Peptides and peptide conjugates for treating mental illness

Abstract

Novel therapeutic agents for the treatment or prevention of mood disorders, anxiety disorders, and hypomotivational disorders are provided. The present invention provides a compound which is a peptide or a salt thereof, the peptide comprising: a. 5 to 10 amino acids in length; b. consists of at least 5 consecutive amino acids from the amino acid sequence LSSTQAQQSX1 (wherein X1 is Y, W, or F), with 1-3 amino acid substitutions optional; and c. Not consisting of the amino acid sequence LSSTQAQQSY, LSSTQAQQS, LSSTQAQQSW, or LSSTQAQQSF; A compound having the activity of shortening the immobility time in the tail suspension test, the activity of shortening the immobility time in the forced swimming test, the activity of increasing the time spent in the open arms in the elevated plus maze test, or the activity of increasing the time spent in the central circle in the open field test.

Description

[Technical Field]

[0001] 1. Cross-reference of related applications This application is a prior art of U.S. Provisional Patent Application No. 62 / 384,333, filed on September 7, 2016. Priority rights are asserted. The contents of this provisional application are incorporated in their entirety by reference herein. It can be done. [Background technology]

[0002] 2. Background technology It is estimated that 9.5% of the adult population in the United States suffers from a mood disorder (Kessle). r et al.,2005,Arch Gen Psychiatry 62(6): 617-627). Only about half of patients suffering from mood disorders are receiving treatment, and Within the population, less than 40% receive minimal and appropriate treatment (Wang et al.). ,2005,Arch Gen Psychiatry 62(6):629-640) .

[0003] It is estimated that 18.1% of the adult population in the United States suffers from an anxiety disorder (Kessl). er et al.,2005,Arch Gen Psychiatry 62(6) (617-627). Less than 40% of patients with anxiety disorders are receiving treatment, Of these, less than 35% receive minimal and appropriate treatment (Wang et al. .,2005,Arch Gen Psychiatry 62(6):629-640 ).

[0004] Decreased motivation disorder frequently occurs in individuals with traumatic brain injury, with an incidence of 5% to 67%. It is estimated that it changes (Marin and Wilkosz, 2005, JH (ead Trauma Rehabil 20(4):377-388). Decreased motivation is Individuals suffering from depression, Parkinson's disease, Alzheimer's disease, and schizophrenia, Furthermore, individuals who have suffered a stroke, and even healthy individuals, especially elderly individuals, may It is often recognized (Bonnelle et al., 2015, Journal of Physiology 109:16-26). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Kessler et al., 2005, Arch Gen Psychiatry 62(6):617-627 [Non-Patent Document 2] Wang et al., 2005, Arch Gen Psychiatry 62(6):629-640 [Non-Patent Document 3] Marin and Wilkosz,2005,J Head Trauma Rehabilitation 20(4):377-388 [Non-Patent Document 4] Bonnelle et al.,2015,Journal of Physiology 109:16-26 [Overview of the project] [Problems that the invention aims to solve]

[0006] There is a need for new treatments for mood disorders, anxiety disorders, and low motivation disorders. [Means for solving the problem]

[0007] 3. Outline of the Invention International application PCT / JP2016 / 0, which is incorporated herein by reference in its entirety. No. 56453 describes a 10 - amino acid peptide derived from the soybean storage protein β - conglycinin having the amino acid sequences LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQ SW (SEQ ID NO: 6) and LSSTQAQQSF (SEQ ID NO: 7), and their usefulness for the treatment of conditions such as depression and low motivation. The present disclosure provides a peptide, its salt, a peptide conjugate, and its salt (sometimes collectively referred to herein as "compounds" "), which are 5 - 15 amino acids in length and contain at least 5 consecutive amino acids common to one of the 10 - amino acid peptides described in International Application No. PCT / JP2016 / 056453

[0008] In one aspect, the present disclosure provides a peptide having an amino acid sequence containing at least 5 consecutive amino acids 5 - 15 amino acids in length and derived from the amino acid sequence LSSTQAQQSX1 (where X1 is Y, W or F) (SEQ ID NO: 34), and its salt. In one embodiment

[0009]

[0009] It contains an acid. In one embodiment, the peptide moiety is 5 - 8, 6 - 10, 7 - 11, 8 - 1 2, 9 - 13, 10 - 14, 11 - 15 or 12 - 15 amino acids in length. Exemplary peptide conjugates and their salts are described in Section 5.2 and Numbered Embodiment 4 - 117 below.

[0010] The present disclosure also provides pharmaceutical compositions and foods containing the compounds of the present disclosure. Exemplary pharmaceutical compositions are described in Section 5.3 and Numbered Embodiment 118 below, and exemplary foods (e.g., nutritional supplements and functional foods) are described in Section 5.4 and Numbered Embodiments 119 - 121 below.

[0011] The present disclosure also provides methods of treating or preventing mood disorders, anxiety disorders, or motivational deficit disorders using the compounds, pharmaceutical compositions, and foods described herein. Exemplary methods of treating or preventing mood disorders, anxiety disorders, and motivational deficit disorders are described in Section 5.5 and Numbered Embodiments 122 - 180 below.

[0012] 4. Brief Description of the Drawings

Brief Description of the Drawings

[0013] [Figure 1] FIG. 1 shows the results of the tail suspension test of mice orally administered with the peptide LSSTQAQQSY (SEQ ID NO: 1). [Figure 2] FIG. 2 shows the results of the forced swim test of mice orally administered with the peptide LSSTQAQQSY (SEQ ID NO: 1). [Figure 3]Figures 3A-3B show the results of the tail suspension test in mice orally administered the peptides LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQS (SEQ ID NO: 2), or SSTQAQQSY (SEQ ID NO: 3) (Figure 3A), or LSSTQAQQSY (SEQ ID NO: 1), LSSTQ (SEQ ID NO: 4), or AQQSY (SEQ ID NO: 5) (Figure 3B). [Figure 4] Figures 4A-4C show the results of an elevated cruciform maze test in mice orally administered the peptide LSSTQAQQSY (SEQ ID NO: 1). Figure 4A shows the percentage of time mice spent in the open arms of the maze. Figure 4B shows the percentage of mice that entered the arms of the maze created with open arms. Figure 4C shows the total number of times mice entered both the open and closed arms of the maze. [Figure 5] Figures 5A-5C show the results of an open-field test in mice orally administered peptide LSSTQAQQSY (Sequence ID 1). Figure 5A shows the percentage of time mice spent in a 12 cm circle in the center of the measurement chamber. Figure 5B shows the number of times mice entered the 12 cm circle. Figure 5C shows the spontaneous motility activity of the mice. [Figure 6] Figure 6 shows the results of a tail suspension test in mice orally administered the peptide LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQSW (SEQ ID NO: 6), or LSSTQAQQSF (SEQ ID NO: 7), or the C-terminally amidated peptide conjugate LSSTQAQQSY-NH2 (SEQ ID NO: 36). [Figure 7] Figure 7 shows the results of the tail suspension test in vagus nerve-transected mice and sham-surgery mice that were orally administered the peptide LSSTQAQQSY (SEQ ID NO: 1). [Figure 8] Figure 8 shows the results of the tail suspension test in mice orally administered peptide LSSTQAQQSY (SEQ ID NO: 1) alone or in combination with serotonin 5-HT1A, dopamine D1, or a GABAA receptor antagonist. [Figure 9] Figure 9 shows the results of the tail suspension test in mice orally administered the peptides LSSTQAQQ (SEQ ID NO: 27), SSTQAQQS (SEQ ID NO: 28), and STQAQQSY (SEQ ID NO: 29). [Figure 10] Figure 10 shows the results of a tail suspension test in mice orally administered the peptides LSSTQAQQSYW (SEQ ID NO: 37), WLSSTQAQQSY (SEQ ID NO: 38), WLSSTQAQQSYW (SEQ ID NO: 39), WLSSTQ (SEQ ID NO: 40), and AQQSYW (SEQ ID NO: 41). [Figure 11] Figure 11 shows the results of a tail suspension test in mice orally administered the peptides ESFFLSSTQAQQSY (SEQ ID NO: 42), LSSTQAQQSYLQGF (SEQ ID NO: 43), and FFLSSTQAQQSYLQ (SEQ ID NO: 44). [Figure 12] Figure 12 shows the results of the tail suspension test in mice orally administered the peptides SSTQAQQS (SEQ ID NO: 28), LSSTQAQQSYW (SEQ ID NO: 37), and WLSSTQ (SEQ ID NO: 40). [Modes for carrying out the invention]

[0014] 5. Detailed explanation 5.1. Peptides This disclosure relates to the amino acid sequence LSSTQAQQSX1 (wherein X1 is Y, W, or F) (sequence) A compound containing or derived from at least five consecutive amino acids from (number 34) It has an amino acid sequence, and the amino acid sequences are LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQ QS (SEQ ID NO: 2), SSTQAQQSY (SEQ ID NO: 3), LSSTQ (SEQ ID NO: 4), AQQSY (sequence number 5), LSSTQAQQSW (sequence number 6), or LSSTQA We propose peptides having an amino acid sequence not composed of QQSF (SEQ ID NO: 7) and their salts. Provided. Where an embodiment described herein refers to a "peptide", that embodiment is Even if the embodiment does not explicitly describe the expression "or its salt" or a similar expression, Unless otherwise required by context, this includes the peptide itself and salts of that peptide. Please understand this.

[0015] The peptides of this disclosure consist of 5 to 15 amino acids (i.e., 5, 6, 7, 8, 9, 10, 1) The length is 1, 12, 13, 14 or 15 amino acids. In some embodiments, this The peptides disclosed are 5 amino acid long. In other embodiments, the peptides disclosed are 6 amino acids long. It is acidic. In other embodiments, the peptide of this disclosure is 7 amino acid long. Other embodiments In this disclosure, the peptide is 8 amino acid long. In other embodiments, the peptide is It has a length of 9 amino acids. In other embodiments, the peptide of this disclosure has a length of 10 amino acids. In one embodiment, the peptide of the Disclosure is 11 amino acids long. In other embodiments, the Disclosure The peptide has a length of 12 amino acids. In other embodiments, the peptide of the present disclosure has a length of 13 amino acids. It is acidic. In other embodiments, the peptide of this disclosure is 14 amino acid long. Other embodiments In this state, the peptide of this disclosure has a length of 15 amino acids.

[0016] The peptides disclosed herein are typically based on the amino acid sequence LSSTQAQQSX1 (SEQ ID NO: 34). It contains or consists of at least five consecutive amino acids. Therefore, In some embodiments, the peptide contains the amino acid sequence SSTQA (SEQ ID NO: 8). In other embodiments, the peptide has the amino acid sequence STQAQ (Sequence ID). 9) comprises or comprises. In other embodiments, the peptide has the amino acid sequence TQA QQ (SEQ ID NO: 10) is included in or derived from QQ. In other embodiments, the peptide is A The amino acid sequence QAQQS (SEQ ID NO: 11) is included in or derived from it. In other embodiments, The peptide contains or is derived from the amino acid sequence AQQSW (SEQ ID NO: 12). In other embodiments, the peptide may include the amino acid sequence AQQSF (SEQ ID NO: 13) or This is what will be. In other embodiments, the peptide has the amino acid sequence LSSTQ(SEQ ID NO: 4 ) contains. In other embodiments, the peptide contains the amino acid sequence AQQSY (SEQ ID NO: 5). nothing.

[0017] In one embodiment, the peptide of this disclosure has the amino acid sequence LSSTQAQQSX1 (sequence number It contains or consists of at least six consecutive amino acids derived from (34). Therefore, in some embodiments, the peptide is an amino acid sequence LSSTQA (Sequence ID). 14) comprises or consists of. In other embodiments, the peptide has the amino acid sequence SS In other embodiments, the peptide is , containing or derived from the amino acid sequence STQAQQ (SEQ ID NO: 16). Other implementations In this state, the peptide contains or has the amino acid sequence TQAQQS (SEQ ID NO: 17) In other embodiments, the peptide has the amino acid sequence QAQQSY (SEQ ID NO: 18). It contains or comprises. In other embodiments, the peptide has the amino acid sequence QAQQSW (SEQ ID NO: 19) comprises or comprises. In other embodiments, the peptide is amino It contains or is derived from the acid sequence QAQQSF (SEQ ID NO: 20).

[0018] In other embodiments, the peptide of this disclosure has the amino acid sequence LSSTQAQQSX1 (SEQ ID NO: It contains or consists of at least seven consecutive amino acids derived from (34). Therefore, in some embodiments, the peptide has the amino acid sequence LSSTQAQ (Sequence ID). 21) comprises or consists of. In other embodiments, the peptide has the amino acid sequence SS In other embodiments, the peptide comprises or consists of TQAQQ (SEQ ID NO: 22). This contains or is derived from the amino acid sequence STQAQQS (SEQ ID NO: 23). In the application form, the peptide contains the amino acid sequence TQAQQSY (SEQ ID NO: 24) or This is what it consists of. In another embodiment, the peptide has the amino acid sequence TQAQQSW(Sequence ID). 25) comprises or consists of. In other embodiments, the peptide has the amino acid sequence TQ Contains or derived from AQQSF (sequence number 26).

[0019] In other embodiments, the peptide of this disclosure has the amino acid sequence LSSTQAQQSX1 Contains or derived from at least eight consecutive amino acids derived from (SEQ ID NO: 34) Therefore, in some embodiments, the peptide has the amino acid sequence LSSTQAQ Q (SEQ ID NO: 27) is included in or derived from Q. In other embodiments, the peptide is ami The no-acid sequence SSTQAQQS (SEQ ID NO 28) is included or derived therefrom. Other embodiments So, does the peptide contain the amino acid sequence STQAQQSY (SEQ ID NO: 29) or this? It consists of the amino acid sequence STQAQQSW (SEQ ID NO: 3). In other embodiments, the peptide has the amino acid sequence STQAQQSW (SEQ ID NO: 3). 0) comprises or consists of. In other embodiments, the peptide has the amino acid sequence STQ Contains or derived from AQQSF (sequence number 31).

[0020] In a further embodiment, the peptide of this disclosure has the amino acid sequence LSSTQAQQSX1( Contains or derived from at least nine consecutive amino acids derived from Sequence ID No. 34 Therefore, in some embodiments, the peptide has the amino acid sequence SSTQAQQS In other embodiments, the peptide is ami Contains or derived from the noacid sequence SSTQAQQSF (SEQ ID NO 33). Other implementations In this state, the peptide contains the amino acid sequence LSSTQAQQS (SEQ ID NO: 2). Other implementations Morphologically, the peptide contains the amino acid sequence SSTQAQQSY (SEQ ID NO: 3).

