Antagonists of neurokinin B in fish reproduction

Patent metadata

Field	Value
Publication number	US-10155790-B2
Application number	US-201515326602-A
Country	US
Kind code	B2
Filing date	Jul 16, 2015
Priority date	Jul 17, 2014
Publication date	Dec 18, 2018
Grant date	Dec 18, 2018

Abstract

Provided are Peptide-based neurokinin antagonists of fish reproduction. Compositions including antagonists of fish neurokinin and methods of inhibiting or delaying puberty, fish maturation or reproduction processes using these compounds are also provided.

First claim

The invention claimed is:

1. A peptidomimetic according to formula I: X 1 -NMeVal-X 4 -Leu-Met-Z (Formula I), wherein:
the peptidomimetic consists of 5-10 amino acids;
X 1 is a stretch of 1-6 natural or non-natural amino acid residues and optionally an N-terminal capping moiety or modification;
NMeVal is an N-methyl-Valine residue or N-methyl-D-Valine residue;
X 4 is —NH(CH2)n-CO— wherein n is 2-6; and
Z represents the C-terminus of the peptide which may be amidated, acylated, reduced or esterified.

2. The peptidomimetic of claim 1 , wherein X 1 comprises at least one aromatic amino acid residue in L or D configuration.

3. The peptidomimetic of claim 1 , wherein X 1 comprises at least one negatively charged acidic amino acid residue.

4. The peptidomimetic of claim 1 , wherein X 1 consists of 2 or 3 amino acid residues comprising an aromatic residue, a negatively charged acidic residue and an N-terminus capping moiety.

5. The peptidomimetic of claim 4 , wherein X 1 comprises a residue selected from an aliphatic amino acid residue and a polar, uncharged residue.

6. The peptidomimetic of claim 1 , wherein X 1 comprises an aromatic residue selected from the group consisting of Phe, DPhe, Trp and DTrp; a negatively charged acidic residue selected from Glu and Asp; and a succinyl (Succ) N-terminus capping moiety.

7. The peptidomimetic of claim 1 , wherein X 1 comprises an aromatic residue selected from Phe, and DTrp; an Asp residue; a succinyl (Succ) N-terminus capping moiety, and optionally a residue selected from Ile and Ser.

8. The peptidomimetic of claim 1 , wherein the peptidomimetic is according to Formula II: X 1 -NMeVal-βAla-Leu-Met-NH 2 (Formula II), and X 1 is selected from the group consisting of: Succ-Asp-Phe; Succ-Asp-DPhe; Succ-Asp-Trp; Succ-Asp-DTrp; Succ-Asp-Ile-Phe; Succ-Asp-Ile-DPhe; Succ-Asp-Ile-Trp; Succ-Asp-Ile-DTrp; Succ-Asp-Ser-Phe; Succ-Asp-Ser-DPhe; Succ-Asp-Ser-Trp; Succ-Asp-Ser-DTrp, Succ-Glu-Phe; Succ-Glu-DPhe; Succ-Glu-Trp; Succ-Glu-DTrp; Succ-Glu-Ile-Phe; Succ-Glu-Ile-DPhe; Succ-Glu-Ile-Trp; Succ-Glu-Ile-DTrp; Succ-Glu-Ser-Phe; Succ-Glu-Ser-DPhe; Succ-Glu-Ser-Trp; and Succ-Glu-Ser-DTrp.

9. The peptidomimetic of claim 1 , consisting of 5-10 amino acid residues comprising the sequence: NMeVal-βAla-Leu-Met (SEQ ID NO: 7).

10. The peptidomimetic of claim 9 , wherein the peptidomimetic comprises a sequence of SEQ ID NO: 7, at least one aromatic amino acid residue, at least one negatively charged amino acid residue, at least one residue selected from an aliphatic amino acid residue and a polar, uncharged residue, and a capped N-terminus.

11. The peptidomimetic of claim 1 , wherein the peptidomimetic is selected from the group consisting of:

(SEQ ID NO: 1, Ant-1)

Succ-Asp-Ile-Phe-N(Me)Val-βAla-Leu-Met-NH 2 ;

(SEQ ID NO: 2, Ant-2)

Succ-Asp-Phe-N(Me)Val-βAla-Leu-Met-NH 2 ;

(SEQ ID NO: 3, Ant-3)

Succ-Asp-Ser-Phe-N(Me)Val-βAla-Leu-Met-NH 2 ;

(SEQ ID NO: 4, Ant-4)

Succ-Asp-Ile-D-Trp-N(Me)Val-βAla-Leu-Met-NH 2 ;

(SEQ ID NO: 5, Ant-5)

Succ-Asp-D-Trp-N(Me)Val-βAla-Leu-Met-NH 2 ; 

and

(SEQ ID NO: 6, Ant-6)

Succ-Asp-Ser-D-Trp-N(Me)Val-βAla-Leu-Met-NH 2 ;

wherein Succ denotes a succinyl.

12. A composition comprising a peptidomimetic according to claim 1 .

13. The composition of claim 12 , wherein the composition is in a form of a pharmaceutical composition comprising at least one acceptable carrier, diluent, salt or excipient or a food composition comprising at least one nutrient and optionally at least one food additive.

14. The composition of claim 13 , formulated for administration to fish by a route selected from the group consisting of: intraparietal administration, oral administration and administration by immersion, or as part of regular food or water consumption.

15. A method of inhibiting at least one parameter of fish reproduction or maturation, the method comprising administering to fish a composition according to claim 12 .

16. The method of claim 15 , wherein inhibition of at least one parameter of fish reproduction or maturation comprises a parameter selected from the group consisting of: delaying or eliminating puberty; delaying or eliminating precocious puberty; regulating gender determination; regulating gender differentiation; spawning and treating hormone-dependent problems or processes connected to reproduction.

17. The method of claim 16 , wherein inhibition of fish reproduction or maturation results in increased weight of the treated fish.

18. The method according to claim 15 , wherein fish is selected from the group consisting of: tilapia, carp, salmon, bass, catfish and mullet.

19. The method according to claim 15 , wherein the composition is administered to fish by a route selected from the group consisting of: parenteral, oral and administration by immersion.

20. The method of claim 15 , wherein the composition is administered to fish as part of food or water consumption.

Assignees

• Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd

Inventors

• Levavi-Sivan Berta
• Gilon Chaim

Classifications

• A61P43/00

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

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A23K20/147

  Polymeric derivatives, e.g. peptides or proteins · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A23K40/30

  by encapsulating; by coating · CPC title