Therapeutic peptide

Abstract

To provide a peptide exhibiting anxiolytic-like activity, and a pharmaceutical and a food including such a peptide.SOLUTION: A peptide comprising any amino acid sequence selected from (i) the amino acid sequence SYLPPLTT (SEQ ID NO: 1), (ii) the amino acid sequence YHIEPV (SEQ ID NO: 2), (iii) the amino acid sequence YLLVK (SEQ ID NO: 3), (iv) the amino acid sequence SYLPPLT (SEQ ID NO: 4), (v) the amino acid sequence FLLVK (SEQ ID NO: 5), and (vi) the amino acid sequence WLLVK (SEQ ID NO: 6).SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority from Japanese Patent Application No. 2017-041181, filed on March 4, 2017, the contents of which are incorporated herein by reference in their entirety.

[0002] 1.Technical Field The present invention relates to peptides and peptide conjugates. The present invention also relates to pharmaceutical compositions and foods comprising the peptides and peptide conjugates. [Background technology]

[0003] 2. Background technology Japan is now known to be at the forefront of a super-aging society, and there are high expectations for achieving active and healthy aging. So-called soft foods that focus on the decline in chewing and swallowing functions have been developed as foods adapted to the elderly. However, there are few foods that focus on the decline in nervous system function, such as physiological anorexia, decreased motivation, and psychological stress, associated with aging.

[0004] Such psychological stress can increase the risk of developing lifestyle-related diseases.

[0005] For caregivers, there is a need to develop next-generation functional foods that can slow, halt, or reverse neurological decline.

[0006] Non-Patent Document 1 states that spinach-derived rubiscolin-6 has anxiolytic activity. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Hirata H, Sonoda S, Agui S, Yoshida M, Ohinata K, Yoshikawa M. Peptides. 2007 Oct;28(10):1998-2003. Summary of the Invention [Problem to be solved by the invention]

[0008] One object of the present invention is to provide peptides having anxiolytic-like activity, and medicines and foods containing such peptides. [Means for solving the problem]

[0009] 3. Summary of the Invention The present inventors aimed to develop a functional component that reduces psychological stress, and as a result, identified peptides that exhibit anxiolytic or antidepressant-like effects. The present invention was completed through further research based on these findings.

[0010] Specifically, the following examples include the following aspects:

[0011] In one aspect, the present disclosure provides peptides derived from pepsin and pepsin plus pancreatin digests of Rubisco protein, salts thereof, peptide conjugates, and salts thereof (collectively sometimes referred to as "compounds"), such as any of SEQ ID NOs: 1 to 6. The present invention provides a peptide having an amino acid sequence of: When an embodiment described herein refers to a "peptide," it is understood that the embodiment encompasses the peptide itself as well as salts of the peptide, unless the context requires otherwise, even if the embodiment does not explicitly recite the phrase "or salts thereof" or similar phrase. Similarly, a disclosure of a peptide encompasses conjugates of the peptide and salts of the conjugate, unless the context requires otherwise.

[0012] In one aspect, the present disclosure provides a peptide having an amino acid sequence that is 3 to 20 amino acids in length and includes at least three consecutive amino acids from the N-terminus or C-terminus of the amino acid sequence X1LX2X3VK (SEQ ID NO: 8), where X1 is a hydrophobic amino acid, and X2 and X3 are each independently selected from any amino acid, preferably an amino acid selected from hydrophobic amino acids. As used herein, "hydrophobic amino acid" refers to an amino acid having a hydrophobic side chain, e.g., A, I, L, M, V, F, W, and Y. In some embodiments, a hydrophobic amino acid is a naturally occurring amino acid. In some embodiments, one, two, or all three of X1, X2, and X3 are aromatic amino acids (e.g., Y, F, or W). In some embodiments, a peptide includes four or five consecutive amino acids from the N-terminus or C-terminus of the amino acid sequence of SEQ ID NO: 8. Thus, a peptide can include X1, L, X2, or X3 at the N-terminal position. A peptide can also have an N-terminal amino acid other than X1, L, X2, or X3. Preferably, the N-terminal amino acid is a hydrophobic amino acid. Such SEQ ID NO: 8-based peptides can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length, or can have lengths ranging between any pair of the foregoing embodiments, e.g., 3-10 amino acids in length, 4-9 amino acids in length, 4-18 amino acids in length, 5-12 amino acids in length, 6-15 amino acids in length, 6-10 amino acids in length, etc.

[0013] In another aspect, the present disclosure provides peptides 5-20 amino acids in length, comprising the amino acid sequence SYLPP (SEQ ID NO: 24) at the N-terminus of the peptide. Such SEQ ID NO: 24-based peptides can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length, or can have lengths ranging between any pair of the foregoing embodiments, e.g., 5-10 amino acids in length, 5-9 amino acids in length, 6-18 amino acids in length, 5-12 amino acids in length, 6-15 amino acids in length, 6-10 amino acids in length, etc.

[0014] In another aspect, the disclosure provides peptides 6-20 amino acids in length, comprising the amino acid sequence YHIEPV (SEQ ID NO: 2). Such SEQ ID NO: 2-based peptides can be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length, or can have lengths ranging between any pair of the foregoing embodiments, e.g., 6-10 amino acids in length, 6-9 amino acids in length, 6-18 amino acids in length, 6-12 amino acids in length, 7-15 amino acids in length, 7-10 amino acids in length, etc.

[0015] In another aspect, the present disclosure provides pharmaceutical compositions and foods comprising the peptides or peptide conjugates of the present disclosure.

[0016] In another aspect, the present disclosure provides methods of treating or preventing mood disorders, anxiety disorders, or reduced motivation disorders using the peptides, peptide conjugates, pharmaceutical compositions, and foods described herein.

[0017] In one aspect, the present disclosure provides the following embodiments, labeled Items 1 to 3:

[0018] Item 1. At least three consecutive amino acids from the amino acid sequence XLLVK (SEQ ID NO: 25) Acid-containing peptides (in SEQ ID NO: 25, X is an aromatic amino acid). As used herein, "aromatic amino acid" refers to an amino acid having an aromatic side chain (e.g., F, W, and Y).

[0019] Item 2. The peptide according to item 1, wherein X is Y (tyrosine), F (phenylalanine) or W (tryptophan).

[0020] Item 3. A peptide comprising any amino acid sequence selected from the following amino acid sequences or the following amino acid sequences in which 1 to 3 amino acids are deleted, substituted, and / or added: (i) the amino acid sequence SYLPPLTT (SEQ ID NO: 1); (ii) the amino acid sequence YHIEPV (SEQ ID NO: 2); (iii) the amino acid sequence YLLVK (SEQ ID NO: 3); (iv) the amino acid sequence SYLPPLT (SEQ ID NO: 4); (v) the amino acid sequence FLLVK (SEQ ID NO: 5), and (vi) Amino acid sequence WLLVK (SEQ ID NO: 6).

[0021] In another aspect, the present disclosure provides the following embodiments labeled Items 1 to 26.

[0022] Item 1. A peptide comprising any amino acid sequence selected from the following: (i) the amino acid sequence SYLPPLTT (SEQ ID NO: 1); (ii) the amino acid sequence YHIEPV (SEQ ID NO: 2); (iii) the amino acid sequence YLLVK (SEQ ID NO: 3); (iv) the amino acid sequence SYLPPLT (SEQ ID NO: 4); (v) the amino acid sequence FLLVK (SEQ ID NO: 5), and (vi) Amino acid sequence WLLVK (SEQ ID NO: 6).

[0023] Item 2. A pharmaceutical composition comprising the peptide according to Item 1 as an active ingredient.

[0024] Item 3. A pharmaceutical composition comprising the peptide according to item 1 and a pharmaceutically acceptable diluent, carrier, or excipient.

[0025] Item 4. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is a therapeutic agent for anxiety disorders.

[0026] Item 5. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is a therapeutic agent for depression.

[0027] Item 6. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is a therapeutic agent for adjustment disorder.

[0028] Item 7. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is a therapeutic agent for bipolar disorder.

[0029] Item 8. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is a therapeutic agent for motivational disorders.

[0030] Item 9. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is a therapeutic agent for blunted affect.

[0031] Item 10. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is a therapeutic agent for abulia.

[0032] Item 11. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is a therapeutic agent for akinetic mutism.

[0033] Item 12. An oral medication comprising the pharmaceutical composition according to any one of items 2 to 11.

[0034] Item 13. A food product containing the peptide according to Item 1.

[0035] Item 14. A food to which the peptide described in Item 1 has been added.

[0036] Item 15. Foods according to items 13 or 14 for delaying, stopping or reversing anxiety states.

[0037] Item 16. A composition comprising Rubisco protein treated with pepsin or pancreatin.

[0038] Item 17. A food product comprising the composition according to Item 16.

[0039] Item 18. A food supplemented with the composition according to Item 16.

[0040] Item 19. A method for ameliorating or treating an anxiety disorder or an anxiety-based condition, comprising administering the peptide according to Item 1 to a patient suffering from or likely to suffer from an anxiety disorder or an anxiety-based condition.

[0041] Item 20. The peptide according to item 1 for use in ameliorating or treating anxiety disorders or anxiety-based symptoms.

[0042] Item 21. Use of the peptide according to Item 1 for producing a medicine or food for the amelioration or treatment of anxiety disorders or symptoms based on anxiety.

[0043] Item 22. Green plants for use in the recovery or treatment of anxiety disorders or anxiety-based symptoms.

[0044] Item 23. A method for ameliorating or treating loss of motivation, depression, depressive mood disorder, or symptoms based thereon, comprising administering the peptide according to Item 1 to a patient suffering from or likely to suffer from loss of motivation, depression, depressive mood disorder, or symptoms based thereon.

[0045] Item 24. The peptide according to Item 1 for use in ameliorating or treating depression, depressive mood disorder, or symptoms associated therewith.

[0046] Item 25. Use of the peptide according to Item 1 for producing a medicine or food for ameliorating or treating depression, depressive mood disorder, or symptoms associated therewith.

[0047] Item 26. Leaves of green plants for use in the treatment or amelioration of depression, depressive mood disorders or symptoms associated therewith. [Effects of the Invention]

[0048] Pharmaceutical compositions and foods containing the peptides of the present invention as active ingredients have a high anxiolytic effect with low adverse reactions, are suitable for long-term use, and / or have an antidepressant effect (hereinafter, "antidepressant effect" includes "antidepressant effect"). Furthermore, the pharmaceutical compositions and foods of the present invention are suitable for oral administration.

[0049] Natural short-chain peptides can be ingested as food, and it is expected that the disease in individuals with anxiety disorders can be prevented by ingesting these peptides as food.

[0050] One aspect of the peptides of the present invention is an enzymatic digest of a chloroplast protein, and therefore The problem of adverse reactions is not involved. Furthermore, the chloroplast Rubisco protein is abundant in green plants and therefore can be produced at low cost.

[0051] 4. Brief description of the drawings [Brief explanation of the drawings]

[0052] [Figure 1] Figure 1 shows the test method for the elevated plus maze (EPM). The test was performed 30 minutes after oral administration of the sample, and evaluation was performed based on a 5-minute test period. ddY mice weighing 23-27 g were used as test animals. The cumulative time spent in the open arms was recorded, and the percentage (%) of time spent in the open arms was used as an index of anxiolytic-like effects. [Figure 2] FIG. 2 shows the extraction method of Rubisco protein from spinach and the SDS-PAGE results. [Figure 3] FIG. 3 shows the results of the elevated plus maze test in Example 1. [Figure 4] FIG. 4 shows the results of the elevated plus maze test in Example 2. [Figure 5] FIG. 5 shows the results of the elevated plus maze test in Example 3. [Figure 6] FIG. 6 shows the results of the elevated plus maze test in Example 4. [Figure 7] FIG. 7 shows the results of the elevated plus maze test in Example 5. [Figure 8] FIG. 8 shows the results of the elevated plus maze test in Example 6. [Figure 9] FIG. 9 shows the results of investigating the mechanism of action of the enzymatic digest using antagonists, as described in Example 7. [Figure 10]FIG. 10 shows the results of the elevated plus maze test in Example 8. [Figure 11] FIG. 11 shows the results of the elevated plus maze test in Example 9. [Figure 12] FIG. 12 shows the results of the elevated plus maze test in Example 10. [Figure 13] FIG. 13 shows the results of the elevated plus maze test in Example 11. [Figure 14] FIG. 14 shows the results of the elevated plus maze test in Example 12. [Figure 15] FIG. 15 shows the results of the elevated plus maze test in Example 13. [Figure 16] FIG. 16 shows the results of the tail suspension test of Example 14. [Figure 17] FIG. 17 shows the results of the elevated plus maze test in Example 15. [Figure 18] FIG. 18 shows the results of the elevated plus maze test in Example 16. [Figure 19] FIG. 19 shows cleavage sites by gastrointestinal proteases in the small (A) and large (B) subunits of Rubisco. [Figure 20] FIG. 20 shows the results of the elevated plus maze test in Example 18. [Figure 21] FIG. 21 shows the results of the intracellular cAMP assay of Example 19. DETAILED DESCRIPTION OF THE INVENTION

[0053] 5. Detailed Description

[0054] 5.1 Peptides

[0055] In one aspect, the present disclosure provides peptides and salts thereof derived from pepsin and pepsin plus pancreatin digests of Rubisco protein, e.g., peptides having any of the amino acid sequences set forth in SEQ ID NOs: 1 to 6. One preferred peptide of the present disclosure, a peptide having the amino acid sequence YLLVK (SEQ ID NO: 3), was identified in pepsin and pepsin plus pancreatin digests of spinach sorghum bisco protein. However, the peptide YLLVK (SEQ ID NO: 3) was not detected in subsequent digests. Nevertheless, this peptide was found to have anxiolytic-like effects upon characterization as described in the Examples. Exemplary peptides based on SEQ ID NOs: 1 to 6 are described herein, including peptides based on the amino acid sequences of SEQ ID NOs: 8, 24, and 28.

[0056] 5.1.1 SEQ ID NOs: 1 to 6 base peptides

[0057] In certain embodiments, the peptides of the present invention are peptides comprising any amino acid sequence selected from the following amino acid sequences or amino acid sequences in which 1 to 3 amino acids have been deleted, substituted, and / or added: (i) the amino acid sequence SYLPPLTT (SEQ ID NO: 1), (ii) the amino acid sequence YHIEPV (SEQ ID NO: 2), (iii) the amino acid sequence YLLVK (SEQ ID NO: 3), (iv) the amino acid sequence SYLPPLT (SEQ ID NO: 4), (v) the amino acid sequence FLLVK (SEQ ID NO: 5), and (vi) the amino acid sequence WLLVK (SEQ ID NO: 6).

[0058] In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with one deletion compared to the amino acid sequence of any one of SEQ ID NOs: 1-6. In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with two deletions compared to the amino acid sequence of any one of SEQ ID NOs: 1-6. In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with three deletions compared to the amino acid sequence of any one of SEQ ID NOs: 1-6.

[0059] In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with one amino acid substitution compared to the amino acid sequence of any one of SEQ ID NOs: 1-6. In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with two amino acid substitutions compared to the amino acid sequence of any one of SEQ ID NOs: 1-6. In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with three amino acid substitutions compared to the amino acid sequence of any one of SEQ ID NOs: 1-6.