[0021] In a further embodiment, the peptide of this disclosure has the amino acid sequence LSSTQAQQSX1( Derived from Sequence ID No. 34), having a minimum length of 11, 12, 13, 14, or 15 amino acids. Each contains 10 consecutive amino acids. In some embodiments, the peptide is composed of amino acids The sequence LSSTQAQQSY (SEQ ID NO: 1) is included. In other embodiments, the peptide is ami It contains the noacid sequence LSSTQAQQSW (SEQ ID NO 6). In other embodiments, the peptide is Contains the amino acid sequence LSSTQAQQSF (SEQ ID NO: 7).

[0022] Peptides with a length of 6-15 amino acids (i.e., 6, 7, 8, 9, 10, 11, 12, 13 Peptides having a length of 14 or 15 amino acids are, for example, those previously described embodiments. The amino acid sequence identified by one of the following (i.e., at least 5 derived from SEQ ID NO: 34) (including sequences having 6, 7, 8, 9, or 10 consecutive amino acids) and soybean storage The sequence LSSTQAQQSY (SEQ ID NO: 1) in the β-conglycinin protein contains a naturally occurring In this state, it can contain one or more adjacent amino acids. For example, amino acid sequence L Includes SSTQ (SEQ ID NO: 4), 6, 7, 8, 9, 10, 11, 12, 13, 14, and The peptide, which is 15 amino acids long, is LSSTQAQQS in the sequence of β-conglycinin. For Y (sequence number 1), the N-terminal elements are 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1. The amino acid at the N-terminus of LSSTQ (SEQ ID NO: 4), which corresponds to 0 amino acids It can include columns. Another example is the amino acid sequence AQQSY (SEQ ID NO: 5). Peptides that are 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid lengths The do is located at the C-terminus of LSSTQAQQSY (SEQ ID NO: 1) in the sequence of β-conglycinin. A corresponds to the 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids on the side. It may include the C-terminal amino acid sequence for QQSY (SEQ ID NO: 5).

[0023] Sequence ID 35 describes the N-terminal and C-terminal aspects of the β-conglycinin sequence, respectively. 30 amino acids consisting of LSSTQAQQSX1 (SEQ ID NO: 34) with 10 adjacent amino acids from - It is a peptide. Therefore, the first 10 amino acids of SEQ ID NO: 35 are β-Kong The 10 A at the N-terminus of LSSTQAQQSY (SEQ ID NO: 1) in the lysinin sequence It is a amino acid, and the last 10 amino acids of SEQ ID NO: 35 are LS in the β-conglycinin sequence. These are the 10 amino acids at the C-terminus of STQAQQSY (Sequence ID 1).

[0024] In one embodiment, the sequence of the peptide of this disclosure is derived from SEQ ID NO: 35. Therefore, This disclosure describes a sequence of 5 to 15 amino acids, each 5 to 15 amino acids long, derived from Sequence ID No. 35. We provide peptides that contain or are derived from the amino acid sequence LS Containing at least five consecutive amino acids derived from STQAQQSX1 (SEQ ID NO: 34), The peptide has the amino acid sequences LSSTQAQQSY (Sequence ID 1), LSSTQAQQS ( Sequence ID 2), SSTQAQQSY (Sequence ID 3), LSSTQ (Sequence ID 4), AQQ SY (Sequence ID 5), LSSTQAQQSW (Sequence ID 6), or LSSTQAQQS It is not F (sequence number 7).

[0025] Peptides having sequence mutations relative to SEQ ID NO: 35 are also intended in this specification. In other embodiments, the peptide is a sequence of 5 to 15 amino acids derived from SEQ ID NO: 35. Compared to amino acid sequences containing [specific amino acid substitutions], amino acid sequences containing one or more amino acid substitutions This is possible, however, for amino acid sequences LSSTQAQQ where the peptide is not substituted. Contains at least five consecutive amino acids derived from SX1 (SEQ ID NO: 34). SEQ ID NO: 35 For a sequence consisting of 5 to 15 consecutive amino acids, the possible characteristics of a given peptide are The maximum number of amino acid substitutions can vary depending on the length of the peptide, and for peptides with a length of 6 amino acids... From one amino acid substitution to 10 amino acid substitutions for a peptide of 15 amino acid length It may be within the range of LSSTQA, however, the amino acid sequence LSSTQA is not substituted for the peptide. Contains at least five consecutive amino acids derived from QQSX1 (SEQ ID NO: 34). Acceptable. Examples of amino acid substitutions include substitutions with conservative amino acids and / or amino acid analogs. However, it is not limited to these.

[0026] Preferably, one or more amino acid substitutions compared to the corresponding sequence in SEQ ID NO: 35. The peptide having the following relative amino acids in SEQ ID NO: 35: 1, 2, 3 It has 4, 5 or more conservative amino acid substitutions. "Conservative amino acid substitution" is This is a substitution in which an amino acid residue is replaced by an amino acid residue that has a similar side chain. The family of amino acid residues having side chains is defined in the art. The family includes the following: amino acids with basic side chains (e.g., lysine, (Arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, gluten) (e.g., tamic acid), amino acids having non-charged side chains (e.g., glycine, asparagine, glucone) (Tamine, serine, threonine, tyrosine, cysteine), amino acids with nonpolar side chains ( For example, alanine, valine, leucine, isoleucine, proline, phenylalanine, (Thionine, tryptophan), amino acids with β-branched side chains (e.g., thionine, variol) (e.g., phenyl, isoleucine), and amino acids having aromatic side chains (e.g., tyrosine, phenyl Alanine, tryptophan). In one embodiment, all amino acids compared to SEQ ID NO: 35. Acid substitution is conservative.

[0027] In some embodiments, the peptides of this disclosure have N-terminus and / or C-terminus Amino acids having aromatic side chains (e.g., phenylalanine, tryptophan, or tyrofoam) It has a syn (syn). In some embodiments, the peptide of this disclosure has a C instead of an N-terminus. -Having an amino acid with an aromatic side chain at the terminal. In some embodiments, the peptide is C It contains terminal tryptophan.

[0028] Compared to the corresponding sequence of SEQ ID NO: 35, the peptide of this disclosure having amino acid substitutions is 1 one or more amino acid analogs (for example, one, two, three, four, or five amino acid analogs) ) may include. Generally, when used herein, amino acids are natural L-alkaline. This refers to isomers, and in some embodiments, each amino acid in the peptide is a natural isomer. It is the L-stereoisomer of [the amino acid]. An amino acid analog refers to a D-stereoisomer or a non-natural amino acid. For example, non-natural amino acids include, but are not limited to, azetidine carboxylic acid, 2-ami Noadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-amino Butyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoiso Butyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4 -Diaminoisobutyric acid, desmosine, 2,2'-diaminopimeric acid, 2,3-diaminop Ropionic acid, N-ethylglycine, N-ethylasparagine, homoproline, hydroxy Lysine, allohydroxylysine, 3-hydroxyproline, 4-hydroxyproline, i Sodesmosine, alloisoleucine, N-methylalanine, N-methylglycine, N-meth Luisoleucine, N-methylpentylglycine, N-methylvaline, naphthoalanine, no Ruvalin, norleucine, ornithine, pentylglycine, pipecolic acid, and thiopro Phosphorus is one example.

[0029] Peptides consist entirely of L-amino acids, entirely of D-amino acids, or a mixture of L-amino acids and D-amino acids. A mixture of acids is possible, but peptides consisting entirely of L-amino acids are preferred. Two or more asymmetric carbon Peptides containing elementary atoms are enantiomers or diastereomers in any form and any ratio. It can be called Mar.

[0030] Peptides can exist in salt form and have pharmaceutically acceptable counterions (e.g., chlorine, sulfuric acid, Contains citric acid, phosphoric acid, acetic acid, sodium, potassium, calcium, and magnesium. This is preferable. The peptide salt can be an acid addition salt or a base addition salt. Examples of acids that can be used include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid, and cucumber. Malic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfonic acid, Examples include benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid. Examples of bases that can be used to form salts include sodium hydroxide, potassium hydroxide, Alkali metal bases, such as lithium hydroxide, calcium hydroxide, and alkaline earth metals. Examples of metal salt bases include magnesium hydroxide, which forms pharmaceutically acceptable salts. Additional acids and bases that can be used for this purpose are listed by Stahl and Wermuth, e. ds.,2008,Handbook of Pharmaceutical Salt s:Properties,Selection and Use,Verlag He lvetica Chimica Acta,Zurich,Switzerland It is described therein. The contents of this document are incorporated in their entirety herein by reference.

[0031] The peptide is prepared, for example, according to a method known in the art (e.g., Benoi ton, N., 2006, Chemistry of Peptide Synthes. is,CRC Press,Boca Raton,FL;Howl,J.,ed.,2 005,Peptide Synthesis and Applications,H umana Press, Totowa, NJ; Chan and White, eds. .,2000,Fmoc Solid Phase Synthesis:A Prac tical Approach,Oxford University Press,O Liquid-phase peptide synthesis or solid-phase peptide synthesis (as described in Xford, UK) It is obtained by [method]. Custom peptide synthesis is also available from many suppliers (e.g., ABI Sc ientific(Sterling,VA);AnaSpec(Freemont C A);Pepscan,(Lelystad,Netherlands),Neo Sc ientific(Cambridge,MA);Sigma-Aldrich(St. It is commercially available from Louis, MO.

[0032] 5.2. Peptide Conjugates This disclosure relates to peptide conjugates including a peptide portion and a conjugate portion. It provides a salt of bi. By binding the conjugate portion to the peptide, for example, non-condi Compared to glycated peptides, it offers improved water solubility, enhanced stability, and reduced clarity. Lance can be provided (Hamley, 2014, Biomacromolecules) 15:1543-1559). Therefore, peptide conjugates are, in some cases Therefore, it may be more suitable as a therapeutic agent compared to those non-conjugate equivalents. The exemplary peptide portion is described in Section 5.2.1, and the exemplary conjugate portion is The embodiments described herein are "peptide cos". When referring to "synjugate," the embodiment is an expression of "or its salt." Or, even if similar expressions are not explicitly described, unless the context requires a different meaning, Including the peptide conjugate itself and the salts of its peptide conjugate. Please understand this. Exemplary salts are given in Section 5.2.3.

[0033] 5.2.1. Peptide portion The peptide portion is derived from the amino acid sequence LSSTQAQQSX1 (SEQ ID NO: 34). It contains at least five consecutive amino acids or has an amino acid sequence consisting of five consecutive amino acids, Amino acid sequences LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQSW (SEQ ID NO: 6) ), or not composed of LSSTQAQQSF (Sequence ID 7). The peptide portion consists of one unit. or multiple conjugate parts (for example, 1, 2, 3, 4, or 5 conjugate parts) It is joined to the (T) portion (i.e., joined by a covalent bond).

[0034] The peptide portion of this disclosure consists of 5 to 15 amino acids (i.e., 5, 6, 7, 8, 9, 10 The length is 11, 12, 13, 14 or 15 amino acids. In some embodiments, The peptide portion of this disclosure is 5 amino acid long. In other embodiments, the peptide portion of this disclosure The portion is 6 amino acids long. In other embodiments, the peptide portion of the present disclosure is 7 amino acids long. In other embodiments, the peptide portion of the disclosure is 8 amino acids long. The peptide portion of this disclosure is 9 amino acids long. In other embodiments, the peptide portion of this disclosure The portion is 10 amino acids long. In other embodiments, the peptide portion of the present disclosure is 11 amino acids long. In other embodiments, the peptide portion of the disclosure is 12 amino acids long. In this embodiment, the peptide portion of the present disclosure is 13 amino acids long. In other embodiments, the peptide portion of the present disclosure The peptide portion is 14 amino acids long. In other embodiments, the peptide portion of the present disclosure is 15 amino acids long. It is a amino acid length.

[0035] The peptide portion of this disclosure is typically the amino acid sequence LSSTQAQQSX1 (SEQ ID NO: 34). It contains or consists of at least five consecutive amino acids derived from [the specified source]. Therefore, In some embodiments, the peptide portion is the amino acid sequence LSSTQ (SEQ ID NO: 4) It contains or consists of. In other embodiments, the peptide portion is the amino acid sequence SSTQ A (SEQ ID NO: 8) is included in or derived from A. In other embodiments, the peptide portion is A The amino acid sequence STQAQ (SEQ ID NO: 9) is included or derived therefrom. In other embodiments, The peptide portion contains or is derived from the amino acid sequence TQAQQ (SEQ ID NO: 10). In other embodiments, the peptide portion includes the amino acid sequence QAQQS (SEQ ID NO: 11). or will be. In other embodiments, the peptide portion has the amino acid sequence AQQSY( The peptide portion comprises or consists of (SEQ ID NO: 5). In other embodiments, the peptide portion is amino The acid sequence AQQSW (SEQ ID NO: 12) is included or derived from it. In other embodiments, The ptide portion contains or is derived from the amino acid sequence AQQSF (SEQ ID NO: 13).

[0036] In one embodiment, the peptide portion of the present disclosure has the amino acid sequence LSSTQAQQSX1 ( Contains or derived from at least six consecutive amino acids derived from row number 34) Therefore, in some embodiments, the peptide portion is the amino acid sequence LSSTQA( The peptide portion comprises or consists of SEQ ID NO: 14. In other embodiments, the peptide portion is amine. The no-acid sequence SSTQAQ (SEQ ID NO 15) is included or derived from it. In other embodiments, The peptide portion contains or is derived from the amino acid sequence STQAQQ (SEQ ID NO: 16). In other embodiments, the peptide portion has the amino acid sequence TQAQQS (SEQ ID NO: 17). In other embodiments, the peptide portion is the amino acid sequence QAQ In other embodiments, the peptide moiety is included in or derived from QSY (SEQ ID NO: 18). This includes or is derived from the amino acid sequence QAQQSW (SEQ ID NO: 19). Other implementations In terms of morphology, the peptide portion contains the amino acid sequence QAQQSF (SEQ ID NO: 20) or This consists of.

[0037] In other embodiments, the peptide portion of the present disclosure is the amino acid sequence LSSTQAQQSX1 (sequence It contains or consists of at least seven consecutive amino acids derived from (number 34). Therefore, in some embodiments, the peptide portion is the amino acid sequence LSSTQAQ( The peptide portion comprises or consists of (SEQ ID NO: 21). In other embodiments, the peptide portion is amine. The no-acid sequence SSTQAQQ (SEQ ID NO 22) is included or derived therefrom. In other embodiments The peptide portion contains the amino acid sequence STQAQQS (SEQ ID NO: 23) or this It consists of the amino acid sequence TQAQQSY(SEQ ID NO:). In other embodiments, the peptide portion consists of the amino acid sequence TQAQQSY(SEQ ID NO:). 24) comprises or consists of. In other embodiments, the peptide portion is an amino acid sequence TQAQQSW (SEQ ID NO: 25) is included in or derived from it. In other embodiments, pep The cydo portion contains or is derived from the amino acid sequence TQAQQSF (SEQ ID NO: 26). .

