according to claim 4 , which comprises or consists of any one of SEQ ID NO: 1 and 11 to 13.

9. The protein according to claim 4 , wherein said protein is labeled.

10. An expression vector comprising a polynucleotide encoding a protein according to claim 4 .

11. A host cell modified with a polynucleotide encoding a protein according to claim 4 .

12. A pharmaceutical composition, comprising at least: (i) a protein according to claim 4 , a polynucleotide encoding said protein, and/or a vector comprising said polynucleotide, and (ii) a pharmaceutically acceptable carrier.

13. A diagnostic or imaging reagent comprising a labeled protein according to claim 9 .

Assignees

• Commissariat Energie Atomique
• Centre Nat De La Rech Scient (Cnrs)
• Inst Nat De La Sante Et De La Rech Medicale (Inserm)
• Univ Of Regensburg
• Univ Liege
• Centre Nat Rech Scient
• Univ Liege

Inventors

• Gilles Nicolas
• Servent Denis
• Quinton Loïc
• Reinfrank Helen
• Witzgall Ralph
• Mouillac Bernard
• Mendre Christiane

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title