[0060] In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with one additional amino acid compared to the amino acid sequence of any one of SEQ ID NOs: 1-6. In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with two additional amino acids compared to the amino acid sequence of any one of SEQ ID NOs: 1-6. In some embodiments, the peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-6, but with three additional amino acids compared to the amino acid sequence of any one of SEQ ID NOs: 1-6.

[0061] In another aspect, the peptide of the present invention is a peptide comprising any amino acid sequence selected from (i) the amino acid sequence SYLPPLTT (SEQ ID NO: 1), (ii) the amino acid sequence YHIEPV (SEQ ID NO: 2), (iii) the amino acid sequence YLLVK (SEQ ID NO: 3), (iv) the amino acid sequence SYLPPLT (SEQ ID NO: 4), (v) the amino acid sequence FLLVK (SEQ ID NO: 5), and (vi) the amino acid sequence WLLVK (SEQ ID NO: 6).

[0062] The peptides based on the amino acid sequences of SEQ ID NOs: 1 to 6 may or may not contain amino acids other than those of SEQ ID NOs: 1 to 6, respectively. Thus, in various embodiments: (1) Peptides of the present disclosure comprising the amino acid sequences of SEQ ID NOs: 3, 5, and 6 can be up to 6, up to 7, up to 8, up to 9, up to 10, up to 12, up to 15, up to 18, up to 20 amino acids, or up to 25 amino acids in length; (2) A peptide of the present disclosure comprising the amino acid sequence of SEQ ID NO:2 can be up to 6, up to 7, up to 8, up to 9, up to 10, up to 12, up to 15, up to 18, up to 20 amino acids, or up to 25 amino acids in length; (3) The peptide of the present disclosure comprising the amino acid sequence of SEQ ID NO: 4 is at most 7, at most 8, at most 9 , up to 10, up to 12, up to 15, up to 18, up to 20 amino acids or up to 25 amino acids in length; (4) Peptides of the present disclosure based on the amino acid sequence of SEQ ID NO:1 can be up to 8, up to 9, up to 10, up to 12, up to 15, up to 18, up to 20 amino acids, or up to 25 amino acids in length.

[0063] Amino acid residues can be added to the N-terminus and / or C-terminus (preferably the C-terminus) of the peptide of the present invention, as long as the resulting peptide contains the above-mentioned amino acid sequence. The number of amino acid residues to be added is not limited, and can be about 20 amino acid residues, preferably about 10 amino acid residues, more preferably about 5 amino acid residues, and even more preferably 4, 3, 2, or 1 amino acid residue.

[0064] As long as the function of the present invention is not impaired, one or more (e.g., two or three), preferably one, amino acid residue in the amino acid sequence can be similarly substituted. As long as the function of the present invention is not impaired, one or more (e.g., two or three), preferably one, amino acid residue can be inserted into the amino acid sequence. As long as the function of the present invention is not impaired, one or more (e.g., two or three), preferably one, amino acid residue can be similarly deleted from the amino acid sequence.

[0065] In some embodiments, no amino acid residues are added to the N-terminus of SYLPPLTT (SEQ ID NO: 1), SYLPPLT (SEQ ID NO: 4), or SYLPPL (SEQ ID NO: 20).

[0066] A preferred form of the peptide of the present invention includes a peptide consisting of (i) the 8-residue amino acid sequence of the amino acid sequence SYLPPLTT (SEQ ID NO: 1), (ii) the 6-residue amino acid sequence of YHIEPV (SEQ ID NO: 2), (iii) the 5-residue amino acid sequence of YLLVK (SEQ ID NO: 3), (iv) the 7-residue amino acid sequence of SYLPPLT (SEQ ID NO: 4), (v) the 5-residue amino acid sequence of FLLVK (SEQ ID NO: 5), or (vi) the 5-residue amino acid sequence of WLLVK (SEQ ID NO: 6).

[0067] 5.1.2 SEQ ID NO:8 Base Peptides

[0068] In one aspect, the disclosure provides a peptide that is 3 to 20 amino acids in length, having an amino acid sequence comprising at least three (e.g., 3, 4, 5, or 6) consecutive amino acids from the N-terminus or C-terminus of the amino acid sequence X1LX2X3VK (SEQ ID NO: 8), where X1 is a hydrophobic amino acid, and X2 and X3 are each independently selected from any amino acid, preferably an amino acid selected from hydrophobic amino acids. In some embodiments, the peptide has a hydrophobic N-terminal amino acid.

[0069] In some embodiments, the peptide is 3-15 amino acids in length. In other embodiments, the peptide is 3-10 amino acids in length. In other embodiments, the peptide is 4-20 amino acids in length. In other embodiments, the peptide is 4-15 amino acids in length. In other embodiments, the peptide is 4-10 amino acids in length. In other embodiments, the peptide is 5-20 amino acids in length. In other embodiments, the peptide is 5-15 amino acids in length. In other embodiments, the peptide is 5-10 amino acids in length.

[0070] In some embodiments, the peptide is 3 amino acids in length. In other embodiments, the peptide is 4 amino acids in length. In other embodiments, the peptide is 5 amino acids in length. In other embodiments, the peptide is 6 amino acids in length. In other embodiments, the peptide is 7 amino acids in length. In other embodiments, the peptide is 8 amino acids in length. In another embodiment, the peptide is 9 amino acids long. In another embodiment, the peptide is 10 amino acids long. In another embodiment, the peptide is 11 amino acids long. In another embodiment, the peptide is 12 amino acids long. In another embodiment, the peptide is 13 amino acids long. In another embodiment, the peptide is 14 amino acids long. In another embodiment, the peptide is 15 amino acids long. In another embodiment, the peptide is 16 amino acids long. In another embodiment, the peptide is 17 amino acids long. In another embodiment, the peptide is 18 amino acids long. In another embodiment, the peptide is 19 amino acids long. In another embodiment, the peptide is 20 amino acids long.

[0071] X1 can be any hydrophobic amino acid, for example, alanine (A), isoleucine (I), leucine (L), methionine (M), valine (V), phenylalanine (F), tryptophan (W), or tyrosine (W). In some embodiments, X1 is an aromatic amino acid selected from F, W, and Y. In some embodiments, X1 is F. In other embodiments, X1 is W. In other embodiments, X1 is Y.

[0072] X2 and X3 are preferably hydrophobic amino acids such as A, I, L, M, V, F, or W. X2 and X3 can be the same or different. In some embodiments, X2 and X3 are the same. In other embodiments, X2 and X3 are different. In some embodiments, X2 and / or X3 are selected from L, I, V, and A. In some embodiments, X2 is L. In some embodiments, X2 is I. In some embodiments, X2 is V. In some embodiments, X2 is A. In some embodiments, X3 is L. In some embodiments, X3 is I. In some embodiments, X3 is V. In some embodiments, X3 is A.

[0073] In some embodiments, the N-terminal amino acid of the peptide is X1. In some embodiments, the two N-terminal amino acids of the peptide are X1L, e.g., YL, FL, or WL.

[0074] In some embodiments, the C-terminal amino acid of the peptide is K. In some embodiments, the two C-terminal amino acids of the peptide are VK.

[0075] In some embodiments, the first two N-terminal amino acids of the peptide are X1L, e.g., YL, FL, or WL, and the two C-terminal amino acids are VK. For example, the peptide can have the amino acid sequence YLLVK (SEQ ID NO: 3), FLLVK (SEQ ID NO: 5), or WLLVK (SEQ ID NO: 6).

[0076] 5.1.3 SEQ ID NO:24-Based Peptides

[0077] In another aspect, the disclosure provides a peptide 5 to 20 amino acids in length, the peptide comprising the amino acid sequence SYLPP (SEQ ID NO: 24) at the N-terminus of the peptide. In some embodiments, the peptide comprises or consists of the amino acid sequence SYLPP (SEQ ID NO: 24). In some embodiments, the peptide comprises or consists of the amino acid sequence SYLPPL (SEQ ID NO: 20). In some embodiments, the peptide comprises or consists of the amino acid sequence SYLPPLT (SEQ ID NO: 4). In some embodiments, the peptide comprises or consists of the amino acid sequence SYLPPLTT (SEQ ID NO: 1).

[0078] In some embodiments, the peptide is 5 to 15 amino acids in length. The peptides are 5 to 10 amino acids in length.

[0079] In some embodiments, the peptide is 5 amino acids long. In some embodiments, the peptide is 6 amino acids long. In some embodiments, the peptide is 7 amino acids long. In some embodiments, the peptide is 8 amino acids long. In some embodiments, the peptide is 9 amino acids long. In some embodiments, the peptide is 10 amino acids long. In other embodiments, the peptide is 6 amino acids long. In other embodiments, the peptide is 7 amino acids long. In other embodiments, the peptide is 8 amino acids long. In other embodiments, the peptide is 9 amino acids long. In other embodiments, the peptide is 10 amino acids long. In other embodiments, the peptide is 11 amino acids long. In other embodiments, the peptide is 12 amino acids long. In other embodiments, the peptide is 13 amino acids long. In other embodiments, the peptide is 14 amino acids long. In other embodiments, the peptide is 15 amino acids long. In other embodiments, the peptide is 16 amino acids long. In other embodiments, the peptide is 17 amino acids long. In other embodiments, the peptide is 18 amino acids long. In other embodiments, the peptide is 19 amino acids long. In other embodiments, the peptide is 20 amino acids long. The peptide can include, for example, the amino acid sequence SYLPP (SEQ ID NO: 24) and one or more additional amino acids C-terminal to the SYLPP (SEQ ID NO: 24) sequence, as shown in SEQ ID NO: 26 in the Rubisco protein.

[0080] 5.1.4 Additional SEQ ID NO:2-Based Peptides

[0081] In another aspect, the disclosure provides a peptide comprising the amino acid sequence YHIEPV (SEQ ID NO: 2) that is 6 to 20 amino acids in length. In some embodiments, the peptide is 6 to 15 amino acids in length. In other embodiments, the peptide is 6 to 10 amino acids in length.

[0082] In some embodiments, the peptide is 6 amino acids in length. In some embodiments, the peptide is 7 amino acids in length. In some embodiments, the peptide is 8 amino acids in length. In some embodiments, the peptide is 9 amino acids in length. In some embodiments, the peptide is 10 amino acids in length. In other embodiments, the peptide is 11 amino acids in length. In other embodiments, the peptide is 12 amino acids in length. In other embodiments, the peptide is 13 amino acids in length. In other embodiments, the peptide is 14 amino acids in length. In other embodiments, the peptide is 15 amino acids in length. In other embodiments, the peptide is 16 amino acids in length. In other embodiments, the peptide is 17 amino acids in length. In other embodiments, the peptide is 18 amino acids in length. In other embodiments, the peptide is 19 amino acids in length. In other embodiments, the peptide is 20 amino acids in length. The peptide can include the amino acid sequence YHIEPV (SEQ ID NO: 2), and one or more additional amino acids N-terminal and / or C-terminal to the YHIEPV (SEQ ID NO: 2) sequence, for example, as set forth in SEQ ID NO: 28 in a Rubisco protein.

[0083] 5.1.5 SEQ ID NO:25 Based Peptides

[0084] In another embodiment, a peptide of the invention is a peptide comprising at least three (eg, three, four, or five) consecutive amino acids from the amino acid sequence XLLVK (SEQ ID NO: 25), wherein X is an aromatic amino acid.

[0085] Unless otherwise specified, the amino acid residues of peptides based on the amino acid sequence of any one of SEQ ID NOS: 1-6, 8, 24, and 25 above may include both natural and / or unnatural amino acid residues. Natural amino acids include alanine, arginine, asparagine, and ribonucleotides. Proteinogenic amino acid residues include glutamine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, as well as other amino acid residues such as selenocysteine, N-formylmethionine, pyrrolysine, and pyroglutamine. Exemplary unnatural amino acids include, but are not limited to, azetidine carboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, homoproline, hydroxylysine, allohydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloisoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid, and thioproline.

[0086] Any of L-amino acids, D-amino acids, and DL-amino acids (including racemates and amino acids having an excess of one enantiomer, so long as they are mixtures of D- and L-amino acids) can be used as amino acids constituting peptides. Peptides consisting of only L-amino acids or only D-amino acids are preferred.

[0087] When the peptide used in the present invention contains two or more asymmetric carbon atoms, the peptide may be in any form and in any ratio of its respective enantiomers or diastereomers. Enantiomers and diastereomers can be separated using commonly used columns. Separation can be performed using any known method, such as a method using an optically active column, a method involving performing optical resolution in a form having an optically active group introduced therein and then removing the optically active group, or a method involving forming an optically active salt with an acid or base and then performing optical resolution.

[0088] The peptides of the present invention can be in the form of salts (acid addition salts or base salts). Examples of acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide, and perchlorate, and organic acid salts such as citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid. Examples of base salts include salts of alkali metals such as sodium, potassium, and lithium; and salts of alkaline earth metals such as calcium and magnesium. Exemplary bases that can be used to prepare base addition salts include sodium hydroxide, potassium hydroxide, and alkali metal bases such as lithium hydroxide and calcium hydroxide. Additional acids and bases that can be used to prepare pharmaceutically acceptable salts are listed in Stahl and Wermuth, eds., 2008, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Verlag Helvetica Chimica Acta, Zurich, Switzerland. The contents of this document are incorporated herein by reference in their entirety.

[0089] The peptides of the present invention can be solvated. Examples of solvates include solvates with water (for hydrates), methanol, ethanol, isopropanol, acetic acid, tetrahydrofuran, acetone, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetamide, ethylene glycol, propylene glycol, dimethoxyethane, etc.

[0090] In one embodiment, some peptides of the present invention can be obtained by hydrolysis of ribulose 1,5-bisphosphate carboxylase / oxygenase (Rubisco) protein with pepsin or pepsin and pancreatin.

[0091] Thus, the present invention encompasses compositions comprising Rubisco protein that has been treated with pepsin or pancreatin, or pepsin plus pancreatin.

[0092] Rubisco protein is a protein involved in carbon dioxide fixation by green leaves. This protein is abundant in plants and is considered the most abundant protein on Earth. Green plants containing Rubisco protein include plants with edible green leaf parts, such as kale, young barley leaves, young wheat leaves, angelica tree, young mulberry leaves, spinach, mulukhiyah, cabbage, and tea. Spinach-derived Rubisco protein is preferred for obtaining peptides having the amino acid sequence SYLPPLTT (SEQ ID NO: 1), the amino acid sequence YHIEPV (SEQ ID NO: 2), or the amino acid sequence SYLPPLT (SEQ ID NO: 4). Tea-derived Rubisco protein is preferred for obtaining peptides having the amino acid sequence YHIEPV (SEQ ID NO: 2) or the amino acid sequence SYLPPLT (SEQ ID NO: 4). The amino acid sequence YLLVK (SEQ ID NO: 3) is preferably obtained by chemical synthesis or recombinant expression as described below.

[0093] Pepsin (EC.3.4.23.1-3) is a known type of protease that functions in animal stomachs. Pepsin is available as a food additive in Japan. Commercially available reagent-grade pepsin and food additive-grade pepsin can be used.

[0094] Pancreatin is a mixture of enzymes secreted by the pancreas, including lipase, amylase, and proteases (trypsin, chymotrypsin, etc.). In Japan, pancreatin can be used as a food additive. Commercially available products include reagent-grade pancreatin and food additive-grade pancreatin.

[0095] The substrate to be hydrolyzed with pepsin or pepsin and pancreatin is not particularly limited as long as it contains Rubisco protein. Examples include green plants themselves, the juice of green plants (so-called green juice), and purified Rubisco protein.