[0038] In other embodiments, the peptide portion of the present disclosure has the amino acid sequence LSSTQAQQS Contains at least 8 consecutive amino acids derived from X1 (SEQ ID NO: 34) or It consists of the following. Therefore, in some embodiments, the peptide portion is the amino acid sequence LSS In other embodiments, the peptide comprises or consists of TQAQQ (SEQ ID NO: 27). The portion contains or consists of the amino acid sequence SSTQAQQS (Sequence ID 28). In other embodiments, the peptide portion has the amino acid sequence STQAQQSY (SEQ ID NO: 29) It contains or consists of. In other embodiments, the peptide portion is the amino acid sequence STQA In other embodiments, the peptide portion is included in or derived from QQSW (SEQ ID NO: 30). The fraction contains or is derived from the amino acid sequence STQAQQSF (SEQ ID NO: 31).

[0039] In a further embodiment, the peptide portion of this disclosure has the amino acid sequence LSSTQAQQSX Contains at least nine consecutive amino acids derived from 1 (SEQ ID NO: 34) Therefore, in some embodiments, the peptide portion is the amino acid sequence LSST The molecule contains or comprises QAQQS (SEQ ID NO: 2). In other embodiments, the peptide portion The fraction contains or is derived from the amino acid sequence SSTQAQQSY (Sequence ID 3). In this embodiment, the peptide portion has the amino acid sequence SSTQAQQSW (SEQ ID NO: 32) It contains or consists of. In other embodiments, the peptide portion is the amino acid sequence SSTQ Contains or derived from AQQSF (sequence number 33).

[0040] In a further embodiment, the peptide portion of this disclosure has the amino acid sequence LSSTQAQQSX It contains 10 consecutive amino acids derived from 1 (SEQ ID NO: 34). In some embodiments, The peptide portion contains the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1). In the application form, the peptide portion contains the amino acid sequence LSSTQAQQSW (SEQ ID NO: 6). In other embodiments, the peptide portion has the amino acid sequence LSSTQAQQSF (SEQ ID NO: 7). ) includes.

[0041] Peptide portions of 6-15 amino acids in length (i.e., 6, 7, 8, 9, 10, 11, 12, The peptide portion, which is 13, 14, or 15 amino acids long, is, for example, previously described The amino acid sequence identified in one of the embodiments (i.e., a small number derived from SEQ ID NO: 34) (including sequences having at least 5, 6, 7, 8, 9, or 10 consecutive amino acids) The sequence LSSTQAQQSY (SEQ ID NO: 1) in the soybean storage protein β-conglycinin. It can contain one or more amino acids adjacent to it in its natural state. For example, amino Contains acid sequence LSSTQ (SEQ ID NO: 4), 6, 7, 8, 9, 10, 11, 12, 13, 1 The peptide portion, which is 4 or 15 amino acids long, is the LSS in the sequence of β-conglycinin. For TQAQQSY (sequence number 1), the N-terminal elements are 1, 2, 3, 4, 5, 6, 7, 8, LSSTQ (SEQ ID NO: 4), corresponding to 9 or 10 amino acids, is located at the N-terminus. It can include an amino acid sequence. Another example is the amino acid sequence AQQSY (sequence number (5) containing 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in length The peptide portion is LSSTQAQQSY(Sequence ID) in the sequence of β-conglycinin. 1) The C-terminal side of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids It contains the C-terminal amino acid sequence corresponding to AQQSY (SEQ ID NO: 5), which corresponds to the acid. can.

[0042] Sequence ID 35 describes the N-terminal and C-terminal aspects of the β-conglycinin sequence, respectively. 30 amino acids consisting of LSSTQAQQSX1 (SEQ ID NO: 34) with 10 adjacent amino acids from - It is a peptide. Therefore, the first 10 amino acids of SEQ ID NO: 35 are β-Kong The 10 A at the N-terminus of LSSTQAQQSY (SEQ ID NO: 1) in the lysinin sequence It is a amino acid, and the last 10 amino acids of SEQ ID NO: 35 are LS in the β-conglycinin sequence. These are the 10 amino acids at the C-terminus of STQAQQSY (Sequence ID 1).

[0043] In one embodiment, the sequence of the peptide portion of the present disclosure is derived from SEQ ID NO: 35. Therefore Therefore, this disclosure includes or comprises amino acids with a length of 5 to 15 amino acids. , containing or consisting of 5 to 15 consecutive amino acids derived from Sequence ID No. 35 The d portion is provided, however, the peptide portion has the amino acid sequence LSSTQAQQSX1 ( It contains at least 5 consecutive amino acids derived from row number 34), and the peptide portion is amino Acid sequences LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQSW (SEQ ID NO: 6), This is not LSSTQAQQSF (sequence number 7).

[0044] Peptide moieties with sequence mutations in SEQ ID NO: 35 are also intended in this specification. However, in other embodiments, the peptide moiety consists of 5 to 15 consecutive units derived from SEQ ID NO: 35 Compared to amino acid sequences containing amino acids, amino acid sequences containing one or more amino acid substitutions An amino acid sequence LS may have columns, but the peptide portion is not substituted. It contains at least five consecutive amino acids derived from STQAQQSX1 (SEQ ID NO: 34). For a sequence of 5 to 15 consecutive amino acids in SEQ ID NO: 35, a given peptide The maximum number of conserved amino acid substitutions that a portion may have can vary depending on the length of the peptide portion. A peptide with a length of 15 amino acids is formed by one amino acid substitution in a peptide portion with a length of 6 amino acids. The range may be up to 10 amino acid substitutions in the portion, however, the peptide portion may be At least one amino acid derived from the unmodified amino acid sequence LSSTQAQQSX1 (SEQ ID NO: 34) It contains five consecutive amino acids. Acceptable amino acid substitutions include conservative amino acids and / Substitutions may also include, but are not limited to, those by amino acid analogs.

[0045] Preferably, one or more amino acid substitutions compared to the corresponding sequence in SEQ ID NO: 35. The peptide portion of this disclosure having 1, 2 amino acids compared to the corresponding amino acid in SEQ ID NO: 35 , 4, 5 or more conservative amino acid substitutions are present. In one embodiment, All amino acid substitutions compared to row number 35 are conservative.

[0046] In some embodiments, the peptide moiety of the present disclosure is its N-terminus and / or C-terminus. Amino acids having aromatic side chains at their ends (e.g., phenylalanine, tryptophan, or It has tyrosine. In some embodiments, the peptide portion of the present disclosure has an N-terminus It does not have an amino acid with an aromatic side chain at its C-terminus. In some embodiments, it has a peptide. The cytoplasm contains C-terminal tryptophan.

[0047] Compared to the corresponding sequence of SEQ ID NO: 35, the peptide portion of this disclosure having amino acid substitutions For example, one or more amino acid analogs (1, 2) as described in Section 5.1. It may contain 3, 4, or 5 amino acid analogs.

[0048] The peptide portion consists entirely of L-amino acids, entirely of D-amino acids, or a combination of L-amino acids and D-amino acids. It can be a mixture of amino acids, but peptide portions consisting entirely of L-amino acids are preferred. (2 or more) The peptide moiety containing the chiral carbon atom is an enantiomer or in any form and in any ratio. It can be a diastereomer.

[0049] The peptide portion is prepared, for example, according to methods known in the art (e.g., Ben oiton, N., 2006, Chemistry of Peptide Synth esis, CRC Press, Boca Raton, FL; Howl, J., ed. ,2005,Peptide Synthesis and Applications ,Humana Press,Totowa,NJ;Chan and White,e ds.,2000,Fmoc Solid Phase Synthesis:A Pr operational approach,Oxford University Press As described in Oxford, UK, liquid-phase peptide synthesis or solid-phase peptide synthesis. It can be obtained by synthesis. Custom peptide synthesis is also available from many suppliers (for example, ABI Scientific(Sterling,VA);AnaSpec(Free mont CA);Pepscan,(Lelystad,Netherlands), Neo Scientific (Cambridge, MA); Sigma-Aldri It is commercially available from ch(St.Louis,MO).

[0050] 5.2.2. Conjugate portion A peptide conjugate is a peptide conjugate with one or more conjugates attached to the peptide portion. Conjugate includes parts (for example, 1, 2, 3, 4, or 5 conjugate parts). The conjugate portion or multiple conjugate portion consists of the N-terminal amino acid, C-terminal amino acid, and N-terminal amino acid. It can bind to amino acids that are neither amino acids nor C-terminal amino acids, or to combinations thereof. For example, the peptide conjugate is preferably bound to the N-terminal amino acid of the peptide portion. A single conjugate that is either attached to the C-terminal amino acid of the peptide portion or is attached to the C-terminal amino acid of the peptide portion. It may contain a peptide. As another example, a peptide conjugate is preferably a peptide. One N-terminal amino acid bound to the portion, and preferably the C-terminal amino acid of the peptide portion. It can contain two conjugate moieties, one more bonded to the acid.

[0051] In embodiments in which the peptide conjugate includes multiple conjugate moieties, each The conjugate parts may be the same, and some conjugate parts may be the same, while the remaining parts are the same. The conjugate parts may be different, or all of the conjugate parts may be different. For example, A peptide conjugate having two conjugate moieties is two identical conjugates. It may have a conjugate portion. Alternatively, it may have a peptide conjugate having two conjugate portions. A gate may have two different conjugate parts. Another example is three conjugate parts. A peptide conjugate having a jugate moiety has three identical conjugate moieties. It may have three different conjugate parts, or two identical conjugate parts It may have a conjugate portion and one different conjugate portion.

[0052] The conjugate portion is attached to the peptide portion, for example, one of the amino acid side chains of the peptide portion. It can be bonded to its main chain, to its N-terminal amino group, or to its C-terminal carboxylic acid group. For example, the conjugate portion is attached to the amino acid side chain, and chemically modified amino acids, such as Thionine sulfoxide, methionine sulfone, S-(carboxymethyl)cysteine, S-(carboxymethyl)cysteine ​​sulfoxide and S-(carboxymethyl)cysteine ​​sulfoxide It can form a thein sulfone. Other side chain modifications include acylation of the lysine ε-amino group, and N-alkylation of ginine, histidine, or lysine, and glutamic acid or asparagus. Alkylation of the ginate carboxylic acid group is one example. The conjugate portion is the peptide backbone. For example, it can bond to the nitrogen atom in the main chain (for example, using N-methylamino acid, methyl The conjugate portion can be introduced into the peptide conjugate main chain to synthesize peptides. The conjugate portion is bound to the N-terminal amino group of the peptide portion, for example, N-low To obtain an N-terminus having a secondary alkyl, N-di-lower alkyl, or N-acyl modification. This can be done by attaching the conjugate portion to the C-terminal carboxyl group, for example, a conjugate The C-terminus of the molecule contains an amide, lower alkylamide, dialkylamide, or lower alkyl A peptide conjugate containing a ster can be obtained. The lower alkyl group is C1-C4. It means alkyl.

[0053] Examples of conjugate moieties that can be used in peptide conjugates include polymers and amino acids. α-groups (e.g., amino(-NH2), alkylamino and dialkylamino), acyl Groups (e.g., formyl or acetyl), alkyl groups (e.g., C1-C4 alkyl), Examples include phosphate groups, lipids, and sugars.

[0054] In some embodiments, at least one, two or more peptide conjugates The or all conjugate portions contain polymers. Used as conjugate portions Examples of polymers that can be used include polyethylene glycol, polyvinylpyrrolidone, and polymilk. Glycolic acid copolymer, N-(2-hydroxypropyl)methacrylamide copolymer Examples include polyglutamic acid and polysaccharides. In some embodiments, , at least one, two or more, or all of the conjugates in the peptide conjugate The gate portion contains polyethylene glycol. In some embodiments, peptide compound At least one, two or more, or all of the conjugate portions in a jugate are Contains polyvinylpyrrolidone. In some embodiments, in the peptide conjugate, At least one, two or more, or all of the conjugate portions are polylactic acid glyco It contains a lic acid copolymer. In some embodiments, at least in the peptide conjugate Each of the conjugate moieties consists of one, two or more, or all of them, N-(2-hydroxyp Contains (ropil) methacrylamide copolymer. In some embodiments, peptide condi At least one, two or more, or all of the conjugate portions in a conjugate are Contains liglutamic acid in some embodiments. In some embodiments, less than Each of the conjugate portions contains one, two or more, or all of them contains a polysaccharide. .

[0055] In some embodiments, at least one, two or more peptide conjugates The or all conjugate moieties contain an amine group. Exemplary amine groups include amino Examples include (-NH2), alkylamino, and dialkylamino groups. Alkyl groups are For example, it may be a C1-C4 alkyl group. In some embodiments, peptide conjugates At least one, two or more, or all of the conjugate parts within the gate are mesh. Contains a group. In some embodiments, at least one of the peptide conjugates Two or more, or all, of the conjugate moieties contain alkylamino groups. In the embodiment, at least one, two or more, or in the peptide conjugate All conjugate portions contain a dialkylamino group.

[0056] In some embodiments, at least one, two or more peptide conjugates The or all conjugate moieties contain an acyl group. Exemplary acyl groups include holmi Examples include acetyl groups and acetyl groups. In some embodiments, peptide conjugates In the middle, at least one, two or more, or all of the conjugate portions are formyl groups Includes. In some embodiments, at least one, 2 in the peptide conjugate One or more, or all, of the conjugate moieties contain an acetyl group.

[0057] In some embodiments, at least one, two or more peptide conjugates The or all conjugate portions contain an alkyl group. In exemplary embodiments, The kill group is a lower alkyl group, for example, methyl or ethyl. In some embodiments This refers to at least one, two or more, or all of the condiments in the peptide conjugate. The conjugate portion contains a methyl group. In some embodiments, the peptide conjugate contains At least one, two or more, or all of the conjugate moieties contain an ethyl group. nothing.

[0058] In some embodiments, at least one, two or more peptide conjugates The conjugate portion, or all of it, is, for example, serine, threonine, or tyrosine. It contains a phosphate group attached to its side chain.

[0059] In some embodiments, at least one, two or more peptide conjugates The or all conjugate portions contain lipids.

[0060] In some embodiments, at least one, two or more peptide conjugates The or all conjugate portions contain sugar.

[0061] In some embodiments, the peptide conjugate is used in International Application No. PCT / JP201 This application includes one or more peptide modifications as described in No. 6 / 056453. The entire text is incorporated herein by reference.

[0062] Methods for attaching the conjugate portion to the peptide portion are known in the art. , which can be used to obtain the peptide conjugates described herein (e.g., Basil e et al.,2010,Chemistry & Biology 17:213 -227;Benoiton, N., 2006, Chemistry of Pepti de Synthesis,CRC Press,Boca Raton,FL;Ern st and Leumann, eds., 1995, Modern Syntheti. c Methods,Verlag Helvetica Chimica Acta, Basel,Switzerland;Hamley,2014,Biomacromo lecules 15:1543-1559; Lundblad, R., 1995, Te chniques in Protein Modification,CRC Pre (As described in ss, Boca Raton, FL). Cash of peptide conjugates Tam synthesis is also commercially available from numerous suppliers (e.g., ABI Sci entific(Sterling,VA);AnaSpec(Freemont CA );Pepscan,(Lelystad,Netherlands),Neo Sci entific(Cambridge,MA);Sigma-Aldrich(St.L (ouis, MO). These include, for example, acetyl groups, formyl groups, fatty acids, and alkyl groups. Peptides having an N-terminal conjugate moiety such as an amide group; amide group, alkyl amide group Peptides having a C-terminal conjugate moiety such as a C-group and an alkyl group; fatty acids Conjugated peptides; peptides conjugated to polyethylene glycol; and peptides having a phosphate conjugate moiety (e.g., phosphoserine, phosphothreone) They offer a variety of products, including those containing nin or phosphotyrosine.

[0063] 5.2.3. Salts of Peptide Conjugates Peptide conjugates can be in the form of salts and have pharmaceutically acceptable counterions (e.g., Chlorine, sulfuric acid, citric acid, phosphoric acid, acetic acid, sodium, potassium, calcium, magnesium It is preferable to include (um). The peptide conjugate salt is an acid addition salt or a base addition salt. Yes, it is possible. Exemplary acids that can be used to form acid addition salts include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Hydrobromic acid, perchloric acid, citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid Acids, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and trifluic acid Oloacetic acid is one example. Exemplary bases that can be used to form base addition salts include hydroxide Sodium, potassium hydroxide, alkali metal bases, for example, lithium hydroxide, potassium hydroxide Examples include calcium and alkaline earth metal salts, such as magnesium hydroxide. Additional acids and bases that can be used to form pharmaceutically acceptable salts include Stahl and Wermuth, eds., 2008, Handbook of Pharm. aceutical Salts:Properties,Selection and Use,Verlag Helvetica Chimica Acta,Zuric It is described in h,Switzerland. The contents of this document are as follows (in their entirety) by reference. This is incorporated herein.

[0064] 5.3. Pharmaceutical Compositions Peptides, salts thereof, and peptide conjugates as described in Sections 5.1 and 5.2, and its salts may be used as one or more pharmaceutically acceptable carriers, diluents, and / or It can be formulated into pharmaceutical compositions containing excipients. Pharmaceutical compositions are administered topically, intraintestinally (e.g., orally or rectally), or parenterally (e.g., intramuscularly). It can be prescribed for internal or intravenous administration. The pharmaceutical composition is prescribed for oral administration. Preferred. Pharmaceutical compositions are based on known technologies in the art (e.g., Allen et al.). al., eds., 2012, Remington: The Science and Practice of Pharmacy,22nd Edition,Pharm According to the information provided by Aceutical Press, London, UK, tablets, Capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, It can be prescribed in any suitable dosage form, such as an inhalant or an injectable solution.

[0065] The liquid pharmaceutical composition may contain water, saline solution, glucose solution, or ethanol, or other suitable liquids. It may contain a solvent. A liquid pharmaceutical composition may, for example, dissolve a certain amount of the compound of this disclosure in a solvent. Alternatively, it can be formulated by suspension. Buffering agents, preservatives, flavoring agents, and coloring agents. These can be included in the liquid formulation as needed. The solid pharmaceutical composition contains a binder, It may contain lubricants, disintegrants, colorants, flavorings, flow accelerators, and melting agents. For example, solid The preparation contains lactose, gelatin, agar, starch, sucrose, glucose, and methylcellulose. Calcium sulfate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, crystalline cellulose It may contain inert carriers such as glycerides. Binders include starch, gelatin, glucose, Sugars such as lactose and trehalose, corn starch, calcium lactate, acacia, Natural and synthetic gums such as tragacanth or sodium alginate, povidone, calcium Voxymethylcellulose, hydroxypropylcellulose, polyethylene glycol, Examples include sodium oleate and sodium stearate. Thorium, magnesium stearate, stearic acid, sodium stearyl fumarate, Examples of disintegrants include anhydrous silicic acid and talc. Examples of disintegrants include starch and methylcellulose. Agar, bentonite, xanthan gum, croscarmellose sodium, glycolic acid Examples include sodium starch. A solid pharmaceutical composition is, for example, methyl methacrylate. Enteric coating can be applied using polymers, ethylcellulose, or carnauba wax. Additional drugs that may be included in the drug composition are specified in International Application No. PCT / JP2016 / 05. It is described in Patent No. 6453. The contents of this application are incorporated herein by reference in their entirety. It gets included.

[0066] The compounds of this disclosure can be included in any preferred amount in a pharmaceutical composition. Typically The compounds of this disclosure constitute 0.1% to less than 100% by weight of the pharmaceutical composition (for example). , 1% to 99% by weight of the pharmaceutical composition, 1% to 90% by weight, 5% to 80% by weight, 10% to 75% by weight, or 15% to 50% by weight, or any of the aforementioned values. (An arbitrary weight percentage range with two boundaries).

[0067] 5.4.Food Peptides, salts thereof, and peptide conjugates as described in Sections 5.1 and 5.2, The salt can be incorporated into foods such as nutritional supplements or functional foods.

[0068] Nutritional supplements can be in various forms, such as tablets, capsules, soft gels, gelatin capsules, liquids, etc. It can be made into a powder. Vitamins, minerals, herbs or other plant-based medicines, Supplements can include amino acids, proteins, fiber, fatty acids, or combinations thereof. It is possible.

[0069] Functional foods are foods to which the compounds of this disclosure are added or mixed. For example, functional foods The products include coffee, cocoa, juice, soft drinks, mineral drinks, tea-based beverages, green tea, Black tea, oolong tea, dairy drinks, lactic acid drinks, yogurt drinks, carbonated drinks, non-alcoholic drinks It can be a food product or a beverage such as an alcoholic beverage. Functional foods include confectionery (for example, Hard candy, gum, gummy candy, jelly, pudding, mousse, cake, candy, cookies, clams Cookies, biscuits, chocolate, ice cream, popsicles, sherbet (Frozen desserts such as shaved ice), dressings, seasonings, soy products (e.g., tofu, miso, fermented soybeans) Oil, tofu (bean curd), soy flour, natto, etc.), processed meat products (for example, hamburgers) (Small burgers, meatloaf, meatballs, etc.), processed fish products (e.g., fish sausage) Fish paste products such as, jelly-like foods (e.g., jelly, agar, jelly-like beverages, etc.), This can be done as follows.

[0070] 5.5. Treatment method Peptides, salts thereof, and peptide conjugates as described in Sections 5.1 and 5.2, and its salts, the pharmaceutical compositions described in Section 5.3, and the compositions described in Section 5.4 These foods can be used to treat or prevent mood disorders. Mood disorders that can be treated or prevented include: These include depression, bipolar disorder, and adjustment disorder.

[0071] This disclosure provides a method for treating subjects suffering from mood disorders, the method being provided to the subjects, A pharmaceutical composition containing the indicated compound or the compound of this disclosure is administered in an effective amount to treat a subject. This includes giving. This disclosure also provides a method for treating or preventing mood disorders, and such method includes A certain amount of food containing the compound of this disclosure is used in individuals prone to or suffering from mood disorders. This includes administering the drug to a subject who is suffering from a mood disorder. In some embodiments, the subject is suffering from a mood disorder. They are prone to developing the condition. In other embodiments, the subject suffers from a mood disorder.

[0072] In some embodiments of the methods described in the previous paragraph, the mood disorder includes depression. In some embodiments of the described method, the mood disorder includes bipolar disorder. In some embodiments of the method, mood disorders include adjustment disorders.

[0073] Peptides, salts thereof, and peptide conjugates as described in Sections 5.1 and 5.2, and its salts, the pharmaceutical compositions described in Section 5.3, and the compositions described in Section 5.4 These foods can be used to treat or prevent anxiety disorders.

[0074] This disclosure provides a method for treating subjects suffering from anxiety disorders, and the method provides to subjects the present A pharmaceutical composition containing the indicated compound or the compound of this disclosure is administered in an effective amount to treat a subject. This includes giving. This disclosure also provides a method for treating or preventing anxiety disorders, and such method includes A certain amount of food containing the compound of this disclosure is used in individuals prone to or suffering from anxiety disorders. This includes administering the drug to a subject who is suffering from an anxiety disorder. In some embodiments, the subject is suffering from an anxiety disorder. They are prone to developing the condition. In other embodiments, the subject suffers from an anxiety disorder.

[0075] Peptides, salts thereof, and peptide conjugates as described in Sections 5.1 and 5.2, and its salts, the pharmaceutical compositions described in Section 5.3, and the compositions described in Section 5.4 These foods can be used to treat or prevent low motivation disorder. Disorders include emotional blunting, apathy, and akinetic mutism.

[0076] This disclosure provides a treatment method for subjects suffering from a lack of motivation disorder, and the method provides to the subjects, This disclosure includes administering the compounds of this disclosure in an effective dose to treat a subject. This disclosure also includes, A method for treating or preventing a lack of motivation disorder is provided, wherein the method comprises a certain amount of the compound of this disclosure. The food was administered to individuals who are prone to or suffering from a lack of motivation disorder. This includes giving. In some embodiments, the subjects tend to suffer from a lack of motivation disorder. In other embodiments, the subject suffers from a lack of motivation disorder.

[0077] In some embodiments of the method described in the previous paragraph, the motivational disorder includes emotional blunting. In other embodiments of the method described in the paragraph above, the disorder of decreased motivation includes apathy. In other embodiments of the method, the lack of motivation disorder includes akinetic mutism.

[0078] The methods described herein are applicable to mammals, for example, humans or domestic pets (e.g., Cats and dogs are preferred. The subject can be of any age, but adults (e.g., 18 years or older, 25 years or older) are preferred. (For humans aged 35 and over, 45 and over, 55 and over, etc.) is preferred. In this embodiment, the target is an elderly person (for example, 65 years of age or older, 70 years of age or older, 75 years of age or older, or (This study targets individuals aged 80 and over.)

[0079] The compounds of this disclosure and pharmaceutical compositions containing them may be administered orally, topically, rectally, or parenterally. It can be administered orally, but oral administration is preferred. The method of administration may vary depending on the patient's condition and age. It can transform.

[0080] The appropriate daily dose of the compound disclosed herein is 0.005 mg / kg to 500 mg / kg. Weight / day (for example, 0.005 mg / kg to 100 mg / kg, 0.005 mg / kg to 3 0mg / kg, 0.005mg / kg~1mg / kg, 0.01mg / kg~30mg / kg, 0.01mg / kg~3mg / kg, 0.01mg / kg~1mg / kg, 0.0 2mg / kg~5mg / kg, 0.02mg / kg~2mg / kg, 0.02mg / kg The dosage can be in the range of ~1 mg / kg. Alternatively, the compound may be 0.1 mg to 50 g / day (for example, 0.1mg~10g, 0.1mg~3g, 0.1mg~100mg, 0. Fixed doses in the range of 1 mg to 1 mg, 0.3 mg to 3 g, or 0.3 mg to 100 mg. It can be administered by [method]. With regard to the administration of a pharmaceutical composition containing the compound of this disclosure, within the scope of one of the above-mentioned [methods]. An amount of a pharmaceutical composition containing such an amount of compound can be administered. Similarly, one or more compounds can be administered. Regarding the administration of food, one or more foods containing the compound in an amount within the aforementioned range. This amount can be administered. [Examples]

[0081] 6. Examples 6.1. Method 6.1.1. Tail suspension test The tail suspension test is an experimental method used to screen for potential antidepressants (C an et al., 2012, J Vis Exp., 59:e3769). In the example... In this test, the test substance will be administered orally to mice (ddY mice, male, 24-30 g). After administration, 30 minutes later, the mice are suspended by their tails for 6 minutes. If the mice remain motionless during the 6 minutes... The time spent being still (i.e., not exhibiting escape behavior) is measured, and the immobility time is obtained. The administration of antidepressants such as benzodiazepines shortens the immobility time. Therefore, in the test of the test substance... If a reduction in immobility time is observed, it can be concluded that the test substance has antidepressant properties. Since immobility is considered a state of resignation, a reduction in immobility time also indicates an increase in motivation. (That is, it indicates that the test substance has properties that increase motivation.)

[0082] 6.1.2. Mandatory Swimming Test The forced swim test, like the tail suspension test, is used to screen for potential antidepressants. This is an experimental method (Can et al., 2012, J Vis Exp., 59: e3638). In this test performed in the examples, the test substance is mouse (ddY mouse, male). The mice were orally administered (24-30 g), and 30 minutes later, they were placed in an inescapable water bath for 8 minutes. The time the mouse is immobile within an 8-minute period is measured, and the immobility time is obtained.

[0083] Similar to the tail suspension test, administering antidepressants such as imipramine can reduce the likelihood of a patient passing the forced swim test. The kinetic time is shortened. Therefore, if a reduction in the kinetic time is observed in the test of the test substance, the test It can be concluded that the test substance has antidepressant properties. The reduction in immobility time also indicates a decrease in motivation. It shows an increase (i.e., it indicates that the test substance has properties that increase motivation).

[0084] 6.1.3. Elevated Cross Maze Test The elevated cruciform maze test is widely used to measure anxiety-like behavior in mice, and the open area This is based on the mice's inherent aversion to the region and high-altitude areas (Komada et al. l.,2008 J.Vis Exp.,22:e1088). The test was conducted to determine the resistance of the test substance. It can be used to evaluate the anxiolytic effect. In this test carried out in the examples, two open arms (25 cm × 5 cm) and two closed arms (25 cm × 5 cm × 15 c m) of the device are placed 50 cm above the floor. Despite the high position, due to the high wall (1 5 cm), the mice can safely walk around in the closed arms. On the other hand, mice walking on the open arms feel a sense of uneasiness because there is no wall to protect the mice from falling. Therefore, the longer the mice stay in the open arms and the more times they enter the open arms compared to the control, the more it indicates the anxiolytic activity of the test substance.

[0085] Mice (ddY mice, male, 24 - 30 g) are administered the test substance 30 minutes before the test. At the beginning of the test, the mice are placed on the device facing one of the open arms. During the 5 - minute test time, the cumulative time staying in the open arms (time in the open arms), the number of entries into the open arms (open - arm entry), and the total number of entries into one of the arms (total entry) are recorded.