[0096] Rubisco protein is conveniently extracted from spinach, which allows for its extraction as a soluble protein.

[0097] Hydrolysis with pepsin or pepsin and pancreatin is carried out under conditions that allow the production of the peptide of the present invention. The reaction temperature can be appropriately selected from 30 to 70°C, 30 to 40°C, 40 to 70°C, 50 to 65°C, etc. The reaction time can be appropriately selected from about 30 minutes to 48 hours, about 1 to 10 hours, about 2 to 8 hours, etc. The pH at which the reaction is carried out can be appropriately selected from about pH 1.5 to 3.5, preferably about pH 2 to 3, in the case of pepsin, and about pH 6.5 to 8.5, preferably about pH 7 to 8, in the case of pancreatin.

[0098] When hydrolysis is performed using both pepsin and pancreatin, it is preferable to perform each hydrolysis reaction separately because the optimum pH of the enzymes is different. In this case, the order of hydrolysis using pepsin and hydrolysis using pancreatin is not limited, and either reaction can be performed first.

[0099] If necessary, each enzyme is inactivated by heating to a temperature that allows for enzyme inactivation (for example, heating at a temperature above 80°C for about 5 to 60 minutes).

[0100] The hydrolysis reaction product can be used directly for pharmaceutical or food applications, or the active ingredient peptide can be separated by purification and then used for pharmaceutical or food applications.

[0101] Alternatively, the peptides of the present invention may be obtained by any known peptide synthesis method (e.g., as described in Benoiton, N., 2006, Chemistry of Peptide Synthesis, CRC Press, Boca Raton, FL; Howl, J., ed., 2005, Peptide Synthesis and Applications, Humana Press, Totowa, NJ; Chan and White, eds., 2000, Fmoc Solid Phase Synthesis: A Practical Approach, Oxford University Press, Oxford, UK). In the liquid phase or solid phase method, which is a commonly used method for peptide synthesis, a starting material having a reactive carboxyl group and a starting material having a reactive amino group can be condensed by a general method for peptide synthesis, for example, a method using an active ester such as HBTU or a method using a coupling agent such as carbodiimide. If the resulting condensate has a protecting group, the protecting group can be removed to produce the peptide.

[0102] In this reaction method, functional groups that should not be involved in the reaction are protected with protecting groups. Examples of protecting groups for amino groups include benzyloxycarbonyl (CBZ), t-butyloxycarbonyl (Boc), and 9-fluorenylmethyloxycarbonyl (Fmoc). Examples of protecting agents for carboxyl groups include groups capable of forming alkyl esters, benzyl esters, etc. In the solid-phase method, the C-terminal carboxyl group is bound to a carrier such as chlorotrityl resin, chloromethyl resin, oxymethyl resin, or p-alkoxybenzyl alcohol resin. The condensation reaction is carried out in the presence of a condensing agent such as a carbodiimide, or using an activated ester of an N-protected amino acid or an activated ester of a peptide.

[0103] After the condensation reaction is completed, the protecting group is removed. In the solid-phase method, the bond between the C-terminus of the peptide and the resin is further cleaved. The peptide of the present invention is then purified by a conventional method, such as ion exchange chromatography, reversed-phase liquid chromatography, and affinity chromatography. The synthesized peptide is analyzed by a protein sequencer, GC-MS, or the like, which reads the amino acid sequence from the C-terminus by the Edman degradation method.

[0104] The peptides of the invention may also be synthesized by enzymatic methods (see WO 2003 / 010307).

[0105] The peptides of the invention may be obtained from a microorganism or cultured cell that has been engineered to produce the peptide of the invention, for example, a microorganism or cultured cell into which a gene encoding such a peptide has been inserted, or may be obtained by in vitro translation.

[0106] 5.2 Peptide conjugates

[0107] The present disclosure provides peptide conjugates and salts thereof, comprising a peptide moiety and a conjugate moiety. The attachment of the conjugate moiety to the peptide can provide, for example, improved water solubility, increased stability, and reduced clearance compared to the unconjugated peptide (Hamley, 2014, Biomacromolecules 15:1543-1559). Thus, peptide conjugates may, in some cases, be more suitable as therapeutic agents than their unconjugated counterparts. The peptide moiety can include any peptide described herein, for example, any peptide described in Section 3 or Section 5.1. Certain embodiments described herein may be "peptide conjugates." When referring to a "peptide conjugate," it is understood that the embodiment encompasses the peptide conjugate itself as well as salts of the peptide conjugate, unless the context requires otherwise, even if the embodiment is not expressly recited with the phrase "or a salt thereof" or similar phrase. Exemplary salts include the acid addition salts and base addition salts described in Section 5.1.

[0108] A peptide conjugate comprises one or more conjugate moieties (e.g., 1, 2, 3, 4, or 5 conjugate moieties) attached to a peptide moiety. The conjugate moiety or moieties can be attached to the N-terminal amino acid, the C-terminal amino acid, an amino acid that is neither the N-terminal nor the C-terminal amino acid, or a combination thereof. For example, a peptide conjugate can preferably comprise one conjugate moiety attached to the N-terminal amino acid of the peptide moiety or attached to the C-terminal amino acid of the peptide moiety. As another example, a peptide conjugate can comprise two conjugate moieties, one preferably attached to the N-terminal amino acid of the peptide moiety and another preferably attached to the C-terminal amino acid of the peptide moiety.

[0109] In embodiments in which a peptide conjugate comprises multiple conjugate moieties, each conjugate moiety can be the same, some conjugate moieties can be the same and others can be different, or all conjugate moieties can be different. For example, a peptide conjugate having two conjugate moieties can have two identical conjugate moieties. Alternatively, a peptide conjugate having two conjugate moieties can have two different conjugate moieties. As another example, a peptide conjugate having three conjugate moieties can have three identical conjugate moieties, three different conjugate moieties, or two identical conjugate moieties and one different conjugate moiety.

[0110] The conjugate moiety can be attached to a peptide moiety, for example, to one of the amino acid side chains of the peptide moiety, to its backbone, to its N-terminal amino group, or to its C-terminal carboxylic acid group. For example, the conjugate moiety can be attached to an amino acid side chain to form a chemically modified amino acid, such as methionine sulfoxide, methionine sulfone, S-(carboxymethyl)cysteine, S-(carboxymethyl)cysteine ​​sulfoxide, and S-(carboxymethyl)cysteine ​​sulfone. Other side chain modifications include acylation of the lysine ε-amino group, N-alkylation of arginine, histidine, or lysine, and alkylation of the glutamic acid or aspartic acid carboxylic acid group. The conjugate moiety can be attached to the peptide backbone, for example, to a nitrogen atom in the backbone (e.g., N-methyl amino acids can be used to synthesize peptides by introducing methyl conjugate moieties into the peptide conjugate backbone). The conjugate moiety can be attached to the N-terminal amino group of the peptide moiety to obtain, for example, an N-terminus with an N-lower alkyl, N-di-lower alkyl, or N-acyl modification. The conjugate moiety can be attached to the C-terminal carboxy group to obtain, for example, a peptide conjugate with an amide, lower alkyl amide, dialkyl amide, or lower alkyl ester at the C-terminus of the conjugate. Lower alkyl means C1-C4 alkyl.

[0111] Representative conjugate moieties that can be used in peptide conjugates include polymers, amine groups (e.g., amino (-NH), alkylamino, and dialkylamino), acyl groups (e.g., formyl or acetyl), alkyl groups (e.g., C1-C4 alkyl), phosphate groups, lipids, and sugars.

[0112] In some embodiments, at least one, two or more in the peptide conjugate Some or all of the conjugate moieties comprise a polymer. Exemplary polymers that can be used as conjugate moieties include polyethylene glycol, polyvinylpyrrolidone, polylactic-co-glycolic acid, N-(2-hydroxypropyl) methacrylamide copolymer, polyglutamic acid, and polysaccharides. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise polyethylene glycol. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise polyvinylpyrrolidone. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise polylactic-co-glycolic acid. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise N-(2-hydroxypropyl) methacrylamide copolymer. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise polyglutamic acid. In some embodiments, at least one, more than one, or all of the conjugate moieties in a peptide conjugate comprise a polysaccharide.

[0113] In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise an amine group. Representative amine groups include amino (-NH), alkylamino, and dialkylamino groups. The alkyl group can be, for example, C1-C4 alkyl. In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise an amino group. In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise an alkylamino group. In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise a dialkylamino group.

[0114] In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise an acyl group. Representative acyl groups include formyl and acetyl groups. In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise a formyl group. In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise an acetyl group.

[0115] In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise an alkyl group. In exemplary embodiments, the alkyl group is a lower alkyl group, such as methyl or ethyl. In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise a methyl group. In some embodiments, at least one, two or more, or all of the conjugate moieties in the peptide conjugate comprise an ethyl group.

[0116] In some embodiments, at least one, more than one, or all of the conjugate moieties in a peptide conjugate comprise a phosphate group attached to the side chain of, for example, serine, threonine, or tyrosine.

[0117] In some embodiments, at least one, more than one, or all of the conjugate moieties in a peptide conjugate comprise a lipid.

[0118] In some embodiments, at least one, two or more in the peptide conjugate Some, or all, of the conjugate moieties comprise a sugar.

[0119] Methods for attaching conjugate moieties to peptide moieties are known in the art and can be used to obtain the peptide conjugates described herein (e.g., as described in Basle et al., 2010, Chemistry & Biology 17:213-227; Benoiton, N., 2006, Chemistry of Peptide Synthesis, CRC Press, Boca Raton, FL; Ernst and Leumann, eds., 1995, Modern Synthetic Methods, Verlag Helvetica Chimica Acta, Basel, Switzerland; Hamley, 2014, Biomacromolecules 15:1543-1559; Lundblad, R., 1995, Techniques in Protein Modification, CRC Press, Boca Raton, FL). Custom synthesis of peptide conjugates is also commercially available from a number of vendors (e.g., ABI Scientific (Sterling, VA); AnaSpec (Freemont, CA); Pepscan, (Lelystad, Netherlands), Neo Scientific (Cambridge, MA); Sigma-Aldrich (St. Louis, MO), which offer a variety of peptides with N-terminal conjugate moieties such as acetyl, formyl, fatty acids, and alkylamino groups; C-terminal conjugate moieties such as amide, alkylamino, and alkyl groups; peptides conjugated to fatty acids; peptides conjugated to polyethylene glycol; and peptides with phosphate conjugate moieties (e.g., containing phosphoserine, phosphothreonine, or phosphotyrosine).

[0120] 5.3 Uses of the Compounds of the Disclosure

[0121] The peptides of the present invention have anxiolytic-like effects and can be used to treat or alleviate anxiety disorders or anxiety-based symptoms (e.g., anxiety disorders and their associated psychological and / or physical symptoms). The peptides and peptide conjugates of the present invention can be used as anxiolytic agents, for example, as active ingredients in the pharmaceutical compositions described herein.

[0122] Anxiety disorders include phobias, generalized anxiety disorders, panic disorders, and substance-induced anxiety disorders. Individuals who have not been diagnosed with an anxiety disorder but experience anxiety due to stress or other factors (subjects with potential anxiety disorders) are also included in the subjects seeking recovery. Treatment according to the present invention includes treating, alleviating, and reversing symptoms and / or completely or partially inhibiting the progression of the disease.

[0123] The anxiolytic effects of peptides or peptide conjugates can be evaluated using the elevated plus maze test, a widely used method developed as an anxiety-related behavioral assessment method for screening anxiolytic agents (Figure 1). Specifically, a candidate substance is administered orally or intraperitoneally to each mouse. After 30 minutes, the mouse is placed in the elevated plus maze. The intensity of the anxiolytic effects can be evaluated using the changes in the number of entries into the open arms and the time spent in the open arms as indicators.

[0124] As will be shown in the Examples below, without wishing to be bound by theory, some peptides of the present invention have the ability to inhibit 5-HT 1A It is believed that the peptide acts through receptor activation and is therefore expected to have antidepressant-like effects as well. The peptide of the present invention can also be used to treat or alleviate depression or depressive mood disorders, or conditions (symptoms) based thereon.

[0125] Antidepressant-like activity can be assessed by the tail suspension test, which is a useful test for screening antidepressant candidates. This is an experimental method used to measure the immobility time (Can et al., 2012, J Vis Exp., 59:e3769). The time that a mouse is immobile (i.e., does not exhibit escape behavior) during a 6-minute period is measured to obtain the immobility time. Administration of antidepressants such as imipramine shortens the immobility time. Therefore, if a reduction in immobility time is observed in a test substance, it can be concluded that the test substance has antidepressant properties. Because immobility is considered a state of resignation, a reduction in immobility time also indicates increased motivation (i.e., the test substance has motivation-enhancing properties).

[0126] Based on their anxiolytic-like effects, the peptides and peptide conjugates of the present invention can be used as active ingredients in therapeutic agents (e.g., pharmaceutical compositions described herein) for treating adjustment disorder, bipolar disorder, motivational disorder (also called hypomotivation disorder), blunted affect, abulia, or akinetic mutism.

[0127] The peptides and peptide conjugates of the present invention can be provided as pharmaceutical compositions or foods (also referred to herein as food compositions).

[0128] The route of administration of the peptide or peptide conjugate of the present invention, or a formulation containing the peptide or peptide conjugate, is not particularly limited, and may include oral administration, parenteral administration (e.g., intramuscular or intravenous administration), rectal administration, etc. Among these, oral administration is preferred from the viewpoint of high effectiveness.

[0129] The dosage of the peptide or peptide conjugate of the present invention may vary depending on the type of compound, the method of administration, the condition or age of the recipient, etc., but is typically 0.01 mg / kg to 500 mg / kg, preferably 0.05 mg / kg to 100 mg / kg, and more preferably 0.1 to 30 mg / kg per day for adults. The peptide or peptide conjugate (active ingredient) of the present invention can be administered in the form of a pharmaceutical composition prepared by mixing with a carrier for formulation. Substances commonly used in the field of formulations and which do not react with the peptide of the present invention can be used as the carrier for formulation.

[0130] The peptides or peptide conjugates of the present invention can be used as pharmaceuticals or foods themselves. The peptides or peptide conjugates of the present invention can be prepared, alone or together with suitable non-toxic carriers, diluents, or excipients for oral ingestion, into pharmaceutical formulations such as foods or tablets (plain tablets, coated tablets, effervescent tablets, film-coated tablets, chewable tablets, etc.), capsules including both hard and soft capsules, lozenges, powders, fine granules, granules, solutions, suspensions, emulsions, pastes, creams, injections (including blends with injections such as amino acid injections and electrolyte injections), or sustained-release preparations, e.g., enteric-coated tablets, capsules, or granules. Pharmaceutical compositions of the present disclosure can be formulated using techniques known in the art (e.g., as described in Allen et al., eds., 2012, Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK).

[0131] In one aspect, the present invention provides a pharmaceutical composition comprising a peptide or peptide conjugate of the invention and a pharmaceutically acceptable diluent, carrier, or excipient. In one aspect, the present invention provides a food product comprising a peptide or peptide conjugate of the invention (e.g., a food product that can include, by addition, a peptide of the invention).

[0132] The content of the peptide or peptide conjugate of the present invention in a pharmaceutical or food product can be appropriately selected and is usually 0.01 to 100% by weight (e.g., 1% to 99%, 1% to 90%, 5% to 80%, 10% to 75%, or 15% to 50% based on the weight of the pharmaceutical composition). or any weight percent range bounded by any two of the foregoing values).

[0133] Specific examples of substances such as carriers for formulations or carriers for oral ingestion, diluents, or excipients that can be added to pharmaceuticals or foods include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminum metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose, ion exchange resins, methylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, Veegum, titanium oxide, sorbitan fatty acid esters, sodium lauryl sulfate, glycerin, fatty acid glycerin esters, purified lanolin, glycerogelatin, polysorbates, macrogol, vegetable oils, waxes, liquid paraffin, white petrolatum (e.g., Vaseline (registered trademark)), fluorocarbons, nonionic surfactants, propylene glycol, and water.

[0134] Examples of dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, and injections. These preparations can be prepared by common methods. Liquid preparations can be in a form that is dissolved in water or other suitable solvents when used. Tablets or granules can be coated by well-known methods. Injections can be prepared by dissolving the peptide or peptide conjugate of the present invention in water. If necessary, injections can be prepared by dissolving the peptide or peptide conjugate of the present invention in physiological saline or glucose solution, which can be supplemented with a buffer or preservative.

[0135] These formulations can contain the peptide or peptide conjugate of the present invention at a ratio of 0.01% to 100% by weight, preferably 1 to 90% by weight (for example, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, 1% to 10%, 5% to 10%, 10% to 20%, 20% to 40%, 40% to 60%, 60% to 80%, or any range bounded by any two of the aforementioned values). These formulations can also contain other therapeutically useful ingredients.

[0136] To prepare solid preparations for oral administration, the active ingredient can be mixed with excipients such as lactose, starch, crystalline cellulose, calcium lactate, and anhydrous silicic acid to prepare a powder, or can be further supplemented with binders (sucrose, hydroxypropyl cellulose, polyvinylpyrrolidone, etc.) or disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, etc.) and wet or dry granulated to prepare granules. To prepare tablets, these powders or granules can be compressed directly or after adding a lubricant such as magnesium stearate or talc. These granules or tablets can be coated with an enteric coating base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer, or coated with ethyl cellulose, carnauba wax, hydrogenated oil, etc. to prepare sustained-release preparations. To prepare capsules, powder or granules can be filled into a hard capsule shell, or the active ingredient can be dissolved directly or in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to prepare soft capsules.

[0137] To prepare a liquid preparation for oral administration, the active ingredient and a sweetener such as sucrose, sorbitol, or glycerin can be dissolved in water and supplemented with clear syrup, essential oils, ethanol, or the like to prepare an elixir, or a mixture of gum arabic, tragacanth, polysorbate, or the like. Emulsions or suspensions can be prepared by supplementing the liquid preparations with PEG-80, sodium carboxymethylcellulose, etc. These liquid preparations can be supplemented with flavoring agents, coloring agents, preservatives, etc., as required.

[0138] Food products containing the peptides or peptide conjugates of the present invention can be prepared, for example, by adding the peptides or peptide conjugates of the present invention to known foods. Examples of specific foods that can be prepared by adding a peptide according to the present invention include beverages (coffee, cocoa, juice, soft drinks, mineral drinks, tea drinks, green tea, black tea, oolong tea, milk drinks, lactic acid bacteria drinks, yogurt drinks, carbonated drinks, other non-alcoholic drinks, alcoholic drinks, etc.), sweets (hard candies, gum, gummy bears, jellies, puddings, mousses, cakes, candies, cookies, crackers, biscuits, chocolates, ice cream (ice cream, popsicles, sorbets, shaved ice, etc.), furikake toppings, dressings, seasonings, processed meat foods (hamburger patties, meatloaf, meatballs, tsukune (yakitori meatballs), etc.), processed fish foods (kamaboko (steamed fish patties), chikuwa (fish sausages), etc.), retort-processed foods, and jelly-like foods (jelly, agar, jelly-like drinks, etc.). Foods supplemented with a peptide or peptide conjugate according to the present invention can be prepared by methods known per se.

[0139] Examples of foods containing the peptides or peptide conjugates of the present invention include foods prepared from green plants as raw materials, such as powdered green tea, green juice, and vegetable juice. Foods containing the peptides or peptide conjugates of the present invention can be produced, for example, by adding a step of hydrolyzing with pepsin or a step of hydrolyzing with pepsin and pancreatin to the process for producing foods derived from green plants as raw materials (powdered green tea, green juice, vegetable juice, etc.). In another aspect, foods containing the peptides or peptide conjugates of the present invention can also be produced by adding a step of forming the peptides of the present invention by freeze-drying, acid and / or alkali treatment, etc. to the process for producing foods derived from green plants as raw materials (powdered green tea, green juice, vegetable juice, etc.).

[0140] Foods comprising the peptides or peptide conjugates of the invention can be so-called health foods, foods with function claims, foods for designated health uses, dietary supplements (e.g., in the form of tablets, capsules, soft gels, gelatin capsules, liquids, or powders, and optionally containing one or more ingredients selected from vitamins, minerals, herbs or other botanicals, amino acids, proteins, fibers, fatty acids, and combinations thereof), supplements, foods for the sick, composite foods for the sick (one of the special dietary foods, Ministry of Health, Labour and Welfare of Japan) or foods for the elderly (one of the special dietary foods, Ministry of Health, Labour and Welfare of Japan).

[0141] It is believed that hydrolysis of Rubisco protein by pepsin or pepsin and pancreatin also occurs in the gastrointestinal tract. From this perspective, the present invention encompasses the use of green plants (e.g., kale, young barley leaves, young wheat leaves, angelica tree, young mulberry leaves, spinach, mulukhiyah, cabbage, and tea) themselves in the amelioration or treatment of anxiety disorders or anxiety-related symptoms. The green plant is preferably spinach or tea, more preferably spinach.

[0142] In some aspects, the present disclosure provides methods of treating a subject with a peptide, peptide conjugate, pharmaceutical composition, or food product of the present disclosure.

[0143] The present disclosure provides a method of treating a subject suffering from an anxiety disorder, the method comprising administering to the subject a compound of the present disclosure in an amount effective to treat the subject. The present disclosure also provides a method of treating a subject suffering from an anxiety disorder. The present invention also provides a method for treating or preventing anxiety disorders, comprising administering an amount of a food product containing a compound of the present disclosure to a subject who is prone to or suffering from an anxiety disorder. In some embodiments, the subject is prone to suffering from an anxiety disorder. In other embodiments, the subject is suffering from an anxiety disorder.

[0144] The present disclosure provides a method for treating a subject suffering from reduced motivation disorder, the method comprising administering to the subject a compound of the present disclosure in an amount effective for treating the subject.The present disclosure also provides a method for treating or preventing reduced motivation disorder, the method comprising administering an amount of food containing a compound of the present disclosure to a subject prone to or suffering from reduced motivation disorder.In some embodiments, the subject is prone to suffer from reduced motivation disorder.In other embodiments, the subject is suffering from reduced motivation disorder.

[0145] In some embodiments of the method described in the preceding paragraph, the reduced motivation disorder comprises blunted affect. In other embodiments of the method described in the preceding paragraph, the reduced motivation disorder comprises abulia. In other embodiments of the method described in the preceding paragraph, the reduced motivation disorder comprises akinetic mutism.

[0146] The present disclosure provides a method for treating a subject suffering from a mood disorder, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure in an amount effective for treating the subject.The present disclosure also provides a method for treating or preventing a mood disorder, the method comprising administering to a subject prone to or suffering from a mood disorder a certain amount of food comprising a compound of the present disclosure.In some embodiments, the subject is prone to suffer from a mood disorder.In other embodiments, the subject is suffering from a mood disorder.

[0147] In some embodiments of the method described in the preceding paragraph, the mood disorder comprises depression. In some embodiments of the method described in the preceding paragraph, the mood disorder comprises bipolar disorder. In some embodiments of the method described in the preceding paragraph, the mood disorder comprises adjustment disorder.

[0148] The subject of the methods described herein is preferably a mammal, e.g., a human or a domestic pet (e.g., a cat, a dog). The subject can be of any age, but is preferably an adult (e.g., a human subject aged 18 years or older, 25 years or older, 35 years or older, 45 years or older, 55 years or older, etc.). In some embodiments, the subject is elderly (e.g., a human subject aged 65 years or older, 70 years or older, 75 years or older, or 80 years or older).

[0149] Suitable daily dosages of the compounds of the present disclosure can be based on the subject's body weight, as described above (e.g., dosages ranging from 0.01 mg / kg to 500 mg / kg). Alternatively, the compounds can be administered in fixed doses ranging from, for example, 0.1 mg to 50 g / day (e.g., 0.1 mg to 10 g, 0.1 mg to 3 g, 0.1 mg to 100 mg, 0.1 mg to 1 mg, 0.3 mg to 3 g, or 0.3 mg to 100 mg). With respect to the administration of pharmaceutical compositions containing the compounds of the present disclosure, an amount of the pharmaceutical composition containing an amount of the compound within one of the aforementioned ranges can be administered. Similarly, with respect to the administration of one or more foods containing the compounds, an amount of the one or more foods containing an amount of the compound within one of the aforementioned ranges can be administered. [Example]

[0150] 6. Working Example

[0151] The present invention will now be described in more detail with reference to examples, which, however, are not intended to limit the scope of the present invention.

[0152] <Test Method> (Elevated Plus Maze (EPM) test) The elevated plus maze consists of two open arms (25 cm × 5 cm) and two closed arms (25 cm × 5 cm × 15 cm), which are connected to a central platform 50 cm above the floor (see Figure 1). Despite this elevated position, mice can safely walk in the closed arms because they are fenced. On the other hand, mice walking in the open arms feel anxious about falling from the high position because the open arms are not fenced. Therefore, a longer time spent in the open arms indicates a greater reduction in the mice's anxiety and serves as an indicator of an anxiolytic effect.

[0153] As shown in the right panel of Figure 1, the sample was administered to each mouse (ddY mouse, male, 23-27 g) 30 minutes before the test. 30 minutes later, to begin the test, the mouse was placed on the central platform facing one of the open arms. The cumulative time spent in the open arms was recorded during the 5-minute test period. The percentage of time spent in the open arms was calculated as an index of anxiolytic-like effects.

[0154] (statistical analysis) The data obtained from the tests were expressed as the sum of the means and the standard error of the mean (SEM). The data shown in Figures 1-9, 17, 18, 20, and 21 were analyzed by one-way or two-way analysis of variance. Multiple comparison tests were then performed using Tukey's test. p values ​​less than 0.05 are indicated by "*" in the figures, and p values ​​less than 0.01 are indicated by "**" in the figures.

[0155] <Preparation Example 1> (Rubisco protein extraction) Spinach was homogenized. The pH of the resulting homogenate was adjusted to pH 11 with 1N NaOH aqueous solution. The homogenate was filtered through two pieces of gauze. The filtrate was centrifuged at 13,500 xg and 5°C for 50 minutes. After centrifugation, the supernatant was filtered. The pH of the resulting filtrate was adjusted to pH 4.5 with acetic acid to precipitate the Rubisco protein. The precipitate was washed with acetone, ethanol, and diethyl ether and dried in a vacuum oven to obtain Rubisco powder.

[0156] In this way, Rubisco protein extracted from spinach and Rubisco protein preparation (Sigma-Aldrich Co. LLC) were analyzed by SDS-PAGE. The results are shown in Figure 2.

[0157] (enzyme digest) An enzymatic digest of the purified Rubisco protein was prepared under the following conditions.

[0158] The enzymes used, the mixing ratio of each enzyme to the protein, and the reaction conditions were as follows: (i) Pepsin digestion Pepsin (Sigma-Aldrich Co. LLC):Rubisco = 1:100 (weight ratio, final concentration of Rubisco: 0.99 mg / ml), reaction temperature: 37°C; reaction time: 5 hours; reaction buffer: pH 2.0. (ii) Pepsin + pancreatin digestion The enzyme treatment was carried out in the order of 1) and 2). 1) Pepsin (Sigma-Aldrich Co. LLC): Rubisco = 1:100 (weight ratio, final Rubisco concentration: 0.99 mg / ml), reaction temperature: 37°C; reaction time: 5 hours; reaction buffer: pH 2.0. 2) Pancreatin (Sigma-Aldrich Co. LLC): Rubisco = 1: 20 (weight ratio, final concentration of Rubisco: 0.86 mg / ml), reaction temperature: 37°C; reaction time: 5 hours; reaction buffer: pH 7.5.

[0159] After the reaction time, the sample was boiled (100°C, 10 min) to terminate the enzyme reaction.

[0160] <Preparation Example 2> (peptide) Peptides SYLPPLTT (SEQ ID NO: 1), YHIEPV (SEQ ID NO: 2), YLLVK (SEQ ID NO: 3) and SYLPPLT (SEQ ID NO: 4) were synthesized by standard methods, usually by solid phase methods based on the Fmoc strategy.

[0161] <Experiment and Results> Example 1: Elevated Plus-Maze Test (Enzyme Digestion) Mice were orally administered a pepsin digest of Rubisco at 3 mg / kg, 10 mg / kg, or 30 mg / kg, and then used in the elevated plus maze test (n = 9-11). Saline alone was used as a control (the same applies below).

[0162] The results are shown in Figure 3. Oral administration of all doses of the digest increased the proportion of time spent in the open arms, with the 10 mg / kg dose showing statistically significant results. This result indicates that the pepsin digest of Rubisco used as the sample has an anxiolytic-like effect when administered orally.

[0163] Example 2: Elevated Plus-Maze Test (Enzyme Digestion) A pepsin + pancreatin digest of Rubisco was orally administered to each mouse at 3 mg / kg, 10 mg / kg, or 30 mg / kg, followed by an elevated plus maze test (n = 9-11).

[0164] The results are shown in Figure 4. Oral administration of all doses of the digest increased the proportion of time spent in the open arms, with statistically significant results at doses of 3 mg / kg and 30 mg / kg. These results indicate that the pepsin and pancreatin digest of Rubisco used as the sample has anxiolytic-like effects when administered orally.

[0165] Example 3: Elevated Plus Maze Test (Peptides) The peptide SYLPPLTT (SEQ ID NO: 1) was orally administered to each mouse at 0.3 mg / kg or 1 mg / kg as a sample, and then used in the elevated plus maze test (n=13 to 16).

[0166] The results are shown in Figure 5. Oral administration of both doses of peptide SYLPPLTT (SEQ ID NO: 1) increased the proportion of time spent in the open arms, with the 1 mg / kg dose showing statistically significant results. This result indicates that the peptide SYLPPLTT (SEQ ID NO: 1) used as a sample has an anxiolytic-like effect when administered orally.

[0167] Example 4: Elevated Plus Maze Test (Peptides) The peptide YHIEPV (SEQ ID NO: 2) was orally administered to each mouse at 1 mg / kg, 3 mg / kg, or 10 mg / kg as a sample, and then used in an elevated plus maze test (n=5 to 7).

[0168] The results are shown in Figure 6. Oral administration of peptide YHIEPV (SEQ ID NO: 2) at all doses resulted in: The proportion of time spent in the open arms increased, and the doses of 3 mg / kg and 10 mg / kg were statistically significant. This result indicates that the peptide YHIEPV (SEQ ID NO: 2) used as a sample has an anxiolytic effect when administered orally.

[0169] Example 5: Elevated Plus Maze Test (Peptides) The peptide YLLVK (SEQ ID NO: 3) was orally administered to each mouse at 0.03 mg / kg or 0.1 mg / kg as a sample, and then used in the elevated plus maze test (n=5 to 7).