[0086] 6.1.4. Open - field test The open - field test is used to measure the anxiety - like behavior of mice (Ba iley and Crawley, 2009, Anxiety - Related Be haviors in Mice, Ch.5 in Methods of Behav ior Analysis in Neurscience, 2nd edition, CRC Press, Boca Raton FL). The mice are placed at the edge of the enclosed area. They prefer smaller areas (e.g., enclosed circles) and typically exhibit very little exploration towards the center. Examples In the tests conducted, mice are administered the test substance 30 minutes before the test. At the time of demonstration, the mice are placed in a circular chamber and their behavior is observed for 5 minutes. Chamber (1 The time spent in the central circle (2 cm), the number of times the central circle of the chamber was entered, and the distance moved. The total distance is measured. In mice administered the test substance, a higher ratio was observed compared to the control. The time spent in the central circle serves as an indicator of the anxiolytic activity of the test substance.

[0087] 6.2. Example 1: Tail suspension test using peptide LSSTQAQQSY (Sequence ID 1) Peptide L at 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, or 3 mg / kg The tail suspension test was performed using mice orally administered SSTQAQQSY (SEQ ID NO: 1). (n=8~10).

[0088] The results are shown in Figure 1. Immobilization time was 0.3 mg / kg and 1 mg / kg compared to the physiological saline control. The time was significantly shortened in the mg / kg and 3 mg / kg groups.

[0089] 6.3. Example 2: Forced swimming experiment using peptide LSSTQAQQSY (SEQ ID NO: 1) trial Peptide LSSTQAQQSY (SEQ ID NO: 1) at 0.3 mg / kg or 1 mg / kg The study involved using mice orally administered a peptide (n=12-13) in a forced swimming test. .

[0090] The results are shown in Figure 2. Immobility time was significantly shorter in the 1 mg / kg group compared to the physiological saline control group. It was shortened to [this].

[0091] 6.4. Example 3: Tail suspension test using peptides LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQ S (SEQ ID NO: 2), SSTQAQQSY (SEQ ID NO: 3), LSSTQ (SEQ ID NO: 4), and AQQSY (SEQ ID NO: 5). Mice orally administered with 0.3 mg / kg of peptides LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQS (SEQ ID NO: 2) ( corresponding to the first 9 amino acids of SEQ ID NO: 1), SSTQAQQSY (SEQ ID NO: 3) ( corresponding to the last 9 amino acids of SEQ ID NO: 1), LSSTQ (SEQ ID NO: 4) (SEQ ID corresponding to the first 5 amino acids of NO: 1), and AQQSY (SEQ ID NO: 5) (SEQ ID NO: 1 corresponding to the last 5 amino acids of) were used for the tail suspension test (n = 5 - 6 or 18 - 19).

[0092] The results are shown in Figure 3. Compared with the control, the immobility time was shortened in all test groups, and each peptide was shown to have antidepressant and motivation-enhancing properties. Only the full-length peptide LSSTQAQQSY (SEQ ID NO: 1) had statistically significant results. The inventors speculated that shorter peptides may obtain more significant effects at higher doses (e.g., 1 mg / kg, 3 mg / kg, or 10 mg / kg).

[0093] 6.5. Example 4: Elevated plus maze test using peptide LSSTQAQQSY (SEQ ID NO: 1)

[0094] Peptide LSSTQAQQSY (SEQ ID NO: 1) was tested in an elevated plus maze test using mice orally administered with 0.1 mg / kg, 0.3 mg / k g, or 1 mg / kg of the peptide (n = 18 - 19). ​​​

[0095] The results are shown in Figure 4. The percentage of time spent with the open arm increased across all groups. The level of statistical significance increased in the 1 mg / kg group.

[0096] 6.6. Example 5: Open-flow using peptide LSSTQAQQSY (SEQ ID NO: 1) Field Test Peptide LSSTQAQQSY (SEQ ID NO: 1) at 0.1 mg / kg and 0.3 mg / kg Open field trials were conducted using mice orally administered with g or 1 mg / kg of peptide. The test was conducted using an experimental method (n=4-5).

[0097] The results are shown in Figure 5. The time that mice spent in the central 12 cm circle increased in all groups. The level of statistical significance increased in the 1 mg / kg group. Similar results were observed in the 12 cm circle. This was also observed in the number of times the activity occurred. On the other hand, there was no significant difference in overall spontaneous motor activity between the groups.

[0098] 6.7. Example 6: Peptide LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQ SW (SEQ ID NO: 6), LSSTQAQQSF (SEQ ID NO: 7), and C-terminal ami tail using the ionized peptide conjugate LSSTQAQQSY-NH2 (SEQ ID NO: 36) Suspension Test Peptides LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQSW (SEQ ID NO: 6) , and LSSTQAQQSF (SEQ ID NO: 7), as well as C-terminal amidated peptide condiments Gate LSSTQAQQSY-NH2 (SEQ ID NO: 36) is administered at a dose of 0.3 mg / kg of peptide. The drug was administered orally to mice, and the tail suspension test was performed (n=11-12).

[0099] The results are shown in Figure 6. All peptides and peptide conjugates have an immobilization period. The abbreviated form is the position of the aromatic side chain at the C-terminus of peptide LSSTQAQQSY (SEQ ID NO: 1). Modification by substitution (changing Y to W or F) or by addition of an amino group is a modification of peptide antidepressants. It demonstrates the maintenance of activity that enhances vitality and motivation.

[0100] 6.8. Example 7: Tail suspension using peptides of amino acids 5, 6, 7, 8, and 9 test

[0101] SSTQA (SEQ ID NO: 8), STQ, a peptide containing 5, 6, 7, 8, and 9 amino acids. AQ (SEQ ID NO: 9), TQAQQ (SEQ ID NO: 10), QAQQS (SEQ ID NO: 11), AQ QSW (sequence number 12), or AQQSF (sequence number 13), LSSTQA (sequence number 12) 14) SSTQAQ (Sequence ID 15), STQAQQ (Sequence ID 16), TQAQQS (Sequence ID 17), QAQQSY (Sequence ID 18), QAQQSW (Sequence ID 19), QAQQSF (Sequence ID 20), LSSTQAQ (Sequence ID 21), SSTQAQQ (Sequence ID 22), STQAQQS (Sequence ID 23), TQAQQSY (Sequence ID 24) , TQAQQSW (Sequence ID 25), TQAQQSF (Sequence ID 26), LSSTQAQ Q (sequence number 27), SSTQAQQS (sequence number 28), STQAQQSY (sequence number 27) 29) STQAQQSW (Sequence ID 30), STQAQQSF (Sequence ID 31), SS TQAQQSW (SEQ ID NO: 32) and SSTQAQQSF (SEQ ID NO: 33) are administered in 1 mg doses. One of these peptides was administered orally at a dose of 3 mg / kg, 3 mg / kg, or 10 mg / kg. The test will be conducted using a tail suspension test with mice.

[0102] Mice administered peptides containing 5, 6, 7, 8, or 9 amino acids showed a shortened immobility period. Shrinkage is observed. An increase in response is observed with increasing peptide dosage.

[0103] 6.9. Example 8: Forced water with peptides of amino acids 5, 6, 7, 8, and 9 Swimming test SSTQA (SEQ ID NO: 8), STQ, a peptide containing 5, 6, 7, 8, and 9 amino acids. AQ (SEQ ID NO: 9), TQAQQ (SEQ ID NO: 10), QAQQS (SEQ ID NO: 11), AQ QSW (sequence number 12), or AQQSF (sequence number 13), LSSTQA (sequence number 12) 14) SSTQAQ (Sequence ID 15), STQAQQ (Sequence ID 16), TQAQQS (Sequence ID 17), QAQQSY (Sequence ID 18), QAQQSW (Sequence ID 19), QAQQSF (Sequence ID 20), LSSTQAQ (Sequence ID 21), SSTQAQQ (Sequence ID 22), STQAQQS (Sequence ID 23), TQAQQSY (Sequence ID 24) , TQAQQSW (Sequence ID 25), TQAQQSF (Sequence ID 26), LSSTQAQ Q (sequence number 27), SSTQAQQS (sequence number 28), STQAQQSY (sequence number 27) 29) STQAQQSW (Sequence ID 30), STQAQQSF (Sequence ID 31), SS TQAQQSW (SEQ ID NO: 32) and SSTQAQQSF (SEQ ID NO: 33) are administered in 1 mg doses. One of these peptides was administered orally at a dose of 3 mg / kg, 3 mg / kg, or 10 mg / kg. The test will be conducted using mice in a forced swimming test.

[0104] Mice administered peptides containing 5, 6, 7, 8, or 9 amino acids showed a shortened immobility period. Shrinkage is observed. An increase in response is observed with increasing peptide dosage.

[0105] 6.10. Example 9: Elevated using peptides of amino acids 5, 6, 7, 8, and 9 Cross Maze Test SSTQA (SEQ ID NO: 8), STQ, a peptide containing 5, 6, 7, 8, and 9 amino acids. AQ (SEQ ID NO: 9), TQAQQ (SEQ ID NO: 10), QAQQS (SEQ ID NO: 11), AQ QSW (sequence number 12), or AQQSF (sequence number 13), LSSTQA (sequence number 12) 14) SSTQAQ (Sequence ID 15), STQAQQ (Sequence ID 16), TQAQQS (Sequence ID 17), QAQQSY (Sequence ID 18), QAQQSW (Sequence ID 19), QAQQSF (Sequence ID 20), LSSTQAQ (Sequence ID 21), SSTQAQQ (Sequence ID 22), STQAQQS (Sequence ID 23), TQAQQSY (Sequence ID 24) , TQAQQSW (Sequence ID 25), TQAQQSF (Sequence ID 26), LSSTQAQ Q (sequence number 27), SSTQAQQS (sequence number 28), STQAQQSY (sequence number 27) 29) STQAQQSW (Sequence ID 30), STQAQQSF (Sequence ID 31), SS TQAQQSW (SEQ ID NO: 32) and SSTQAQQSF (SEQ ID NO: 33) are administered in 1 mg doses. One of these peptides was administered orally at a dose of 3 mg / kg, 3 mg / kg, or 10 mg / kg. The test will be conducted using mice in an elevated cross maze test.

[0106] In mice administered peptides containing 5, 6, 7, 8, and 9 amino acids, open-air The percentage of time spent in the area increases. With increasing peptide dosage, the response increases. Observed.

[0107] 6.11. Example 10: Using peptides of amino acids 5, 6, 7, 8, and 9 Openfield Test SSTQA (SEQ ID NO: 8), STQ, a peptide containing 5, 6, 7, 8, and 9 amino acids. AQ (SEQ ID NO: 9), TQAQQ (SEQ ID NO: 10), QAQQS (SEQ ID NO: 11), AQ QSW (sequence number 12), or AQQSF (sequence number 13), LSSTQA (sequence number 12) 14) SSTQAQ (Sequence ID 15), STQAQQ (Sequence ID 16), TQAQQS (Sequence ID 17), QAQQSY (Sequence ID 18), QAQQSW (Sequence ID 19), QAQQSF (Sequence ID 20), LSSTQAQ (Sequence ID 21), SSTQAQQ (Sequence ID 22), STQAQQS (Sequence ID 23), TQAQQSY (Sequence ID 24) , TQAQQSW (Sequence ID 25), TQAQQSF (Sequence ID 26), LSSTQAQ Q (sequence number 27), SSTQAQQS (sequence number 28), STQAQQSY (sequence number 27) 29) STQAQQSW (Sequence ID 30), STQAQQSF (Sequence ID 31), SS TQAQQSW (SEQ ID NO: 32) and SSTQAQQSF (SEQ ID NO: 33) are administered in 1 mg doses. One of these peptides was administered orally at a dose of 3 mg / kg, 3 mg / kg, or 10 mg / kg. The test will be conducted using mice in an open-field setting.

[0108] In mice administered peptides containing 5, 6, 7, 8, and 9 amino acids, the central 12 cm The time spent in the circle increases. An increase in response is observed with increasing peptide dose. ru.

[0109] 6.12. Example 11: Test of mechanism of action To investigate the mechanism of action of the peptide, the peptide LSSTQAQQSY (SEQ ID NO: 1) was used. 0.3 mg / kg of this drug was administered to vagus nerve-transected mice and sham-surgery mice one week after surgery. The drug was administered orally. Subsequently, these mice were subjected to a tail suspension test.

[0110] The results are shown in Figure 7. Vagus nerve resection eliminated the antidepressant-like effect of orally administered peptides. These results suggest that the peptides act in the gut, and their signals are transmitted to the central nervous system via the vagus nerve. This suggests that the compounds of this disclosure are transmitted to peptide LSSTQA. We believe that it may share the same mechanism of action as QQSY (Sequence ID 1).

[0111] 6.13. Example 12: Antidepressant effect of peptide LSSTQAQQSY (SEQ ID NO: 1) Investigation of the mediators involved 0.3 mg / kg of peptide LSSTQAQQSY (SEQ ID NO: 1) was administered to mice alone. or serotonin 5-HT 1A , dopamine D1, or GABA A Receptor antagonist When administered orally in combination with a stimulant, it is subjected to a tail suspension test to investigate the peptide's antidepressant effect. The mediator was investigated. 5-HT 1A WAY1001 is a receptor antagonist. 35 was administered at 10 mg / kg. SCH is a dopamine D1 receptor antagonist. 23390 was administered at 30 μg / kg. GABA A The receptor antagonist is bic Clin was administered at a dose of 30 mg / kg.

[0112] The results are shown in Figure 8. The peptide-induced antidepressant-like effect was due to serotonin 5-HT 1A , Do Pamine D1 and GABA A The peptide was blocked by the receptor antagonist. It did not show affinity for these receptors. This is because the peptide did not affect these neurotransmitters. Suggests stimulating the release of substances. The order of receptor activation is 5-HT 1A , D1, and also GABA A , which was also determined using selective agonists and antagonists (data not shown). In summary, the peptide, after oral administration, appears to exhibit an antidepressant-like effect through the activation of the brain-gut axis and the 5-HT 1A , D1, and GABA A systems. The inventors believe that the compounds of the present disclosure may share the same mechanism of action as the peptide LSSTQAQQSY (SEQ ID NO: 1

[0113]

[0113] 6.14. Example 13: Tail suspension test using peptides LSSTQAQQ (SEQ ID NO: 27), SSTQAQQ S (SEQ ID NO: 2), and STQAQQSY (SEQ ID NO: 29) Peptides LSSTQAQQ (SEQ ID NO: 27), SSTQAQQS (SEQ ID NO: 28), and also STQAQQSY (SEQ ID NO: 29) were tested in a tail suspension test using mice orally administered 0.3 mg / kg of the peptide (n = 5 - 6).

[0114] The results are shown in Figure 9. Compared to the control, all peptides shortened the immobility time.