[0170] The results are shown in Figure 7. Oral administration of 0.03 mg / kg and 0.1 mg / kg of peptide YLLVK (SEQ ID NO: 3) increased the ratio of time spent in the open arms. This result indicates that the peptide YLLVK (SEQ ID NO: 3) used as a sample has an anxiolytic effect when administered orally.

[0171] Example 6: Elevated Plus Maze Test (Peptides) The peptide SYLPPLT (SEQ ID NO: 4) was used as a sample and orally administered to each mouse at 0.1 mg / kg, 0.3 mg / kg, or 1 mg / kg, and then used in an elevated plus maze test (n=5-13).

[0172] The results are shown in Figure 8. Oral administration of peptide SYLPPLT (SEQ ID NO: 4) at all doses increased the proportion of time spent in the open arms, with the 1 mg / kg dose showing statistically significant results. This result indicates that the peptide SYLPPLT (SEQ ID NO: 4) used as a sample has an anxiolytic-like effect when administered orally.

[0173] Example 7: Investigation of mechanism of action using antagonists (peptides) Peptide SYLPPLTT (SEQ ID NO: 1) or peptide SYLPPLT (SEQ ID NO: 4) (dose: 1.0 mg / kg) was administered to mice receiving serotonin 5-HT 1A The compound was used in combination with the receptor antagonist WAY100135 (dosage: 10 mg / kg) and orally administered (po) to each mouse, which was then used in the elevated plus maze test (n = 4-6).

[0174] The results are shown in Figure 9. The combined use of either peptide with the inhibitor significantly reduced the percentage of time spent in the open arms. This result suggests that the anxiolytic effect of the peptide is due to the serotonin 5-HT 1A This indicates that it is receptor-mediated.

[0175] In the figures, the letter a or b indicates that there is no significant difference (p<0.05) between the means with the same letter.

[0176] (Reference example 1) The peptides SYLPPLTT (SEQ ID NO: 1), SYLPPLT (SEQ ID NO: 4), YHIEPV (SEQ ID NO: 2), and YLLVK (SEQ ID NO: 3) contained in the pepsin digest of Rubisco (referred to as "pepsin" in the table) and the pepsin + pancreatin digest of Rubisco (referred to as "pepsin → pancreatin" in the table) were quantified by LC-MS.

[0177] LC-MS was carried out under the following conditions (manufactured by Waters Corp.). LC: Acquity UPLC System Column: Acquity BEH-C18 MS: Xevo Q-TOF.

[0178] The results are shown in Table 1. The values ​​are shown as mol% yield and mass (ng) / 1 mg digest.

[0179] [Table 1]

[0180] <Preparation Example 3> (peptide) Peptides FLLVK (SEQ ID NO: 5), WLLVK (SEQ ID NO: 6), YLL (SEQ ID NO: 7), LVK (SEQ ID NO: 9), YLLV (SEQ ID NO: 10), LLVK (SEQ ID NO: 11), YLVK (SEQ ID NO: 12), YLLVR (SEQ ID NO: 13), NYLLVKG (SEQ ID NO: 21), YLLAVK (SEQ ID NO: 22), YLLNNK (SEQ ID NO: 23), SYLPPL (SEQ ID NO: 20) were synthesized by standard methods.

[0181] Example 8: Elevated Plus Maze Test (Peptides) Peptides YLLVK (SEQ ID NO: 3), FLLVK (SEQ ID NO: 5) and WLLVK (SEQ ID NO: 6) were orally administered to each mouse at 0.1 mg / kg as samples, and then used in the elevated plus maze test (n=6).

[0182] The results are shown in Figure 10. Oral administration of 0.1 mg / kg of peptides YLLVK (SEQ ID NO: 3), FLLVK (SEQ ID NO: 5), and WLLVK (SEQ ID NO: 6) increased the percentage of time spent in the open arms. This result indicates that the peptides YLLVK (SEQ ID NO: 3), FLLVK (SEQ ID NO: 5), and WLLVK (SEQ ID NO: 6) used as samples have anxiolytic-like effects when administered orally.

[0183] Example 9: Elevated Plus Maze Test (Peptides) Peptides YLLVK (SEQ ID NO: 3), YLL (SEQ ID NO: 7), LVK (SEQ ID NO: 9) and LLVK (SEQ ID NO: 11) were orally administered to each mouse at 0.1 mg / kg, which were then used in the elevated plus maze test (n=5).

[0184] The results are shown in Figure 11. Oral administration of 0.1 mg / kg of peptides YLLVK (SEQ ID NO: 3), YLL (SEQ ID NO: 7), LVK (SEQ ID NO: 9), and LLVK (SEQ ID NO: 11) increased the proportion of time spent in the open arms. This result indicates that the peptides YLLVK (SEQ ID NO: 3), YLL (SEQ ID NO: 7), LVK (SEQ ID NO: 9), and LLVK (SEQ ID NO: 11) used as samples have anxiolytic-like effects when administered orally.

[0185] Example 10: Elevated Plus Maze Test (Peptides) Peptides YLLVR (SEQ ID NO: 13), NYLLVKG (SEQ ID NO: 21), YLLAVK (SEQ ID NO: 22), and YLLNNK (SEQ ID NO: 23) were orally administered to each mouse at 0.1 mg / kg, which were then used in the elevated plus maze test (n=5). ).

[0186] The results are shown in Figure 12. Oral administration of 0.1 mg / kg of peptides YLLVR (SEQ ID NO: 13), NYLLVKG (SEQ ID NO: 21), YLLAVK (SEQ ID NO: 22), and YLLNNK (SEQ ID NO: 23) increased the proportion of time spent in the open arms. This result indicates that the peptides YLLVR (SEQ ID NO: 13), NYLLVKG (SEQ ID NO: 21), YLLAVK (SEQ ID NO: 22), and YLLNNK (SEQ ID NO: 23) used as samples have anxiolytic-like effects when administered orally.

[0187] Example 11: Elevated Plus Maze Test (Peptides) Peptides YLLVK (sequence number 3), YLLV (sequence number 10), YLVK (sequence number 12), and YLLAVK (sequence number 22) were orally administered to each mouse at 0.1 mg / kg, which were then used in the elevated plus maze test (n=5).

[0188] The results are shown in Figure 13. Oral administration of 0.1 mg / kg of peptides YLLVK (SEQ ID NO: 3), YLLV (SEQ ID NO: 10), YLVK (SEQ ID NO: 12), and YLLAVK (SEQ ID NO: 22) increased the proportion of time spent in the open arms. This result indicates that the peptides YLLVK (SEQ ID NO: 3), YLLV (SEQ ID NO: 10), YLVK (SEQ ID NO: 12), and YLLAVK (SEQ ID NO: 22) used as samples have anxiolytic-like effects when administered orally.

[0189] Example 12: Elevated Plus Maze Test (Peptides) The peptide SYLPPL (SEQ ID NO: 20) was orally administered to each mouse at a dose of 0.3 mg / kg, 1.0 mg / kg, or 10 mg / kg, and then used in an elevated plus maze test (n=4 to 6).

[0190] The results are shown in Figure 14. Oral administration of 0.3 mg / kg, 1.0 mg / kg, and 10 mg / kg of peptide SYLPPL (SEQ ID NO: 20) increased the proportion of time spent in the open arms. This result indicates that the peptide SYLPPL (SEQ ID NO: 20) used as a sample has an anxiolytic effect when administered orally.

[0191] Example 13: Elevated Plus Maze Test (Peptides) Peptide YLPPL (SEQ ID NO: 14) was used as a sample and orally administered to each mouse at 0.3 mg / kg, 3 mg / kg, and 10 mg / kg, which were then used in the elevated plus maze test (n=6).

[0192] The results are shown in Figure 15. Without being bound by theory, it is believed that the N-terminal S on the peptide containing the sequence YLPPL (SEQ ID NO: 14) increases activity compared to peptides lacking the N-terminal S.

[0193] Example 14: Tail suspension test (peptide) Mice (ddY mice, male, 24-30 g) were orally administered 0.03 mg / kg, 0.1 mg / kg, or 0.3 mg / kg of peptide SYLPPLT (SEQ ID NO: 4). Thirty minutes later, the mice were hung by their tails for 6 minutes (n=11-14).

[0194] The results are shown in Figure 16. A reduction in immobility time was observed in mice administered with 0.03 mg / kg, 0.1 mg / kg or 0.3 mg / kg of peptide SYLPPLT (SEQ ID NO: 4).

[0195] This result shows that the peptide SYLPPLT (SEQ ID NO: 4) used as a sample was It has been shown to have antidepressant-like effects when administered.

[0196] Example 15: Elevated Plus-Maze Test (Enzyme Digestion) Mice were orally administered a pepsin digest of Rubisco at 10 mg / kg or 30 mg / kg, followed by an elevated plus-maze test (n = 18-19). Mice were orally administered a pepsin-pancreatin digest of Rubisco at 3 mg / kg, 10 mg / kg, or 30 mg / kg, followed by an elevated plus-maze test (n = 6-14).

[0197] The results are shown in Figure 17. Oral administration of all doses of the digest increased the percentage of time spent in the open arms. This result indicates that the pepsin and pepsin + pancreatin digests of Rubisco used as samples have anxiolytic-like effects when administered orally.

[0198] Example 16: Elevated Plus Maze Test (Peptides) The peptides SYLPPLTT (SEQ ID NO: 1), SYLPPLT (SEQ ID NO: 4), and YHIEPV (SEQ ID NO: 2) were orally administered to mice at (i) 0.3 mg / kg and 1 mg / kg, (ii) 0.1 mg / kg, 0.3 mg / kg, and 1 mg / kg, and (iii) 1 mg / kg, 3 mg / kg, and 10 mg / kg, respectively, and then used in the elevated plus maze test (n = 13-16, 5-13, and 5-6, respectively). Diazepam was orally administered to mice at 1 mg / kg, 3 mg / kg, and 10 mg / kg, and then used in the elevated plus maze test (n = 11-12) and tested as a comparative compound.

[0199] The results are shown in Figure 18. Oral administration of the peptides SYLPPLTT (SEQ ID NO: 1), SYLPPLT (SEQ ID NO: 4), YHIEPV (SEQ ID NO: 2), and YLLAVK (SEQ ID NO: 22) increased the proportion of time spent in the open arms. At some doses, the increase in time spent in the open arms was greater than that observed with diazepam. These results indicate that the peptides SYLPPLTT (SEQ ID NO: 1), SYLPPLT (SEQ ID NO: 4), YHIEPV (SEQ ID NO: 2), and YLLAVK (SEQ ID NO: 22) used as samples have anxiolytic-like effects when administered orally.

[0200] Example 17: Spinach Soulvisco Cleavage Site The cleavage sites by gastrointestinal proteases leading to the release of rALPs in the small and large subunits of spinach Souvisco were identified. The cleavage sites in the small subunit (A) and large subunit (B) are shown in Figure 19. The solid arrows indicate the cleavage sites.

[0201] Example 18: Elevated Plus Maze Test (Peptides) As a sample, peptide YHIEPV (SEQ ID NO: 2) was synthesized by 5-HT 1A Mice were orally administered with or without the receptor-selective antagonist WAY100135 30 minutes before the elevated plus-maze test (n = 13-15). WAY100135 was administered 50 minutes before the elevated plus-maze test. Separately, as a sample, peptide YHIEPV (SEQ ID NO: 2) was orally administered with or without the δ-opioid receptor antagonist naltrindole 30 minutes before the elevated plus-maze test (n = 11-15). Naltrindole was administered 50 minutes before the elevated plus-maze test.

[0202] The results are shown in Figure 20. The results show that the anxiolytic-like effects of peptides SYLPPLTT (SEQ ID NO: 1) and SYLPPLT (SEQ ID NO: 4) are due to the serotonin 5-HT 1A The anxiolytic-like effects of peptide YHIEPV (SEQ ID NO: 2) are mediated by activation of serotonin 5-HT receptors.1A It is not mediated by the activation of the δ-opioid receptor, but is mediated by the activation of the δ-opioid receptor. This indicates that it is more mediated.

[0203] Example 19: Increase in intracellular cAMP (peptide) 5-HT 1A It has been reported that receptors and δ-opioid receptors act via G protein-mediated inhibition of adenylyl cyclase. The peptides SYLPPLTT (SEQ ID NO: 1), SYLPPLT (SEQ ID NO: 4), and YHIEPV (SEQ ID NO: 2) were applied to Neuro-2a cells at concentrations of 0.3 mM and 1 mM in the presence of forskolin (FSK), and whether the peptides suppressed the increase in cAMP in forskolin-stimulated cells was evaluated. The results are shown in Figure 21. The results suggest that the peptide inhibits forskolin-stimulated intracellular cAMP elevation.