[0115] 6.15. Example 14: Tail suspension test using peptides LSSTQAQQSYW (SEQ ID NO: 37), WLSS TQAQQSY (SEQ ID NO: 38), WLSSTQAQQSYW (SEQ ID NO: 39), WLS STQ (SEQ ID NO: 40), and AQQSYW (SEQ ID NO: 41)

[0116] Peptides LSSTQAQQSYW (SEQ ID NO: 37), WLSSTQAQQSY (SEQ ID NO: 38), WLSSTQAQQSYW (SEQ ID NO: 39), WLSSTQ (SEQ ID NO: 40) , and AQQSYW (SEQ ID NO: 41) were administered orally at a peptide dose of 0.3 mg / kg. The test was conducted using mice in a tail suspension test (n=3-5).

[0117] The results are shown in Figure 10. Compared to the control, all peptides reduced immobility time.

[0118] 6.16. Example 15: Peptide ESFFLSSTQAQQSY (SEQ ID NO: 42), L SSTQAQQSYLQGF (Sequence ID 43), and FFLSSTQAQQSYLQ( Tail suspension test using Sequence ID No. 44) Peptides ESFFLSSTQAQQSY (SEQ ID NO: 42), LSSTQAQQSYLQ GF (sequence number 43) and FFLSSTQAQQSYLQ (sequence number 44) are set to 0. The study involved a tail suspension test using mice orally administered 3 mg / kg of peptide (n=6~). 7).

[0119] The results are shown in Figure 11. Compared to the control, the peptide FFLSSTQAQQSYLQ (peptide Column number 44) reduced idle time.

[0120] 6.17. Example 16: Peptides SSTQAQQS (SEQ ID NO: 28), LSSTQAQ Tail suspension test using QSYW (Sequence ID 37) and WLSSTQ (Sequence ID 40) Peptides SSTQAQQS (SEQ ID NO: 28), LSSTQAQQSYW (SEQ ID NO: 37) ) and WLSSTQ (SEQ ID NO: 40) were administered orally at a peptide dose of 0.3 mg / kg. The tail suspension test was repeated using mice (n=5-7).

[0121] The results are shown in Figure 12. Compared to the control, all peptides reduced immobility time.

[0122] 6.18. Example 17: Analysis of tail suspension test data We analyzed the tail suspension test data from Examples 1, 3, 6, 13, 14, 15, and 16. We identified the correlation between sequence and activity. First, we used tail suspension test data for each peptide. This was normalized as the percentage of immobility time in the control group in the test. The value "T" indicates greater activity. The results are shown in Table 1.

[0123] [Table 1]

[0124] Subsequently, the normalized data for each peptide was obtained from peptide LSSTQAQQSY( The relative activity of the peptides was ranked compared to the normalized data of SEQ ID NO: 1). Using the percentage reduction rate of the unresponsive particles, the activity grades are classified as excellent, good, moderate, and low, respectively. Assigned to Tide. For peptides tested two or more times (including SEQ ID NO: 1 and the reference peptide). The average control immobility reduction rate was used in these calculations. The resulting activity scores were taken from Sequence ID 1. Table 2 shows the amino acid changes along with the underlined amino acid alignment.

[0125] [Table 2]

[0126] Although not bound by theory, the inventors have identified the core amino acid sequence SSTQAQQS( (Sequence ID 28) contains a total amino acid length of 8-12 (and more specifically, 8-10 a Peptides having a (mino acid length) typically contain the SSTQAQQS (SEQ ID NO: 28) core sequence. It has higher activity than peptides without aromatic amino acids at one or both ends, particularly the C-terminus. (Y, W, or F) enhances activity, and activity is usually achieved when the peptide length is outside these ranges. We believe that it will gradually decrease as it changes.