[0204] 7. Specific Embodiments

[0205] The present disclosure is illustrated by the following specific embodiments. 1. A compound which is a peptide or a salt thereof, wherein the peptide is: (a) 3 to 20 amino acids in length; (b) an amino acid sequence containing at least three consecutive amino acids from the N-terminus or C-terminus of the amino acid sequence X1LX2X3VK (SEQ ID NO: 8); (i) X1 is a hydrophobic amino acid; (ii) X2 and X3 are each independently selected from any amino acid; (c) has a hydrophobic N-terminal amino acid; and (d) A compound that does not consist of the amino acid sequence YLLVR (SEQ ID NO: 13), X4LX5 (SEQ ID NO: 30), X4LX5EIAR (SEQ ID NO: 31), VYLPR (SEQ ID NO: 32), YLPR (SEQ ID NO: 33), or VLQRF (SEQ ID NO: 34), wherein X4 is Y, F, W, or H, and X5 is Y, F, W, Q, or L. 2. The compound of embodiment 1, wherein X1 is an aromatic amino acid. 3. The compound of embodiment 2, wherein X1 is Y. 4. The compound of embodiment 2, wherein X1 is F. 5. The compound of embodiment 2, wherein X1 is W. 6. The compound of embodiment 1, wherein X1 is A. 7. The compound of embodiment 1, wherein X1 is I. 8. The compound of embodiment 1, wherein X1 is L. 9. The compound of embodiment 1, wherein X1 is V. 10. The compound of embodiment 1, wherein X1 is M. 11. The compound of any one of embodiments 1-10, wherein X2 is a hydrophobic amino acid. 12. The compound of embodiment 11, wherein X2 is selected from L, I, V, and A. 13. The compound according to embodiment 12, wherein X2 is L. 14. The compound of embodiment 12, wherein X2 is I. 15. The compound according to embodiment 12, wherein X2 is V. 16. The compound according to embodiment 12, wherein X2 is A. 17. The compound according to any one of embodiments 1-16, wherein X3 is a hydrophobic amino acid. 18. The compound of embodiment 17, wherein X3 is selected from L, I, V, and A. 19. The compound according to embodiment 18, wherein X3 is L. 20. The compound of embodiment 18, wherein X3 is I. 21. The compound according to embodiment 18, wherein X3 is V. 22. The compound according to embodiment 18, wherein X3 is A. 23. Embodiments 1-2, wherein the peptide comprises the amino acid sequence X1LX2 (SEQ ID NO: 15). 2. The compound according to any one of claims 1 to 11. 24. The compound according to embodiment 23, wherein X1 is the N-terminal amino acid of the peptide. 25. The compound of any one of embodiments 1-22, wherein the peptide comprises the amino acid sequence X3VK (SEQ ID NO: 16). 26. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence YLL (SEQ ID NO: 7). 27. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence LVK (SEQ ID NO: 9). 28. The compound of any one of embodiments 1-22, wherein the peptide comprises the amino acid sequence X1LX2X3 (SEQ ID NO: 17). 29. The compound of embodiment 28, wherein the peptide comprises the amino acid sequence X1LX2X3K (sequence number 29). 30. The compound of embodiment 28 or embodiment 29, wherein X1 is the N-terminal amino acid of the peptide. 31. The compound of any one of embodiments 1-22, wherein the peptide comprises the amino acid sequence X2X3VK (SEQ ID NO: 18). 32. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence YLLV (SEQ ID NO: 10). 33. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence LLVK (SEQ ID NO: 11). 34. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence YLVK (SEQ ID NO: 12). 35. The compound of any one of embodiments 1-22, wherein the peptide comprises the amino acid sequence X1LX2X3V (SEQ ID NO: 19). 36. The compound according to embodiment 35, wherein X1 is the N-terminal amino acid of the peptide. 37. The compound of any one of embodiments 1-22, wherein the peptide comprises the amino acid sequence LX2X3VK (SEQ ID NO: 27). 38. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence YLLVK (SEQ ID NO: 3). 39. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence FLLVK (SEQ ID NO: 5). 40. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence WLLVK (SEQ ID NO: 6). 41. The compound of embodiment 1, wherein the peptide comprises the amino acid sequence YLLVR (SEQ ID NO: 13). 42. The compound according to any one of embodiments 1-22, wherein the peptide comprises the amino acid sequence X1LX2X3VK (SEQ ID NO: 8). 43. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence YLLAVK (SEQ ID NO: 22). 44. The compound of embodiment 1, wherein the peptide comprises or consists of the amino acid sequence YLLNNK (SEQ ID NO: 22). 45. The compound according to any one of embodiments 1-44, wherein the peptide is 3-15 amino acids in length. 46. ​​The compound according to any one of embodiments 1-44, wherein the peptide is 3-10 amino acids in length. 47. The compound according to any one of embodiments 1-44, wherein the peptide is 4-20 amino acids in length. 48. The compound according to any one of embodiments 1-44, wherein the peptide is 4-15 amino acids in length. 49. Any one of embodiments 1 to 44, wherein the peptide is 4 to 10 amino acids in length. The compound described. 50. The compound of any one of embodiments 1-44, wherein the peptide is 5-20 amino acids in length. 51. The compound according to any one of embodiments 1-44, wherein the peptide is 5-15 amino acids in length. 52. The compound according to any one of embodiments 1-44, wherein the peptide is 5-10 amino acids in length. 53. The compound according to any one of embodiments 1-27, wherein the peptide is 3 amino acids in length. 54. The compound according to any one of embodiments 1-34, wherein the peptide is 4 amino acids in length. 55. The compound of any one of embodiments 1-40, wherein the peptide is 5 amino acids in length. 56. The compound according to any one of embodiments 1-44, wherein the peptide is 6 amino acids in length. 57. The compound according to any one of embodiments 1-44, wherein the peptide is 7 amino acids in length. 58. The compound according to any one of embodiments 1-44, wherein the peptide is 8 amino acids in length. 59. The compound of any one of embodiments 1-44, wherein the peptide is 9 amino acids in length. 60. The compound of any one of embodiments 1-44, wherein the peptide is 10 amino acids in length. 61. The compound according to any one of embodiments 1-44, wherein the peptide is 11 amino acids in length. 62. The compound according to any one of embodiments 1-44, wherein the peptide is 12 amino acids in length. 63. The compound according to any one of embodiments 1-44, wherein the peptide is 13 amino acids in length. 64. The compound according to any one of embodiments 1-44, wherein the peptide is 14 amino acids in length. 65. The compound according to any one of embodiments 1-44, wherein the peptide is 15 amino acids in length. 66. The compound according to any one of embodiments 1-44, wherein the peptide is 16 amino acids in length. 67. The compound according to any one of embodiments 1-44, wherein the peptide is 17 amino acids in length. 68. The compound according to any one of embodiments 1-44, wherein the peptide is 18 amino acids in length. 69. The compound of any one of embodiments 1-44, wherein the peptide is 19 amino acids in length. 70. The compound of any one of embodiments 1-44, wherein the peptide is 20 amino acids in length. 71. A compound which is a peptide or a salt thereof, wherein the peptide is: (a) is 5 to 20 amino acids in length; and (b) A compound comprising the amino acid sequence SYLPP (SEQ ID NO: 24) at the N-terminus of the peptide. 72. The compound according to embodiment 71, wherein the peptide comprises or consists of the amino acid sequence SYLPPL (SEQ ID NO: 20). 73. The compound according to embodiment 71, wherein the peptide comprises or consists of the amino acid sequence SYLPPLT (SEQ ID NO: 4). 74. The compound according to embodiment 71, wherein the peptide comprises or consists of the amino acid sequence SYLPPLTT (SEQ ID NO: 1). 75. The peptide of any one of embodiments 71 to 74, which is 5 to 15 amino acids in length. 76. The peptide of any one of embodiments 71 to 74, which is 5 to 10 amino acids in length. 77. The compound of embodiment 71, wherein the peptide is 5 amino acids in length. 78. The compound of embodiment 71 or embodiment 72, wherein the peptide is 6 amino acids in length. 79. The compound of any one of embodiments 71-73, wherein the peptide is 7 amino acids in length. 80. The compound of any one of embodiments 71-74, wherein the peptide is 8 amino acids in length. 81. The compound of any one of embodiments 71-74, wherein the peptide is 9 amino acids in length. 82. The compound according to any one of embodiments 71-74, wherein the peptide is 10 amino acids in length. 83. The compound according to any one of embodiments 71-74, wherein the peptide is 11 amino acids in length. 84. The compound according to any one of embodiments 71-74, wherein the peptide is 12 amino acids in length. 85. The compound according to any one of embodiments 71-74, wherein the peptide is 13 amino acids in length. 86. The compound according to any one of embodiments 71-74, wherein the peptide is 14 amino acids in length. 87. The compound according to any one of embodiments 71-74, wherein the peptide is 15 amino acids in length. 88. The compound according to any one of embodiments 71-74, wherein the peptide is 16 amino acids in length. 89. The compound of any one of embodiments 71-74, wherein the peptide is 17 amino acids in length. 90. The compound of any one of embodiments 71-74, wherein the peptide is 18 amino acids in length. 91. The compound of any one of embodiments 71-74, wherein the peptide is 19 amino acids in length. 92. The compound according to any one of embodiments 71-74, wherein the peptide is 20 amino acids in length. 93. A compound which is a peptide or a salt thereof, wherein the peptide is: (a) is 6 to 20 amino acids in length; and (b) A compound comprising the amino acid sequence YHIEPV (SEQ ID NO: 2). 94. The compound of embodiment 93, wherein the peptide comprises the amino acid sequence YHIEPV (SEQ ID NO: 2) at the N-terminus of the peptide. 95. The compound of embodiment 93, wherein the peptide comprises the amino acid sequence YHIEPV (SEQ ID NO: 2) at the C-terminus of the peptide. 96. The compound according to embodiment 93, wherein the peptide consists of the amino acid sequence YHIEPV (SEQ ID NO: 2). 97. The compound according to any one of embodiments 93-96, wherein the peptide is 6-15 amino acids in length. 98. The compound according to any one of embodiments 93-96, wherein the peptide is 6-10 amino acids in length. 99. The compound of any one of embodiments 93-96, wherein the peptide is 7 amino acids in length. 100. The compound of any one of embodiments 93-96, wherein the peptide is 8 amino acids in length. 101. The compound of any one of embodiments 93-96, wherein the peptide is 9 amino acids in length. 102. The compound according to any one of embodiments 93-96, wherein the peptide is 10 amino acids in length. 103. The compound according to any one of embodiments 93-96, wherein the peptide is 11 amino acids in length. 104. The compound according to any one of embodiments 93-96, wherein the peptide is 12 amino acids in length. 105. The compound according to any one of embodiments 93-96, wherein the peptide is 13 amino acids in length. 106. The compound according to any one of embodiments 93-96, wherein the peptide is 14 amino acids in length. 107. The compound according to any one of embodiments 93-96, wherein the peptide is 15 amino acids in length. 108. The compound according to any one of embodiments 93-96, wherein the peptide is 16 amino acids in length. 109. The compound according to any one of embodiments 93-96, wherein the peptide is 17 amino acids in length. 110. The compound according to any one of embodiments 93-96, wherein the peptide is 18 amino acids in length. 111. The compound according to any one of embodiments 93-96, wherein the peptide is 19 amino acids in length. 112. The compound according to any one of embodiments 93-96, wherein the peptide is 20 amino acids in length. 113. A compound which is a conjugate or a salt thereof, wherein the conjugate is: (a) a peptide moiety, (i) 3 to 20 amino acids in length; (ii) an amino acid sequence comprising at least three consecutive amino acids from the N-terminus or C-terminus of the amino acid sequence X1LX2X3VK (SEQ ID NO: 8); X1 is a hydrophobic amino acid, X2 and X3 are a peptide moiety, each independently selected from any amino acid; Attached to the peptide moiety (b) one or more conjugate moieties. 114. The compound of embodiment 113, wherein the peptide portion does not consist of the amino acid sequence YLLVR (SEQ ID NO: 13), X4LX5 (SEQ ID NO: 30), X4LX5EIAR (SEQ ID NO: 31), VYLPR (SEQ ID NO: 32), YLPR (SEQ ID NO: 33), or VLQRF (SEQ ID NO: 34), wherein X4 is Y, F, W, or H, and X5 is Y, F, W, Q, or L. 115. The compound according to embodiment 113 or embodiment 114, wherein X1 is an aromatic amino acid. 116. The compound according to embodiment 115, wherein X1 is Y. 117. The compound according to embodiment 115, wherein X1 is F. 118. The compound according to embodiment 115, wherein X1 is W. 119. The compound according to embodiment 113, wherein X1 is A. 120. The compound according to embodiment 113, wherein X1 is I. 121. The compound according to embodiment 113, wherein X1 is L. 122. The compound according to embodiment 113, wherein X1 is V. 123. The compound according to embodiment 113, wherein X1 is M. 124. The compound according to any one of embodiments 113-123, wherein X2 is a hydrophobic amino acid. 125. The compound according to embodiment 124, wherein X2 is selected from L, I, V, and A. 126. The compound according to embodiment 125, wherein X2 is L. 127. The compound according to embodiment 125, wherein X2 is I. 128. The compound according to embodiment 125, wherein X2 is V. 129. The compound according to embodiment 125, wherein X2 is A. 130. The compound according to any one of embodiments 113-129, wherein X3 is a hydrophobic amino acid. 131. The compound according to embodiment 130, wherein X3 is selected from L, I, V, and A. 132. The compound according to embodiment 131, wherein X3 is L. 133. The compound according to embodiment 131, wherein X3 is I. 134. The compound according to embodiment 131, wherein X3 is V. 135. The compound according to embodiment 131, wherein X3 is A. 136. The compound according to any one of embodiments 113-135, wherein the peptide portion comprises the amino acid sequence X1LX2 (SEQ ID NO: 15). 137. The compound according to embodiment 136, wherein X1 is the N-terminal amino acid of the peptide moiety. 138. The compound according to any one of embodiments 113-135, wherein the peptide portion comprises the amino acid sequence X3VK (SEQ ID NO: 16). 139. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence YLL (SEQ ID NO: 7). 140. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence LVK (SEQ ID NO: 9). 141. The compound according to any one of embodiments 113-135, wherein the peptide portion comprises the amino acid sequence X1LX2X3 (SEQ ID NO: 17). 142. The compound according to embodiment 141, wherein the peptide portion comprises the amino acid sequence X1LX2X3K (SEQ ID NO: 29). 143. The compound according to embodiment 141 or embodiment 142, wherein X1 is the N-terminal amino acid of the peptide. 144. The compound according to any one of embodiments 113-135, wherein the peptide portion comprises the amino acid sequence X2X3VK (SEQ ID NO: 18). 145. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence YLLV (SEQ ID NO: 10). 146. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence LLVK (SEQ ID NO: 11). 147. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence YLVK (SEQ ID NO: 12). 148. The compound according to any one of embodiments 113-135, wherein the peptide portion comprises the amino acid sequence X1LX2X3V (SEQ ID NO: 19). 149. The compound according to embodiment 148, wherein X1 is the N-terminal amino acid of the peptide moiety. 150. The compound according to any one of embodiments 113-135, wherein the peptide portion comprises the amino acid sequence LX2X3VK (SEQ ID NO: 27). 151. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence YLLVK (SEQ ID NO: 3). 152. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence FLLVK (SEQ ID NO: 5). 153. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence WLLVK (SEQ ID NO: 6). 154. The compound according to embodiment 113, wherein the peptide portion comprises the amino acid sequence YLLVR (SEQ ID NO: 13). 155. The compound according to any one of embodiments 113-135, wherein the peptide portion comprises the amino acid sequence X1LX2X3VK (SEQ ID NO: 8). 156. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence YLLAVK (SEQ ID NO: 22). 157. The compound according to embodiment 113, wherein the peptide portion comprises or consists of the amino acid sequence YLLNNK (SEQ ID NO: 22). 158. The compound according to any one of embodiments 113-157, wherein the peptide portion is 3-15 amino acids in length. 159. The compound according to any one of embodiments 113-157, wherein the peptide portion is 3-10 amino acids in length. 160. The compound according to any one of embodiments 113-157, wherein the peptide portion is 4-20 amino acids in length. 161. The compound according to any one of embodiments 113-157, wherein the peptide portion is 4-15 amino acids in length. 162. The compound according to any one of embodiments 113-157, wherein the peptide portion is 4-10 amino acids in length. 163. The compound according to any one of embodiments 113-157, wherein the peptide portion is 5-20 amino acids in length. 164. The compound according to any one of embodiments 113-157, wherein the peptide portion is 5-15 amino acids in length. 165. The compound according to any one of embodiments 113-157, wherein the peptide portion is 5-10 amino acids in length. 166. The compound according to any one of embodiments 113-140, wherein the peptide portion is 3 amino acids in length. 167. The compound according to any one of embodiments 113-147, wherein the peptide portion is 4 amino acids in length. 168. The compound according to any one of embodiments 113-154, wherein the peptide portion is 5 amino acids in length. 169. The compound according to any one of embodiments 113-157, wherein the peptide portion is 6 amino acids in length. 170. The compound according to any one of embodiments 113-157, wherein the peptide portion is 7 amino acids in length. 171. The compound according to any one of embodiments 113-157, wherein the peptide portion is 8 amino acids in length. 172. The compound according to any one of embodiments 113-157, wherein the peptide portion is 9 amino acids in length. 173. The compound according to any one of embodiments 113-157, wherein the peptide portion is 10 amino acids in length. 174. The compound according to any one of embodiments 113-157, wherein the peptide portion is 11 amino acids in length. 175. The compound according to any one of embodiments 113-157, wherein the peptide portion is 12 amino acids in length. 176. The compound according to any one of embodiments 113-157, wherein the peptide portion is 13 amino acids in length. 177. The compound according to any one of embodiments 113-157, wherein the peptide portion is 140 amino acids in length. 178. The compound according to any one of embodiments 113-157, wherein the peptide portion is 15 amino acids in length. 179. The compound according to any one of embodiments 113-157, wherein the peptide portion is 16 amino acids in length. 180. The compound according to any one of embodiments 113-157, wherein the peptide portion is 17 amino acids in length. 181. The compound according to any one of embodiments 113-157, wherein the peptide portion is 18 amino acids in length. 182. The compound according to any one of embodiments 113-157, wherein the peptide portion is 19 amino acids in length. 183. The compound according to any one of embodiments 113-157, wherein the peptide portion is 20 amino acids in length. 184. The compound according to any one of embodiments 113-183, wherein the peptide moiety has a hydrophobic N-terminal amino acid. 185. A compound which is a conjugate or a salt thereof, wherein the conjugate comprises a peptide moiety consisting of a peptide according to any one of embodiments 71 to 112 and one or more conjugate moieties. 186. The compound of any one of claims 113-185, wherein at least one of the one or more conjugate moieties comprises a polymer, an amino group, an acyl group, an alkyl group, a phosphate group, a lipid, or a sugar. 187. The compound of embodiment 186, wherein at least one of the one or more conjugated moieties comprises a polymer. 188. The compound according to embodiment 187, wherein the polymer comprises polyethylene glycol, polyvinylpyrrolidone, polylactic-co-glycolic acid, N-(2-hydroxypropyl) methacrylamide copolymer, polyglutamic acid, or a polysaccharide. 189. The compound of any one of embodiments 186-188, wherein at least one of the one or more conjugated moieties comprises an amine group. 190. The compound according to embodiment 189, wherein the amine group is an amino group, an alkylamino group, or a dialkylamino group. 191. The compound of any one of embodiments 186-190, wherein at least one of the one or more conjugated moieties comprises an acyl group. 192. The compound according to embodiment 191, wherein the acyl group is a formyl group or an acetyl group. 193. The compound of any one of embodiments 186-192, wherein at least one of the one or more conjugated moieties comprises an alkyl group. 194. The compound according to embodiment 193, wherein the alkyl group is a methyl group or an ethyl group. 195. The compound according to any one of embodiments 186-194, wherein at least one of the one or more conjugated moieties comprises a phosphate group. 196. The compound according to any one of embodiments 186-195, wherein at least one of the one or more conjugated moieties comprises a lipid. 197. The compound according to any one of embodiments 186-196, wherein at least one of the one or more conjugated moieties comprises a sugar. 198. A compound according to any one of embodiments 113 to 190, or, to the extent dependent on embodiment 186, a compound according to any one of embodiments 191 to 197, comprising a single conjugated moiety. 199. The compound according to embodiment 198, wherein the conjugate moiety is attached to the N-terminal amino acid of the peptide moiety. 200. The compound according to embodiment 198, wherein the conjugate moiety is attached to the C-terminal amino acid of the peptide moiety. 201. The compound of any one of embodiments 113-197, comprising two or more conjugated moieties. 202. The compound according to embodiment 201, wherein all conjugated moieties are the same. 203. The compound according to embodiment 201, wherein the conjugate moieties are not all the same. 204. The compound according to embodiment 201, wherein all conjugated moieties are different. 205. The compound according to embodiment 201, comprising a conjugate moiety attached to the N-terminal amino acid of the peptide moiety and a conjugate moiety attached to the C-terminal amino acid of the peptide moiety. 206. The compound according to embodiment 205, wherein the conjugate moiety attached to the N-terminal amino acid of the peptide moiety is the same as the conjugate moiety attached to the C-terminal amino acid of the peptide moiety. 207. The compound according to embodiment 205, wherein the conjugate moiety attached to the N-terminal amino acid of the peptide moiety is different from the conjugate moiety attached to the C-terminal amino acid of the peptide moiety. 208. A compound which is a peptide or a salt thereof, wherein the peptide consists of the amino acid sequence YLLVR (SEQ ID NO: 13), for treating mood disorder, anxiety disorder, or reduced motivation disorder. 209. The compound according to any one of embodiments 1-208, which is a salt. 210. The compound according to embodiment 209, wherein the salt is an acid addition salt. 211. Acid: (a) Hydrochloric acid; (b) sulfuric acid; (c) nitric acid; (d) phosphoric acid; (e) hydrobromic acid; (f) perchloric acid; (g) citric acid; (h) succinic acid; (i) Maleic acid; (j) fumaric acid; (k) Malic acid; (l) Tartaric acid; (m) p-toluenesulfonic acid; (n) benzenesulfonic acid; (o) methanesulfonic acid; or The compound of embodiment 210, wherein (p) trifluoroacetic acid. 212. The compound according to embodiment 209, wherein the salt is a base addition salt. 213. Bases are: (a) sodium hydroxide; (b) potassium hydroxide; (c) lithium hydroxide; (d) calcium hydroxide; or (e) The compound of embodiment 212, which is magnesium hydroxide. 214. A pharmaceutical composition comprising a compound according to any one of embodiments 1-213 and one or more pharmaceutically acceptable carriers, diluents and / or excipients, optionally formulated for oral administration. 215. A food product comprising a compound according to any one of embodiments 1 to 213 as an additive. . 216. The food product of embodiment 215, which is a dietary supplement. 217. The food product of embodiment 215, which is a functional food product. 218. A method for treating a subject suffering from a mood disorder, anxiety disorder, or reduced motivation disorder, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 213 or a pharmaceutical composition according to embodiment 214. 219. The method of embodiment 218, comprising treating a subject suffering from a mood disorder. 220. The method of embodiment 219, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder. 221. The method of embodiment 220, comprising treating a subject suffering from depression. 222. The method of embodiment 220, comprising treating a subject suffering from bipolar disorder. 223. The method of embodiment 220, comprising treating a subject suffering from an adjustment disorder. 224. The method of embodiment 218, comprising treating a subject suffering from an anxiety disorder. 225. The method of embodiment 218, comprising treating a subject suffering from reduced motivation disorder. 226. The method of embodiment 225, wherein the reduced motivation disorder comprises blunted affect, abulia, or akinetic mutism. 227. The method of embodiment 226, comprising treating a subject suffering from blunted affect. 228. The method of embodiment 226, comprising treating a subject suffering from abulia. 229. The method of embodiment 226, comprising treating a subject suffering from akinetic mutism. 230. The method of any one of embodiments 218-229, wherein the compound or pharmaceutical composition is administered orally. 231. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.005 mg / kg to 500 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.005 mg / kg to 500 mg / kg of the compound. 232. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.005 mg / kg to 100 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.005 mg / kg to 100 mg / kg of the compound. 233. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.005 mg / kg to 30 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.005 mg / kg to 30 mg / kg of the compound. 234. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.005 mg / kg to 1 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.005 mg / kg to 1 mg / kg of the compound. 235. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.01 mg / kg to 30 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.01 mg / kg to 30 mg / kg of the compound. 236. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.01 mg / kg to 3 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.01 mg / kg to 3 mg / kg of the compound. 237. The amount of the compound administered to the subject per day is 0.01 mg / kg to 1 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day is 0.01 mg / kg to 1 mg / kg. 231. The method of embodiment 230, comprising administering to a subject in need thereof at a dose of from 1 mg / kg to 1 mg / kg of the compound. 238. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.02 mg / kg to 5 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.02 mg / kg to 5 mg / kg of the compound. 239. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.02 mg / kg to 2 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.02 mg / kg to 2 mg / kg of the compound. 240. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.02 mg / kg to 1 mg / kg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.02 mg / kg to 1 mg / kg of the compound. 241. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.1 mg to 50 g, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.1 mg to 50 g of the compound. 242. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.1 mg to 10 g, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.1 mg to 10 g of the compound. 243. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.1 mg to 3 g, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.1 mg to 3 g of the compound. 244. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.1 mg to 100 mg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.1 mg to 100 mg of the compound. 245. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.1 mg to 1 mg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.1 mg to 1 mg of the compound. 246. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.3 mg to 3 g, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.3 mg to 3 g of the compound. 247. The method of embodiment 230, wherein the amount of the compound administered to the subject per day is 0.3 mg to 100 mg, or the amount of the pharmaceutical composition administered to the subject per day comprises 0.3 mg to 100 mg of the compound. 248. A method for treating or preventing a mood disorder, anxiety disorder, or reduced motivation disorder, comprising administering to a subject prone to or suffering from a mood disorder, anxiety disorder, or reduced motivation disorder an effective amount of one or more food products described in any one of embodiments 215 to 217. 249. The method of embodiment 248, comprising treating or preventing a mood disorder. 250. The method of embodiment 249, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder. 251. The method of embodiment 250, comprising treating or preventing depression. 252. The method of embodiment 250, comprising treating or preventing bipolar disorder. 253. The method of embodiment 250, comprising treating or preventing adjustment disorder. 254. The method of embodiment 248, comprising treating or preventing an anxiety disorder. 255. The method of embodiment 248, comprising treating or preventing reduced motivation disorder. 256. The method of embodiment 255, wherein the reduced motivation disorder comprises blunted affect, abulia, or akinetic mutism. 257. The method of embodiment 256, comprising treating or preventing apathy. 258. The method of embodiment 256, comprising treating or preventing abulia. 259. The method of embodiment 256, comprising treating or preventing akinetic mutism. 260. The method of any one of embodiments 248-259, wherein the amount of one or more foods administered to the subject per day comprises 0.005 mg / kg to 500 mg / kg of the compound. 261. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.005 mg / kg to 100 mg / kg of the compound. 262. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.005 mg / kg to 30 mg / kg of the compound. 263. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.005 mg / kg to 1 mg / kg of the compound. 264. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.01 mg / kg to 30 mg / kg of the compound. 265. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.01 mg / kg to 3 mg / kg of the compound. 266. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.01 mg / kg to 1 mg / kg of the compound. 267. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.02 mg / kg to 5 mg / kg of the compound. 268. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.02 mg / kg to 2 mg / kg of the compound. 269. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.02 mg / kg to 1 mg / kg of the compound. 270. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.1 mg to 50 g of the compound. 271. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.1 mg to 10 g of the compound. 272. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.1 mg to 3 g of the compound. 273. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.1 mg to 100 mg of the compound. 274. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.1 mg to 1 mg of the compound. 275. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.3 mg to 3 g of the compound. 276. The method of embodiment 260, wherein the amount of one or more foods administered to the subject per day comprises 0.3 mg to 100 mg of the compound. 277. A compound according to any one of embodiments 1-213, for use as a medicament. 278. A compound according to any one of embodiments 1-213 for use in a method for the treatment of a mood disorder. 279. The compound for use according to embodiment 278, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder. 280. The compound for use according to embodiment 279, wherein the mood disorder comprises depression. 281. The compound for use according to embodiment 279, wherein the mood disorder comprises bipolar disorder. 282. The compound for use according to embodiment 279, wherein the mood disorder comprises adjustment disorder. 283. A compound according to any one of embodiments 1-213 for use in a method for the treatment of an anxiety disorder. 284. A compound according to any one of embodiments 1-213 for use in a method for the treatment of reduced motivation disorder. 285. In embodiment 2, the reduced motivation disorder comprises apathy, abulia, or akinetic mutism. 84. A compound for use as described in 286. The compound for use according to embodiment 285, wherein the reduced motivation disorder comprises apathy. 287. The compound for use according to embodiment 285, wherein the reduced motivation disorder comprises abulia. 288. The compound for use according to embodiment 285, wherein the reduced motivation disorder comprises akinetic mutism. 289. The compound for use according to any one of embodiments 278-288, wherein the method comprises orally administering to the subject an effective amount of the compound. 290. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.005 mg / kg to 500 mg / kg of the compound per day. 291. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.005 mg / kg to 100 mg / kg of the compound per day. 292. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.005 mg / kg to 30 mg / kg of the compound per day. 293. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.005 mg / kg to 1 mg / kg of the compound per day. 294. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.01 mg / kg to 30 mg / kg of the compound per day. 295. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.01 mg / kg to 3 mg / kg of the compound per day. 296. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.01 mg / kg to 1 mg / kg of the compound per day. 297. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.02 mg / kg to 5 mg / kg of the compound per day. 298. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.02 mg / kg to 2 mg / kg of the compound per day. 299. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.02 mg / kg to 1 mg / kg of the compound per day. 300. The compound for use according to embodiment 289, wherein the method comprises administering to the subject between 0.1 mg and 50 g of the compound per day. 301. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.1 mg to 10 g of the compound per day. 302. The compound for use according to embodiment 289, wherein the method comprises administering to the subject between 0.1 mg and 3 g of the compound per day. 303. The compound for use according to embodiment 289, wherein the method comprises administering to the subject between 0.1 mg and 100 mg of the compound per day. 304. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.1 mg to 1 mg of the compound per day. 305. The compound for use according to embodiment 289, wherein the method comprises administering to the subject 0.3 mg to 3 g of the compound per day. 306. The compound for use according to embodiment 289, wherein the method comprises administering to the subject between 0.3 mg and 100 mg of the compound per day. 307. The pharmaceutical composition according to embodiment 214, for use in a method for the treatment of mood disorders. 308. The pharmaceutical composition for use according to embodiment 307, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder. 309. The pharmaceutical composition for use according to embodiment 307, wherein the mood disorder comprises depression. 310. The pharmaceutical composition for use according to embodiment 307, wherein the mood disorder comprises bipolar disorder. 311. The pharmaceutical composition for use according to embodiment 307, wherein the mood disorder comprises an adjustment disorder. 312. The pharmaceutical composition according to embodiment 214, for use in a method for the treatment of anxiety disorders. 313. The pharmaceutical composition according to embodiment 214, for use in a method for the treatment of reduced motivation disorder. 314. The pharmaceutical composition for use according to embodiment 313, wherein the reduced motivation disorder comprises blunted affect, abulia, or akinetic mutism. 315. The pharmaceutical composition for use according to embodiment 313, wherein the motivation-decreased disorder comprises apathy. 316. The pharmaceutical composition for use according to embodiment 313, wherein the reduced motivation disorder comprises abulia. 317. The pharmaceutical composition for use according to embodiment 313, wherein the motivation-decreased disorder comprises akinetic mutism. 318. The pharmaceutical composition for use according to any one of embodiments 307-317, wherein the method comprises orally administering to the subject an effective amount of the pharmaceutical composition. 319. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.005 mg / kg to 500 mg / kg of the compound per day. 320. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.005 mg / kg to 100 mg / kg per day of the compound. 321. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.005 mg / kg to 30 mg / kg of the compound per day. 322. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.005 mg / kg to 1 mg / kg of the compound per day. 323. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.01 mg / kg to 30 mg / kg of the compound per day. 324. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.01 mg / kg to 3 mg / kg of the compound per day. 325. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.01 mg / kg to 1 mg / kg of the compound per day. 326. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.02 mg / kg to 5 mg / kg of the compound per day. 327. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.02 mg / kg to 2 mg / kg of the compound per day. 328. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.02 mg / kg to 1 mg / kg of the compound per day. 329. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.1 mg to 50 g of the compound per day. 330. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.1 mg to 10 g of the compound per day. 331. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.1 mg to 3 g of the compound per day. 332. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.1 mg to 100 mg of the compound per day. 333. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.1 mg to 1 mg of the compound per day. 334. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.3 mg to 3 g of the compound per day. 335. The pharmaceutical composition for use according to embodiment 318, wherein the method comprises administering to the subject an amount of the pharmaceutical composition comprising 0.3 mg to 100 mg of the compound per day. 336. A food product according to any one of embodiments 215-217, for use in a method for the treatment or prevention of mood disorders. 337. The food for use according to embodiment 336, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder. 338. The food for use according to embodiment 337, wherein the mood disorder comprises depression. 339. The food for use according to embodiment 337, wherein the mood disorder comprises bipolar disorder. 340. The food for use according to embodiment 337, wherein the mood disorder comprises an adjustment disorder. 341. A food product according to any one of embodiments 215-217, for use in a method for the treatment or prevention of anxiety disorders. 342. Food for use according to any one of embodiments 215 to 217, for use in a method for the treatment or prevention of reduced motivation disorder. 343. The food for use according to embodiment 342, wherein the reduced motivation disorder comprises blunted affect, abulia, or akinetic mutism. 344. The food for use according to embodiment 343, wherein the motivation-decreasing disorder comprises apathy. 345. The food for use according to embodiment 343, wherein the reduced motivation disorder comprises abulia. 346. The food for use according to embodiment 343, wherein the reduced motivation disorder comprises akinetic mutism. 347. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.005 mg / kg to 500 mg / kg of the compound per day. 348. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.005 mg / kg to 100 mg / kg of the compound per day. 349. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.005 mg / kg to 30 mg / kg of the compound per day. 350. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.005 mg / kg to 1 mg / kg of the compound per day. 351. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.01 mg / kg to 30 mg / kg of the compound per day. 352. A method comprising administering to a subject a fixed amount of one or more food products according to any one of embodiments 215-217, wherein the fixed amount of one or more food products administered to the subject 347. The food product for use according to any one of embodiments 336 to 346, wherein the amount comprises the compound in an amount of 0.01 mg / kg to 3 mg / kg per day. 353. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.01 mg / kg to 1 mg / kg of the compound per day. 354. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.02 mg / kg to 5 mg / kg of the compound per day. 355. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.02 mg / kg to 2 mg / kg of the compound per day. 356. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.02 mg / kg to 1 mg / kg of the compound per day. 357. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises between 0.1 mg and 50 g of the compound per day. 358. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises between 0.1 mg and 10 g of the compound per day. 359. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises between 0.1 mg and 3 g of the compound per day. 360. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises between 0.1 mg and 100 mg of the compound per day. 361. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.1 mg to 1 mg of the compound per day. 362. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises 0.3 mg to 3 g of the compound per day. 363. The food product for use according to any one of embodiments 336-346, wherein the method comprises administering to a subject a quantity of one or more food products according to any one of embodiments 215-217, wherein the quantity of the one or more food products administered to the subject comprises between 0.3 mg and 100 mg of the compound per day. 364. A composition comprising Rubisco protein treated with pepsin or pepsin and pancreatin for use in a method for treating anxiety disorders, mood disorders, or reduced motivation disorders. 365. The composition for use according to embodiment 364, wherein the Rubisco protein is spinach rubisco. 366. The composition for use according to embodiment 364 or embodiment 365, for use in a method for the treatment of anxiety disorders. 367. The composition for use according to embodiment 364 or embodiment 365, for use in a method for the treatment of mood disorders. 368. The composition for use according to embodiment 367, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder. 369. The composition for use according to embodiment 364 or embodiment 365, for use in a method for the treatment of reduced motivation disorder. 370. The composition for use according to embodiment 369, wherein the reduced motivation disorder comprises blunted affect, abulia, or akinetic mutism.