[0127] 7. Specific Embodiments This disclosure is illustrated by the following specific embodiments. 1. A compound which is a peptide or a salt thereof, wherein the peptide is: a. It is 5-15 amino acid length; b. At least five sequences derived from the amino acid sequence LSSTQAQQSX1 (SEQ ID NO: 34) Having an amino acid sequence containing consecutive amino acids; and c. Amino acid sequences LSSTQAQQSY (Sequence No. 1), LSSTQAQQS (Sequence No. 1) No. 2), SSTQAQQSY (Sequence No. 3), LSSTQ (Sequence No. 4), AQQSY ( Sequence ID 5), LSSTQAQQSW (Sequence ID 6), or LSSTQAQQSF (Sequence ID 5), Compounds that are not composed of (series number 7). 2. The peptide contains or is derived from the amino acid sequence SSTQA (SEQ ID NO: 8). The compound described in Embodiment 1. 3. The peptide contains or is derived from the amino acid sequence STQAQ (SEQ ID NO: 9). The compound described in Embodiment 1. 4. The peptide contains or is derived from the amino acid sequence TQAQQ (SEQ ID NO: 10) The compound described in Embodiment 1. 5. The peptide contains or is derived from the amino acid sequence QAQQS (SEQ ID NO: 11). The compound described in Embodiment 1. 6. The peptide contains or is derived from the amino acid sequence AQQSW (SEQ ID NO: 12). The compound described in Embodiment 1. 7. The peptide contains or is derived from the amino acid sequence AQQSF (SEQ ID NO: 13). The compound of Embodiment 1. 8. The peptide according to Embodiment 1, comprising the amino acid sequence LSSTQ (SEQ ID NO: 4). compound. 9. The peptide comprises the amino acid sequence AQQSY (SEQ ID NO: 5) as described in Embodiment 1. compound. 10. Does the peptide contain or have the amino acid sequence LSSTQA (SEQ ID NO: 14)? The compound described in Embodiment 1. 11. Does the peptide contain or have the amino acid sequence SSTQAQ (SEQ ID NO: 15)? The compound described in Embodiment 1. 12. Does the peptide contain or have the amino acid sequence STQAQQ (SEQ ID NO: 16)? The compound described in Embodiment 1. 13. Does the peptide contain or have the amino acid sequence TQAQQS (SEQ ID NO: 17)? The compound described in Embodiment 1. 14. Does the peptide contain or have the amino acid sequence QAQQSY (SEQ ID NO: 18)? The compound described in Embodiment 1. 15. Does the peptide contain or have the amino acid sequence QAQQSW (SEQ ID NO: 19)? The compound described in Embodiment 1. 16. Does the peptide contain or have the amino acid sequence QAQQSF (SEQ ID NO: 20)? The compound described in Embodiment 1. 17. The peptide contains or has the amino acid sequence LSSTQAQ (SEQ ID NO: 21) The compound according to Embodiment 1, comprising the above. 18. The peptide contains or has the amino acid sequence SSTQAQQ (SEQ ID NO: 22) The compound according to Embodiment 1, comprising the above. 19. The peptide contains or has the amino acid sequence STQAQQS (SEQ ID NO: 23) The compound according to Embodiment 1, comprising the above. 20. The peptide contains or has the amino acid sequence TQAQQSY (SEQ ID NO: 24) The compound according to Embodiment 1, comprising the above. 21. The peptide contains or has the amino acid sequence TQAQQSW (SEQ ID NO: 25) The compound according to Embodiment 1, comprising the above. 22. The peptide contains or has the amino acid sequence TQAQQSF (SEQ ID NO: 26) The compound according to Embodiment 1, comprising the above. 23. The peptide contains the amino acid sequence LSSTQAQQ (SEQ ID NO: 27) or The compound according to Embodiment 1, comprising the above. 24. The peptide contains the amino acid sequence SSTQAQQS (SEQ ID NO: 28) or The compound according to Embodiment 1, comprising the above. 25. The peptide contains the amino acid sequence STQAQQSY (SEQ ID NO: 29) or The compound according to Embodiment 1, comprising the above. 26. The peptide contains the amino acid sequence STQAQQSW (SEQ ID NO: 30) or The compound according to Embodiment 1, comprising the above. 27. The peptide contains the amino acid sequence STQAQQSF (SEQ ID NO: 31) or The compound according to Embodiment 1, comprising the above. 28. The peptide contains the amino acid sequence SSTQAQQSW (SEQ ID NO: 32) or The compound according to Embodiment 1, comprising the same. 29. The peptide contains the amino acid sequence SSTQAQQSF (SEQ ID NO: 33) or The compound according to Embodiment 1, comprising the same. 30. Embodiments in which the peptide comprises the amino acid sequence LSSTQAQQS (SEQ ID NO: 2) The compound described in 1. 31. Embodiments in which the peptide comprises the amino acid sequence SSTQAQQSY (SEQ ID NO: 3) The compound described in 1. 32. The peptide contains the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1), in its actual form. The compound described in state 1. 33. The peptide contains the amino acid sequence LSSTQAQQSW (SEQ ID NO: 6), in its implemented form. The compound described in state 1. 34. The peptide contains the amino acid sequence LSSTQAQQSF (SEQ ID NO: 7), in its actual form. The compound described in state 1. 35. The compound according to any one of Embodiments 1 to 7, wherein the peptide has a length of 5 amino acids. thing. 36. The peptide is 6 amino acid long, as described in any one of Embodiments 1 to 16. Compound. 37. The peptide is 7 amino acid long, as described in any one of Embodiments 1 to 22. Compound. 38. The peptide is 8 amino acid long, as described in any one of Embodiments 1 to 27. Compound. 39. The peptide is 9 amino acid long, as described in any one of Embodiments 1 to 29. Compound. 40. The peptide is 10 amino acid long, as described in any one of Embodiments 1 to 31. compound. 41. The peptide is 11 amino acids long, as described in any one of Embodiments 1 to 34. compound. 42. The peptide is 12 amino acid long, as described in any one of Embodiments 1 to 34. compound. 43. The peptide is 13 amino acid long, as described in any one of Embodiments 1 to 34. compound. 44. The peptide is 14 amino acid long, as described in any one of Embodiments 1 to 34. compound. 45. The peptide is 15 amino acid long, as described in any one of Embodiments 1 to 34. compound. 46. ​​A compound that is a conjugate or a salt thereof, wherein the conjugate is: a. The peptide portion, i. It is 5 to 15 amino acids long; ii. At least five amino acid sequences derived from LSSTQAQQSX1 (SEQ ID NO: 34) Containing consecutive amino acids; iii. Amino acid sequences LSSTQAQQSY (Sequence ID 1), LSSTQAQQSW ( Peptide portion not composed of SEQ ID NO: 6) or LSSTQAQQSF (SEQ ID NO: 7) minutes; and b. A compound comprising one or more conjugate moieties bound to the peptide moiety. . 47. Does the peptide portion contain or have the amino acid sequence LSSTQ (SEQ ID NO: 4)? The compound described in Embodiment 46. 48. Does the peptide portion contain or have the amino acid sequence SSTQA (SEQ ID NO: 8)? The compound described in Embodiment 46. 49. Does the peptide portion contain or have the amino acid sequence STQAQ (SEQ ID NO: 9)? The compound described in Embodiment 46. 50. The peptide portion contains or includes the amino acid sequence TQAQQ (SEQ ID NO: 10) The compound according to embodiment 46, comprising the above. 51. The peptide portion contains or includes the amino acid sequence QAQQS (SEQ ID NO: 11). The compound according to embodiment 46, comprising the above. 52. Does the peptide portion contain or have the amino acid sequence AQQSY (SEQ ID NO: 5)? The compound described in Embodiment 46. 53. The peptide portion contains or includes the amino acid sequence AQQSW (SEQ ID NO: 12). The compound according to embodiment 46, comprising the above. 54. The peptide portion contains or includes the amino acid sequence AQQSF (SEQ ID NO: 13). The compound according to embodiment 46, comprising the above. 55. The peptide portion contains the amino acid sequence LSSTQA (SEQ ID NO: 14) or The compound according to embodiment 46, comprising the above. 56. The peptide portion contains the amino acid sequence SSTQAQ (SEQ ID NO: 15) or The compound according to embodiment 46, comprising the above. 57. The peptide portion contains the amino acid sequence STQAQQ (SEQ ID NO: 16) or The compound according to embodiment 46, comprising the above. 58. The peptide portion contains the amino acid sequence TQAQQS (SEQ ID NO: 17) or The compound according to embodiment 46, comprising the above. 59. The peptide portion contains the amino acid sequence QAQQSY (SEQ ID NO: 18) or The compound according to embodiment 46, comprising the above. 60. The peptide portion contains the amino acid sequence QAQQSW (SEQ ID NO: 19) or The compound according to embodiment 46, comprising the above. 61. The peptide portion contains the amino acid sequence QAQQSF (SEQ ID NO: 20) or The compound according to embodiment 46, comprising the above. 62. The peptide portion contains the amino acid sequence LSSTQAQ (SEQ ID NO: 21) or The compound according to embodiment 46, comprising the same. 63. The peptide portion contains the amino acid sequence SSTQAQQ (SEQ ID NO: 22) or The compound according to embodiment 46, comprising the same. 64. The peptide portion contains the amino acid sequence STQAQQS (SEQ ID NO: 23) or The compound according to embodiment 46, comprising the same. 65. The peptide portion contains the amino acid sequence TQAQQSY (SEQ ID NO: 24) or The compound according to embodiment 46, comprising the same. 66. The peptide portion contains the amino acid sequence TQAQQSW (SEQ ID NO: 25) or The compound according to embodiment 46, comprising the same. 67. The peptide portion contains the amino acid sequence TQAQQSF (SEQ ID NO: 26) or The compound according to embodiment 46, comprising the same. 68. The peptide portion contains the amino acid sequence LSSTQAQQ (SEQ ID NO: 27) or The compound described in Embodiment 46 is formed from the following. 69. The peptide portion contains the amino acid sequence SSTQAQQS (Sequence ID 28) or The compound described in Embodiment 46 is formed from the following. 70. The peptide portion contains the amino acid sequence STQAQQSY (SEQ ID NO: 29) or The compound described in Embodiment 46 is formed from the following. 71. The peptide portion contains the amino acid sequence STQAQQSW (SEQ ID NO: 30) or The compound described in Embodiment 46 is formed from the following. 72. The peptide portion contains the amino acid sequence STQAQQSF (Sequence ID 31) or The compound described in Embodiment 46 is formed from the following. 73. The peptide portion contains the amino acid sequence LSSTQAQQS (Sequence ID 2) or The compound described in Embodiment 46 is formed from the following. 74. The peptide portion contains the amino acid sequence SSTQAQQSY (Sequence ID 3) or The compound described in Embodiment 46 is formed from the following. 75. The peptide portion contains the amino acid sequence SSTQAQQSW (SEQ ID NO: 32). The compound described in Embodiment 46 is the compound described herein. 76. The peptide portion contains the amino acid sequence SSTQAQQSF (SEQ ID NO: 33). The compound described in Embodiment 46 is the compound described herein. 77. The peptide portion contains the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1). The compound described in application form 46. 78. The peptide portion contains the amino acid sequence LSSTQAQQSW (SEQ ID NO: 6). The compound described in application form 46. 79. The peptide portion contains the amino acid sequence LSSTQAQQSF (SEQ ID NO: 7). The compound described in application form 46. 80. The peptide portion is 5 amino acid long, as described in any one of Embodiments 46 to 54. The compound listed. 81. The peptide portion is 6 amino acid long, as described in any one of embodiments 46 to 61. The compound listed. 82. The peptide portion is 7 amino acid long, as described in any one of embodiments 46 to 67. The compound listed. 83. The peptide portion is 8 amino acid long, as described in any one of Embodiments 46 to 72. The compound listed. 84. The peptide portion is 9 amino acid long, as described in any one of Embodiments 46 to 76. The compound listed. 85. The peptide portion is 10 amino acid long, in any one of embodiments 46 to 76. The compound described. 86. The peptide portion is 11 amino acids long, in any one of embodiments 46 to 79. The compound described. 87. The peptide portion is 12 amino acids long, in any one of embodiments 46 to 79. The compound described. 88. The peptide portion is 13 amino acid long, in any one of embodiments 46 to 79. The compound described. 89. The peptide portion is 14 amino acid long, in any one of embodiments 46 to 79. The compound described. 90. The peptide portion is 15 amino acid long, in any one of embodiments 46 to 79. The compound described. 91. At least one of the 1 or more conjugate portions is a polymer, amine Embodiments 46 to 90 include a no group, acyl group, alkyl group, phosphate group, lipid or sugar. The compound listed in either one of the following. 92. At least one of the 1 or more conjugate portions contains a polymer. , the compound described in Embodiment 91. 93. The polymer is polyethylene glycol, polyvinylpyrrolidone, polylactic acid glyco Poly(2-hydroxypropyl)methacrylamide copolymer, poly(2-hydroxypropyl)methacrylamide copolymer, The compound according to Embodiment 92, comprising glutamic acid or a polysaccharide. 94. At least one of the 1 or more conjugate moieties contains an amine group. , as described in any one of embodiments 91 to 93 95. The amine group is an amino group, an alkylamino group, or a dialkylamino group. The compound described in Embodiment 94. 96. At least one of the 1 or more conjugate moieties contains an acyl group. , as described in any one of Embodiments 91 to 95 97. The compound according to Embodiment 96, wherein the acyl group is a formyl group or an acetyl group. . 98. At least one of the 1 or more conjugate moieties contains an alkyl group. The compound described in any one of embodiments 91 to 97 99. The compound according to Embodiment 98, wherein the alkyl group is a methyl group or an ethyl group. 100. At least one of the 1 or more conjugate moieties contains a phosphate group. The compound described in any one of Embodiments 91 to 99 101. At least one of the 1 or more conjugate moieties contains lipids. The compound described in any one of Embodiments 91 to 100 102. At least one of the 1 or more conjugate portions contains sugar, The compound described in any one of the application methods 91 to 101 103. As described in any one of Embodiments 46 to 93, including a single conjugate portion. A compound of the above, or any one of the embodiments 94 to 102 to the extent dependent on embodiment 91. The compounds described above. 104. Embodiment in which the conjugate portion is bonded to the N-terminal amino acid of the peptide portion. The compound described in 103. 105. Embodiment in which the conjugate portion is bonded to the C-terminal amino acid of the peptide portion. The compound described in 103. 106. Any one of embodiments 46 to 102, including 2 or more conjugate portions. The compounds described above. 107. The compound according to embodiment 106, wherein all conjugate portions are the same. 108. Compounds described in Embodiment 106, where the conjugate portions are not all the same. . 109. The compound according to Embodiment 106, wherein all conjugate moieties are different. 110. The conjugate portion attached to the N-terminal amino acid of the peptide portion and the peptide itself. The chemical compound according to Embodiment 106, which includes a conjugate portion bonded to the C-terminal amino acid of the portion. Compound. 111. The conjugate portion attached to the N-terminal amino acid of the peptide portion is the peptide portion This is the same as the conjugate portion bonded to the C-terminal amino acid, as described in Embodiment 110. A compound of [this]. 112. The conjugate portion attached to the N-terminal amino acid of the peptide portion is the peptide portion The conjugate portion bonded to the C-terminal amino acid of the portion described in Embodiment 110 is different from the conjugate portion of the portion described in Embodiment 110. compound. 113. A compound according to any one of Embodiments 1 to 112, which is a salt. 114. The compound according to Embodiment 113, wherein the salt is an acid addition salt. 115. Acids: a. Hydrochloric acid; b. Sulfuric acid; c. Nitric acid; d. Phosphate; e. Hydrobromic acid; f. Perchloric acid; g. Citric acid; h. succinic acid; i. Maleic acid; j. Fumaric acid; k. Malic acid; l.Tartaric acid; mp-toluenesulfonic acid; n. Benzenesulfonic acid; o. Methanesulfonic acid; or p. Trifluoroacetic acid The compound described in Embodiment 114. 116. The compound according to Embodiment 113, wherein the salt is a base addition salt. 117. The base is: a. Sodium hydroxide; b. Potassium hydroxide; c. Lithium hydroxide; d. Calcium hydroxide; or e. Magnesium hydroxide, The compound described in Embodiment 116. 118. Compounds and one or more drugs described in any one of Embodiments 1 to 117 A pharmaceutical composition comprising a scientifically acceptable carrier, diluent, and / or excipient. 119. Food containing a compound described in any one of Embodiments 1 to 117 as an additive. . 120. A food according to Embodiment 119, which is a nutritional supplement. 121. A functional food, as described in Embodiment 119. 122. Methods of treating individuals suffering from mood disorders, anxiety disorders, or low motivation disorders. The compound described in any one of Embodiments 1 to 117 or the compound described in Embodiment 118. A method comprising administering an effective amount of the listed pharmaceutical composition to a target. 123. The embodiment described in Embodiment 122, which includes treating a subject suffering from a mood disorder. method. 124. The mood disorder includes depression, bipolar disorder, or adjustment disorder, as described in Embodiment 122. Method of loading. 125. The method of Embodiment 124, which includes treating a subject suffering from depression. . 126. Embodiment 124, which includes treating a subject suffering from bipolar disorder. The method. 127. The embodiment described in Embodiment 124, which includes treating a subject suffering from adjustment disorder. method. 128. The embodiment described in Embodiment 122, which includes treating a subject suffering from an anxiety disorder. method. 129. Embodiment 122, which includes treating a subject suffering from a lack of motivation disorder. Method of loading. 130. Embodiment 1, in which a lack of motivation disorder includes emotional blunting, apathy, or akinetic mutism. The method described in section 29. 131. The embodiment of 130, which includes treating a subject suffering from emotional blunting. method. 132. The method according to Embodiment 130, which includes treating a subject suffering from apathy. Law. 133. Embodiment 130, which includes treating a subject suffering from akinetic mutism. Method of loading. 134. The compound or pharmaceutical composition is administered orally, according to any of the embodiments 122 to 133. The method described in one of the following options. 135. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The amount of the pharmaceutical composition contains compounds ranging from 0.005 mg / kg to 500 mg / kg. The method described in morphology 134. 136. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The amount of the pharmaceutical composition contains a compound in an amount of 0.005 mg / kg to 100 mg / kg, The method described in morphology 134. 137. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The amount of the pharmaceutical composition contains a compound ranging from 0.005 mg / kg to 30 mg / kg, in practice. The method described in condition 134. 138. The amount of the compound administered to the subject per day, or the amount administered to the subject per day Embodiments in which the amount of the pharmaceutical composition contains a compound in an amount of 0.005 mg / kg to 1 mg / kg The method described in 134. 139. The amount of the compound administered to the subject per day, or the amount administered to the subject per day Embodiments in which the amount of the pharmaceutical composition contains a compound in an amount of 0.01 mg / kg to 30 mg / kg The method described in 134. 140. The amount of the compound administered to the subject per day, or the amount administered to the subject per day Embodiment 1 contains a pharmaceutical composition in an amount of 0.01 mg / kg to 3 mg / kg of the compound. The method described in 34. 141. The amount of the compound administered to the subject per day, or the amount administered to the subject per day Embodiment 1 contains a compound in an amount of 0.01 mg / kg to 1 mg / kg of the pharmaceutical composition. The method described in 34. 142. The amount of the compound administered to the subject per day, or the amount administered to the subject per day Embodiment 1 contains a pharmaceutical composition in an amount of 0.02 mg / kg to 5 mg / kg of the compound. The method described in 34. 143. The amount of the compound administered to the subject per day, or the amount administered to the subject per day Embodiment 1 contains a compound in an amount of 0.02 mg / kg to 2 mg / kg of the pharmaceutical composition. The method described in 34. 144. The amount of the compound administered to the subject per day, or the amount administered to the subject per day Embodiment 1 contains a compound in an amount of 0.02 mg / kg to 1 mg / kg of the pharmaceutical composition. The method described in 34. 145. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The method according to Embodiment 134, wherein the amount of the pharmaceutical composition is 0.1 mg to 50 g. 146. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The pharmaceutical composition described in Embodiment 134 contains a compound in an amount of 0.1 mg to 10 g. Law. 147. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The method according to Embodiment 134, wherein the amount of the pharmaceutical composition contains 0.1 mg to 3 g of the compound. . 148. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The amount of the pharmaceutical composition is 0.1 mg to 100 mg of the compound, as described in Embodiment 134. The method. 149. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The pharmaceutical composition described in Embodiment 134 contains 0.1 mg to 1 mg of the compound. Law. 150. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The method according to Embodiment 134, wherein the amount of the pharmaceutical composition contains 0.3 mg to 3 g of the compound. . 151. The amount of the compound administered to the subject per day, or the amount administered to the subject per day The amount of the pharmaceutical composition described in Embodiment 134 includes 0.3 mg to 100 mg of the compound. The method. 152. A method for treating or preventing mood disorders, anxiety disorders, or low motivation disorders. Those who are prone to or suffer from mood disorders, anxiety disorders, or low motivation disorders The elephant receives an effective amount of one or more foods described in any one of embodiments 119 to 121. A method including administration. 153. The method according to Embodiment 152, comprising treating or preventing a mood disorder. 154. The mood disorder includes depression, bipolar disorder, or adjustment disorder, as described in Embodiment 152. Method of loading. 155. The method according to Embodiment 154, comprising treating or preventing depression. 156. The method according to Embodiment 154, comprising treating or preventing bipolar disorder. 157. The method according to Embodiment 154, comprising treating or preventing adjustment disorder. 158. The method according to Embodiment 152, comprising treating or preventing an anxiety disorder. 159. The method according to Embodiment 152, which includes treating or preventing a lack of motivation disorder. . 160. Embodiment 1, in which a lack of motivation disorder includes emotional blunting, apathy, or akinetic mutism. The method described in 59. 161. The method according to Embodiment 160, comprising treating or preventing emotional blunting. 162. The method according to Embodiment 160, comprising treating or preventing apathy. 163. The method according to Embodiment 160, which includes treating or preventing akinetic mutism. . 164. The amount of one or more foods administered to the subject per day is 0.005 mg The compound is contained in a quantity of 500 mg / kg or more, as described in any one of Embodiments 152 to 163. Method of loading. 165. The amount of one or more foods administered to the subject per day is 0.005 mg The compound is contained in any one of embodiments 152 to 163, including a compound in a quantity of 100 mg / kg to 100 mg / kg. Method of loading. 166. The amount of one or more foods administered to the subject per day is 0.005 mg The compound is described in any one of Embodiments 152 to 163, containing a compound of 30 mg / kg to 30 mg / kg. The method. 167. The amount of one or more foods administered to the subject per day is 0.005 mg The compound is contained in any one of embodiments 152 to 163, with a concentration of 1 mg / kg to 1 mg / kg. method. 168. The amount of one or more foods administered to the subject per day is 0.01 mg / The compound described in any one of Embodiments 152 to 163, comprising 30 mg / kg of the compound. method. 169. The amount of one or more foods administered to the subject per day is 0.01 mg / The method according to any one of Embodiments 152 to 163, comprising a compound of 3 mg / kg. Law. 170. The amount of one or more foods administered to the subject per day is 0.01 mg / The method described in any one of Embodiments 152 to 163, comprising a compound of 1 mg / kg to 1 mg / kg. Law. 171. The amount of one or more foods administered to the subject per day is 0.02 mg / The method according to any one of Embodiments 152 to 163, comprising a compound of 5 mg / kg. Law. 172. The amount of one or more foods administered to the subject per day is 0.02 mg / The method according to any one of Embodiments 152 to 163, comprising a compound of 2 mg / kg. Law. 173. The amount of one or more foods administered to the subject per day is 0.02 mg / The method described in any one of Embodiments 152 to 163, comprising a compound of 1 mg / kg to 1 mg / kg. Law. 174. The amount of one or more foods administered to the subject per day is 0.1 mg to 5 mg. The method according to any one of embodiments 152 to 163, comprising 0 g of the compound. 175. The amount of one or more foods administered to the subject per day is 0.1 mg to 1 The method according to any one of embodiments 152 to 163, comprising 0 g of the compound. 176. The amount of one or more foods administered to the subject per day is 0.1 mg to 3 mg. The method according to any one of embodiments 152 to 163, comprising a compound g. 177. The amount of one or more foods administered to the subject per day is 0.1 mg to 1 The method according to any one of embodiments 152 to 163, comprising 00 mg of the compound. 178. The amount of one or more foods administered to the subject per day is 0.1 mg to 1 The method according to any one of embodiments 152 to 163, comprising mg of the compound. 179. The amount of one or more foods administered to the subject per day is 0.3 mg to 3 mg. The method according to any one of embodiments 152 to 163, comprising a compound g. 180. The amount of one or more foods administered to the subject per day is 0.3 mg to 1 The method according to any one of embodiments 152 to 163, comprising 00 mg of the compound. 181. Compounds according to any one of Embodiments 1 to 117 for use as a drug thing. 182. Any one of Embodiments 1 to 117 for use in a method of treating mood disorders The compound described. 183. The mood disorder includes depression, bipolar disorder, or adjustment disorder, as described in Embodiment 182. Compounds for use in the field. 184. A compound for use in a mood disorder, including depression, as described in Embodiment 183. 185. A compound for use according to Embodiment 183, wherein the mood disorder includes bipolar disorder. . 186. A compound for use according to Embodiment 183, for mood disorders, including adjustment disorders. 187. Any one of Embodiments 1 to 117 for use in a method of treating anxiety disorders The compound described. 188. Any one of Embodiments 1 to 117 for use in the treatment of motivational disorder The compound described above. 189. Embodiment 1, in which a lack of motivation disorder includes emotional blunting, apathy, or akinetic mutism. Compounds for use as described in 88. 190. A compound for use in Embodiment 189, including a disorder of decreased motivation and emotional blunting. thing. 191. Compounds for use according to Embodiment 189, including apathy, for disorders of decreased motivation. . 192. For use in Embodiment 189, including akinetic mutism, for a lack of motivation disorder compound. 193. Embodiments 182- , in which the method includes oral administration of an effective amount of the compound. A compound for use as described in any one of 192. 194. The method targets compounds at a dosage of 0.005 mg / kg to 500 mg / kg per day. The compound for use according to Embodiment 193, including administration to [a specific body part]. 195. The method targets compounds at a daily dose of 0.005 mg / kg to 100 mg / kg. The compound for use according to Embodiment 193, including administration to [a specific body part]. 196. The method targeted compounds at a daily dose of 0.005 mg / kg to 30 mg / kg. The compound for use according to Embodiment 193, including administration. 197. The method involves administering a compound at a dose of 0.005 mg / kg to 1 mg / kg per day. A compound for use according to Embodiment 193, including giving. 198. The method involves administering compounds at a dose of 0.01 mg / kg to 30 mg / kg per day. A compound for use according to Embodiment 193, including giving. 199. The method involves administering compounds at a dose of 0.01 mg / kg to 3 mg / kg per day. A compound for use as described in Embodiment 193, including the act of... 200. The method involves administering compounds at a dose of 0.01 mg / kg to 1 mg / kg per day. A compound for use as described in Embodiment 193, including the act of... 201. The method involves administering compounds at a dose of 0.02 mg / kg to 5 mg / kg per day. A compound for use as described in Embodiment 193, including the act of... 202. The method involves administering compounds at a dose of 0.02 mg / kg to 2 mg / kg per day. A compound for use as described in Embodiment 193, including the act of... 203. The method involves administering compounds at a dose of 0.02 mg / kg to 1 mg / kg per day. A compound for use as described in Embodiment 193, including the act of... 204. The method includes administering 0.1 mg to 50 g of the compound per day. , the compound for use as described in Embodiment 193. 205. The method includes administering 0.1 mg to 10 g of the compound per day. , the compound for use as described in Embodiment 193. 206. The method includes administering a compound at a dose of 0.1 mg to 3 g per day. Compounds for use as described in Embodiment 193. 207. The method involves administering 0.1 mg to 100 mg of the compound per day. Including the compounds for use described in Embodiment 193. 208. The method includes administering 0.1 mg to 1 mg of the compound per day to the target. , the compound for use as described in Embodiment 193. 209. The method includes administering a compound at a dose of 0.3 mg to 3 g per day. Compounds for use as described in Embodiment 193. 210. The method involves administering 0.3 mg to 100 mg of the compound per day. Including the compounds for use described in Embodiment 193. 211. The pharmaceutical composition according to Embodiment 118 for use in a method for treating mood disorders. 212. The mood disorder includes depression, bipolar disorder, or adjustment disorder, as described in Embodiment 211. A pharmaceutical composition for use in the field. 213. A pharmaceutical composition for use according to Embodiment 211, wherein mood disorders include depression. 214. A medicinal combination for use according to Embodiment 211, for mood disorders including bipolar disorder. Finished product. 215. A pharmaceutical composition for use according to Embodiment 211, including mood disorders, including adjustment disorders. thing. 216. The pharmaceutical composition according to Embodiment 118 for use in a method for treating anxiety disorders. 217. Pharmaceutical composition according to Embodiment 118 for use in a method for treating a disorder of decreased motivation thing. 218. Embodiment 2, in which the lack of motivation disorder includes emotional blunting, apathy, or akinetic mutism. A pharmaceutical composition for use as described in 17. 219. A pharmacopoeia for use according to Embodiment 217, which includes a disorder of decreased motivation and emotional blunting. composition. 220. A pharmaceutical combination for use in Embodiment 217, including apathy disorder, for a lack of motivation Finished product. 221. For use in Embodiment 217, including akinetic mutism, for a lack of motivation disorder Pharmaceutical composition. 222. Embodiment 21, in which the method includes orally administering an effective amount of the pharmaceutical composition. A pharmaceutical composition for use as described in any one of 1 to 221. 223. The method involves a compound administered at a dose of 0.005 mg / kg to 500 mg / kg per day. A pharmaceutical for use according to Embodiment 222, which includes administering a target amount of the pharmaceutical composition. composition. 224. The method involves a compound administered at a dose of 0.005 mg / kg to 100 mg / kg per day. A pharmaceutical for use according to Embodiment 222, which includes administering a target amount of the pharmaceutical composition. composition. 225. The method involves a medical treatment containing 0.005 mg / kg to 30 mg / kg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administering a target amount of the pharmaceutical composition. Finished product. 226. A method involving a pharmaceutical containing 0.005 mg / kg to 1 mg / kg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administering a target amount of the composition. thing. 227. The method involves a pharmaceutical product containing 0.01 mg / kg to 30 mg / kg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administering a target amount of the composition. thing. 228. The method involves a pharmaceutical compound containing 0.01 mg / kg to 3 mg / kg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administering a target amount of the product. . 229. The method involves a pharmaceutical compound containing 0.01 mg / kg to 1 mg / kg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administering a target amount of the product. . 230. The method involves a pharmaceutical compound containing 0.02 mg / kg to 5 mg / kg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administering a target amount of the product. . 231. The method involves a pharmaceutical compound containing 0.02 mg / kg to 2 mg / kg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administering a target amount of the product. . 232. The method involves a pharmaceutical compound containing 0.02 mg / kg to 1 mg / kg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administering a target amount of the product. . 233. The method targets the amount of a pharmaceutical composition containing 0.1 mg to 50 g of the compound per day. A pharmaceutical composition for use according to Embodiment 222, comprising administering to a person. 234. The method targets the amount of a pharmaceutical composition containing 0.1 mg to 10 g of the compound per day. A pharmaceutical composition for use according to Embodiment 222, comprising administering to a person. 235. The method targets the amount of a pharmaceutical composition containing 0.1 mg to 3 g of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administration. 236. The method involves determining the amount of a pharmaceutical composition containing 0.1 mg to 100 mg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, comprising administration to a target. 237. The method targets the amount of a pharmaceutical composition containing 0.1 mg to 1 mg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, comprising administering to [a specific body part]. 238. The method targets the amount of a pharmaceutical composition containing 0.3 mg to 3 g of the compound per day. A pharmaceutical composition for use according to Embodiment 222, which includes administration. 239. The method involves determining the amount of a pharmaceutical composition containing 0.3 mg to 100 mg of the compound per day. A pharmaceutical composition for use according to Embodiment 222, comprising administration to a target. 240. Embodiments 119-121 for use in the treatment or prevention of mood disorders Foods listed in any one of the following categories. 241. The mood disorder includes depression, bipolar disorder, or adjustment disorder, as described in Embodiment 240. Food intended for use in packaging. 242. A food for use according to Embodiment 241, for mood disorders, including depression. 243. A food for use according to Embodiment 241, wherein the mood disorder includes bipolar disorder. 244. A food for use according to Embodiment 241, for mood disorders, including adjustment disorders. 245. Embodiments 119-121 for use in the treatment or prevention of anxiety disorders Foods listed in any one of the following categories. 246. Embodiments 119-12 for use in the treatment or prevention of low motivation disorder Food for use as described in any one of the items in item 1. 247. Embodiment 2, in which the lack of motivation disorder includes emotional blunting, apathy, or akinetic mutism. Food for use as described in 46. 248. Food for use according to Embodiment 247, including a disorder of decreased motivation and emotional blunting. . 249. A food for use according to Embodiment 247, for which apathy disorder is present, including apathy. 250. For use in Embodiment 247, including akinetic mutism, for a lack of motivation disorder food. 251. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiment 2 contains a compound in an amount of 0.005 mg / kg to 500 mg / kg per day. Food for use as described in one of the following categories: 40-250. 252. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiment 2 contains a compound in an amount of 0.005 mg / kg to 100 mg / kg per day. Food for use as described in one of the following categories: 40-250. 253. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiment 24 contains a compound in an amount of 0.005 mg / kg to 30 mg / kg per day. Food for use as indicated in one of the numbers from 0 to 250. 254. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiment 240 contains a compound in an amount of 0.005 mg / kg to 1 mg / kg per day. Food for use as described in any one of the following ~250 items. 255. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiment 240 contains a compound in an amount of 0.01 mg / kg to 30 mg / kg per day. Food for use as described in any one of the following ~250 items. 256. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiments 240~ contain the compound in an amount of 0.01 mg / kg to 3 mg / kg per day. Food for use as described in any one of 250. 257. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiments 240~ contain the compound in an amount of 0.01 mg / kg to 1 mg / kg per day. Food for use as described in any one of 250. 258. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiments 240~ contain the compound in an amount of 0.02 mg / kg to 5 mg / kg per day. Food for use as described in any one of 250. 259. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiments 240~ contain the compound in an amount of 0.02 mg / kg to 2 mg / kg per day. Food for use as described in any one of 250. 260. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Embodiments 240~ contain the compound in an amount of 0.02 mg / kg to 1 mg / kg per day. Food for use as described in any one of 250. 261. A method which involves one or more foods as described in any one of embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. The amount of the compound is 0.1 mg to 50 g per day, as in any of Embodiments 240 to 250. Food for use as described in one of the items. 262. A method which involves one or more foods as described in any one of embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. The amount of the compound is 0.1 mg to 10 g per day, as in any of Embodiments 240 to 250. Food for use as described in one of the items. 263. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. The amount of the compound is 0.1 mg to 3 g per day, one of the embodiments 240 to 250. Food for use as described in one. 264. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. The amount of the compound is 0.1 mg to 100 mg per day, according to Embodiments 240 to 250. Food for use as described in any one of the following. 265. A method which involves one or more foods as described in any one of Embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. Any of Embodiments 240 to 250, containing a compound in an amount of 0.1 mg to 1 mg per day. Food for use as described in one of the items. 266. A method which involves one or more foods as described in any one of embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. The amount of the compound is 0.3 mg to 3 g per day, one of the embodiments 240 to 250. Food for use as described in one. 267. A method which involves one or more foods as described in any one of embodiments 119 to 121. This includes administering a certain amount of the product to the target, and a certain amount of one or more foods administered to the target. The amounts of the compound included in embodiments 240 to 250 were 0.3 mg to 100 mg per day. Food for use as described in any one of the following.