[0206] 8. Incorporation by Reference

[0207] All publications, patents, patent applications, and other documents cited in this application are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated herein by reference. In the event of a conflict between the teachings of one or more documents incorporated herein and the present disclosure, the teachings of this disclosure control.

[0208] 9. Sequence Listing

[0209] Table 2 [Table 2]

[0210] Table 3 [Table 3]

Claims

1. 1. A compound which is a peptide or a salt thereof, said peptide comprising: (a) is 3 to 20 amino acids in length; (b) amino acid sequence X １ LX ２ X ３ having an amino acid sequence containing at least 3 consecutive amino acids from the N-terminus or C-terminus of VK (SEQ ID NO: 8); (i) X １ is a hydrophobic amino acid, (ii) X ２ and X ３ are each independently selected from any amino acid; (c) has a hydrophobic N-terminal amino acid; and (d) amino acid sequence YLLVR (SEQ ID NO: 13), X ４ LX ５ (SEQ ID NO: 30), X ４ LX ５ does not consist of EIAR (SEQ ID NO: 31), VYLPR (SEQ ID NO: 32), YLPR (SEQ ID NO: 33), or VLQRF (SEQ ID NO: 34); ４ is Y, F, W, or H, and X ５ is Y, F, W, Q, or L.

2. X １ The compound of claim 1 , wherein is an aromatic amino acid.

3. X １ is Y, F, W, A, I, L, V, or M.

4. X １ is Y, F, or W.

5. X ２ and / or X ３ The compound according to any one of claims 1 to 4, wherein is L, I, V, or A.

6. The peptide has the amino acid sequence: (a) X １ LX ２ (SEQ ID NO: 15), optionally X １ is the N-terminal amino acid of the peptide; (b) X ３ VK (SEQ ID NO: 16): (c) YLL (SEQ ID NO: 7); or (d) The compound according to any one of claims 1 to 5, comprising LVK (SEQ ID NO: 9).

7. The peptide has the amino acid sequence: (a) X １ LX ２ X ３ (SEQ ID NO: 17), optionally X １ is the N-terminal amino acid of said peptide; and / or The peptide has the amino acid sequence X １ LX ２ X ３ K (SEQ ID NO: 29); (b) X ２ X ３ VK (SEQ ID NO: 18): (c) YLLV (SEQ ID NO: 10); (d) LLVK (SEQ ID NO: 11); or (e) YLVK.

8. The peptide has the amino acid sequence: (a) X １ LX ２ X ３ V (SEQ ID NO: 19), optionally X １ is the N-terminal amino acid of the peptide; (b) LX ２ X ３ VK (SEQ ID NO: 27): (c) YLLVK (SEQ ID NO: 3); (d) FLLVK (SEQ ID NO: 5); (e) WLLVK (SEQ ID NO: 6); or (f) The compound according to any one of claims 1 to 5, comprising YLLVR (SEQ ID NO: 13).

9. The peptide has the amino acid sequence: (a) X １ LX ２ X ３ VK (SEQ ID NO: 8), optionally X １ is the N-terminal amino acid of the peptide; (b) YLLAVK (SEQ ID NO: 22): or (c) The compound according to any one of claims 1 to 5, comprising YLLNNK (SEQ ID NO: 22).

10. The compound of any one of claims 1 to 6, wherein the peptide is 3 to 15 amino acids in length or 3 to 10 amino acids in length.

11. 8. The compound of any one of claims 1 to 7, wherein the peptide is 4 to 20 amino acids in length, 4 to 15 amino acids in length, or 4 to 10 amino acids in length.

12. 9. The compound of any one of claims 1 to 8, wherein the peptide is 5 to 20 amino acids in length, 5 to 15 amino acids in length, or 5 to 10 amino acids in length.

13. 10. The compound of any one of claims 1 to 9, wherein the peptide is 6 to 20 amino acids in length, 6 to 15 amino acids in length, or 6 to 10 amino acids in length.

14. 10. The compound of any one of claims 1 to 9, wherein the peptide is 7 to 20 amino acids in length, 7 to 15 amino acids in length, or 7 to 10 amino acids in length.

15. 10. The compound of any one of claims 1 to 9, wherein the peptide is 8 to 20 amino acids in length, 8 to 15 amino acids in length, or 8 to 10 amino acids in length.

16. 10. The compound of any one of claims 1 to 9, wherein the peptide is 9 to 20 amino acids in length, 9 to 15 amino acids in length, or 9 to 10 amino acids in length.

17. 2. The compound of claim 1, wherein the peptide consists of the amino acid sequence YLLVK (SEQ ID NO: 3), FLLVK (SEQ ID NO: 5), or WLLVK (SEQ ID NO: 6).

18. 1. A compound which is a peptide or a salt thereof, said peptide comprising: (a) is 5 to 20 amino acids in length; and (b) A compound comprising the amino acid sequence SYLPP (SEQ ID NO: 24) at the N-terminus of the peptide.

19. 19. The compound of claim 18, wherein the peptide comprises or consists of the amino acid sequence SYLPPL (SEQ ID NO: 20), SYLPPLT (SEQ ID NO: 4), or SYLPPLTT (SEQ ID NO: 1).

20. 19. The compound of claim 18, wherein the peptide is 5 to 15 amino acids in length or 5 to 10 amino acids in length.

21. 20. The compound of claim 18 or claim 19, wherein the peptide is 6 to 20 amino acids in length, 6 to 15 amino acids in length, or 6 to 10 amino acids in length.

22. 20. The compound of claim 18 or claim 19, wherein the peptide is 7 to 20 amino acids in length, 7 to 15 amino acids in length, or 7 to 10 amino acids in length.

23. 20. The compound of claim 18 or claim 19, wherein the peptide is 8 to 20 amino acids in length, 8 to 15 amino acids in length, or 8 to 10 amino acids in length.

24. 20. The compound of claim 18 or claim 19, wherein the peptide is 9 to 20 amino acids in length, 9 to 15 amino acids in length, or 9 to 10 amino acids in length.

25. 20. The compound of claim 18 or claim 19, wherein the peptide is 10 to 20 amino acids in length, or 10 to 15 amino acids in length.

26. 19. The compound of claim 18, wherein the peptide consists of the amino acid sequence SYLPPLTT (SEQ ID NO: 1) or SYLPPLT (SEQ ID NO: 4).

27. 1. A compound which is a peptide or a salt thereof, said peptide comprising: (a) is 6 to 20 amino acids in length; and (b) A compound comprising the amino acid sequence YHIEPV (SEQ ID NO: 2).

28. 28. The compound of claim 27, wherein the peptide consists of the amino acid sequence YHIEPV (SEQ ID NO: 2).

29. 28. The compound of claim 27, wherein the peptide is 7 to 20 amino acids in length, 7 to 15 amino acids in length, or 7 to 10 amino acids in length.

30. 28. The compound of claim 27, wherein the peptide is 8 to 20 amino acids in length, 8 to 15 amino acids in length, or 8 to 10 amino acids in length.

31. 28. The compound of claim 27, wherein the peptide is 9 to 20 amino acids in length, 9 to 15 amino acids in length, or 9 to 10 amino acids in length.

32. 28. The compound of claim 27, wherein the peptide is 10 to 20 amino acids in length or 10 to 15 amino acids in length.

33. 1. A compound which is a conjugate or a salt thereof, said conjugate comprising: (a) a peptide moiety, (i) is 3 to 20 amino acids in length; (ii) amino acid sequence X １ LX ２ X ３ having an amino acid sequence comprising at least 3 consecutive amino acids from the N-terminus or C-terminus of VK (SEQ ID NO: 8); X １ is a hydrophobic amino acid, X ２ and X ３ are each independently selected from any amino acid, and (iii) optionally a peptide moiety having a hydrophobic N-terminal amino acid; Attached to the peptide moiety (b) one or more conjugate moieties.

34. X １ 34. The compound of claim 33, wherein is an aromatic amino acid.

35. X １ is Y, F, W, A, I, L, V, or M.

36. X １ is Y, F, or W.

37. X ２ and / or X ３ The compound of any one of claims 33 to 36, wherein is L, I, V, or A.

38. The peptide portion has the amino acid sequence: (a) X １ LX ２ (SEQ ID NO: 15), optionally X １ is the N-terminal amino acid of the peptide moiety; (b) X ３ VK (SEQ ID NO: 16): (c) YLL (SEQ ID NO: 7); or (d) The compound according to any one of claims 33 to 37, comprising LVK (SEQ ID NO: 9).

39. The peptide portion has the amino acid sequence: (a) X １ LX ２ X ３ (SEQ ID NO: 17), optionally X １ is the N-terminal amino acid of the peptide moiety; and / or The peptide portion has the amino acid sequence X １ LX ２ X ３ K (SEQ ID NO: 29); (b) X ２ X ３ VK (SEQ ID NO: 18): (c) YLLV (SEQ ID NO: 10); (d) LLVK (SEQ ID NO: 11); or (e) YLVK.

40. The peptide portion has the amino acid sequence: (a) X １ LX ２ X ３ V (SEQ ID NO: 19), optionally X １ is the N-terminal amino acid of the peptide moiety; (b) LX ２ X ３ VK (SEQ ID NO: 27): (c) YLLVK (SEQ ID NO: 3); (d) FLLVK (SEQ ID NO: 5); (e) WLLVK (SEQ ID NO: 6); or (f) The compound according to any one of claims 33 to 37, comprising YLLVR (SEQ ID NO: 13).

41. The peptide portion has the amino acid sequence: (a) X １ LX ２ X ３ VK (SEQ ID NO: 8), optionally X １ is the N-terminal amino acid of the peptide; (b) YLLAVK (SEQ ID NO: 22): or (c) The compound according to any one of claims 33 to 37, comprising YLLNNK (SEQ ID NO: 22).

42. A compound which is a conjugate or a salt thereof, said conjugate comprising a peptide moiety consisting of a peptide according to any one of claims 18 to 32 and one or more conjugate moieties.

43. 43. The compound of any one of claims 33-42, wherein at least one of the one or more conjugate moieties comprises a polymer, an amino group, an acyl group, an alkyl group, a phosphate group, a lipid, or a sugar.

44. The compound according to any one of claims 1 to 43, which is a salt.

45. A pharmaceutical composition comprising a compound according to any one of claims 1 to 44 and one or more pharmaceutically acceptable carriers, diluents and / or excipients.

46. A food product comprising the compound according to any one of claims 1 to 44 as an additive.

47. A compound according to any one of claims 1 to 44 for use in a method for the treatment of anxiety disorders, mood disorders or reduced motivation disorders.

48. 48. A compound for use according to claim 47 for use in a method for the treatment of anxiety disorders.

49. 48. A compound for use according to claim 47 for use in a method for the treatment of a mood disorder.

50. 50. The compound for use according to claim 49, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder.

51. 48. A compound for use according to claim 47 for use in a method for the treatment of reduced motivation disorder.

52. The motivation reduction disorder is 52. The compound for use according to claim 51, including blunted affect, abulia, or akinetic mutism.

53. 46. ​​The pharmaceutical composition of claim 45 for use in a method for the treatment of anxiety disorders, mood disorders, or reduced motivation disorders.

54. 54. A pharmaceutical composition for use according to claim 53 for use in a method for the treatment of anxiety disorders.

55. 54. A pharmaceutical composition for use according to claim 53 for use in a method for the treatment of a mood disorder.

56. 56. The pharmaceutical composition for use according to claim 55, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder.

57. 54. A pharmaceutical composition for use according to claim 53 for use in a method for the treatment of reduced motivation disorder.

58. 58. The pharmaceutical composition for use according to claim 57, wherein the reduced motivation disorder comprises blunted affect, abulia, or akinetic mutism.

59. 47. The food product of claim 46 for use in a method for treating anxiety disorders, mood disorders, or reduced motivation disorders.

60. 60. A food product for use according to claim 59 for use in a method for the treatment of anxiety disorders.

61. 60. A food product for use according to claim 59 for use in a method for the treatment of mood disorders.

62. 62. The food product for use of claim 61, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder.

63. 60. A food product for use according to claim 59 for use in a method for the treatment of reduced motivation disorder.

64. 64. The food product for use of claim 63, wherein the reduced motivation disorder comprises apathy, abulia, or akinetic mutism.

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