[0128] While various embodiments have been illustrated and described, they do not deviate from the spirit and scope of this disclosure. It should be understood that various changes can be made without abandoning the original system.

[0129] 8. Sequence Listing

[0130] [Table 3]

[0131] [Table 4]

[0132] 9. Citation of Literature All publications, patents and patent applications and other documents cited in this application are provided for. Perhaps, each individual publication, patent or patent application or other document may refer to separately. Therefore, to the same extent that it is shown to be incorporated herein, the entirety is referred to in this Specified. The teachings of one or more documents incorporated herein and the disclosure In the event of any inconsistency between the two, the teachings in this specification shall apply.

Claims

1. A compound which is a peptide or a salt thereof, wherein the peptide is: a. 5 to 10 amino acid lengths; b. Composed of at least five consecutive amino acids derived from the amino acid sequence LSSTQAQQSX1 (wherein X1 is Y, W, or F) (SEQ ID NO: 34) (provided to have one conservative amino acid substitution); and c. Not composed of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQS (SEQ ID NO: 2), LSSTQAQQSW (SEQ ID NO: 6), or LSSTQAQQSF (SEQ ID NO: 7), A compound having activity that shortens immobility time in the tail suspension test, activity that shortens immobility time in the forced swimming test, activity that increases the time spent in the open arm in the elevated cross maze test, or activity that increases the time spent in the central circle in the open field test.

2. A compound which is a peptide or a salt thereof, wherein the peptide is: a. Having a length of 6 to 12 amino acids; b. An amino acid sequence consisting of at least five consecutive amino acids derived from the amino acid sequence LSSTQAQQSX1 (wherein X1 is Y, W, or F) (SEQ ID NO: 34), with aromatic amino acids added to one or both ends of this amino acid sequence (provided to have one conservative amino acid substitution); and c. Not composed of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQS (SEQ ID NO: 2), LSSTQAQQSW (SEQ ID NO: 6), or LSSTQAQQSF (SEQ ID NO: 7), A compound having activity that shortens immobility time in the tail suspension test, activity that shortens immobility time in the forced swimming test, activity that increases the time spent in the open arm in the elevated cross maze test, or activity that increases the time spent in the central circle in the open field test.

3. A compound which is a conjugate or a salt thereof, wherein the conjugate is: a. The peptide portion, i. Having a length of 5 to 10 amino acids; and ii. Amino acid sequence LSSTQAQQSX １ (In the formula, X １ It consists of at least five consecutive amino acids derived from (where is Y, W, or F) (Sequence ID 34) (provided to have one conservative amino acid substitution); iii. Peptide moieties not composed of the amino acid sequences LSSTQAQQSY (SEQ ID NO: 1), LSSTQAQQSW (SEQ ID NO: 6), or LSSTQAQQSF (SEQ ID NO: 7); and b. comprising one or more conjugate moieties bound to the peptide moiety, A compound having activity that shortens immobility time in the tail suspension test, activity that shortens immobility time in the forced swimming test, activity that increases the time spent in the open arm in the elevated cross maze test, or activity that increases the time spent in the central circle in the open field test.

4. A compound which is a conjugate or a salt thereof, wherein the conjugate is: a. The peptide portion, i. Having a length of 6 to 12 amino acids; and ii. Amino acid sequence LSSTQAQQSX １ A peptide moiety comprising an amino acid sequence having aromatic amino acids attached to one or both ends of an amino acid sequence consisting of at least five consecutive amino acids derived from (SEQ ID NO: 34) (wherein X1 is Y, W, or F), provided that it has one conservative amino acid substitution; and b. comprising one or more conjugate moieties bound to the peptide moiety, A compound having activity that shortens immobility time in the tail suspension test, activity that shortens immobility time in the forced swimming test, activity that increases the time spent in the open arm in the elevated cross maze test, or activity that increases the time spent in the central circle in the open field test.

5. The compound according to claim 3 or 4, wherein at least one of the one or more conjugate portions comprises a polymer, an amino group, an acyl group, an alkyl group, a phosphate group, a lipid, or a sugar.

6. A pharmaceutical composition comprising the compound described in any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers, diluents and / or excipients.

7. A food product comprising a compound according to any one of claims 1 to 5 as an additive.

8. The food according to claim 7, which is a nutritional supplement.

9. The food according to claim 7, which is a functional food.

10. A compound according to any one of claims 1 to 5, for the treatment of mood disorders, anxiety disorders, or low motivation disorders.

11. The pharmaceutical composition according to claim 6, for the treatment of mood disorders, anxiety disorders, or low motivation disorders.

12. A food according to any one of claims 7 to 9, for the treatment or prevention of mood disorders, anxiety disorders, or low motivation disorders.

Images