Use of Therapeutic Peptides

Abstract

(a) peptides and pharmaceutically acceptable salts thereof, and peptide conjugates and pharmaceutically acceptable salts thereof, having an amino acid sequence having 5 to 15 amino acids and comprising at least 5 consecutive amino acids from the amino acid sequence LSSTQAQQSX1 (SEQ ID NO: 1), for use in treating a subject suffering from or at risk of an inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease, a gastrointestinal disease or disorder, pain, rheumatoid arthritis, migraine, headache, substance abuse, drug addiction, seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, depression in the presence of a neurodegenerative disease, cognitive impairment, COVID-19 associated cognitive impairment and / or depression, ADHD, autism spectrum disorder.

Description

[Technical field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 289,915, filed December 15, 2021, the contents of which are incorporated by reference in their entirety herein.

[0002] 2. Sequence Listing This application contains a Sequence Listing XML that has been submitted electronically and is incorporated herein by reference in its entirety. The Sequence Listing XML (created on December 9, 2022) is named DGS-005WO_SL.xml and is 37,105 bytes in size. [Background technology]

[0003] 3.Background PCT International Publication Nos. WO 2016 / 140277 and WO 2018 / 047852 describe peptides and peptide conjugates, such as LSSTQAQQSY (SEQ ID NO: 2), that are useful for treating psychiatric disorders, such as mood disorders, anxiety disorders, and disorders of diminished motivation. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2016 / 140277 [Patent Document 2] International Publication No. 2018 / 047852 Summary of the Invention [Means for solving the problem]

[0005] 4. Abstract The present disclosure is based in part on new insights into the biological activity of peptides and peptide conjugates described in WO 2016 / 140277 and WO 2018 / 047852. Specifically, it has been surprisingly discovered that peptide LSSTQAQQSY (SEQ ID NO: 2) has biological activity that exceeds that previously reported. For example, microdialysis studies (detailed in Section 7) performed with peptide LSSTQAQQSY (SEQ ID NO: 2) have surprisingly clearly shown that oral administration of the peptide affects the levels of certain neurotransmitters in the brain, including histamine and norepinephrine. Without being bound by theory, it is believed that these neurotransmitters are associated with various diseases, disorders, and conditions, such as schizophrenia and neurodegenerative diseases (e.g., Parkinson's disease), and in particular, the negative symptoms associated with these diseases. Furthermore, studies performed with peptide LSSTQAQQSY (SEQ ID NO: 2) in a lipopolysaccharide-induced inflammation model (also detailed in Section 7) have demonstrated that oral administration of the peptide surprisingly inhibits the release of TNF-α, an inflammatory cytokine associated with various diseases, including rheumatoid arthritis and inflammatory bowel disease. Furthermore, studies performed with peptide LSSTQAQQSY (SEQ ID NO: 2) in a scopolamine-induced memory impairment model (also detailed in Section 7) have demonstrated that oral administration of the peptide surprisingly results in improved memory. Furthermore, studies performed with peptide LSSTQAQQSY (SEQ ID NO: 2) in human subjects (also detailed in Section 7) have demonstrated that oral administration of the peptide provides a cognitive enhancing effect. Thus, the studies described in Section 7 indicate that the peptides and peptide conjugates described herein can be used to treat diseases, disorders, and conditions beyond those described in WO 2016 / 140277 and WO 2018 / 047852. Thus, in some aspects, the disclosure provides methods for treating diseases, disorders and conditions amenable to treatment by vagus nerve stimulation and / or modulation of histamine and / or norepinephrine levels and / or modulation of TNF-α. In various aspects, the disclosure provides methods for treating diseases, disorders and conditions amenable to treatment by vagus nerve stimulation and / or modulation of histamine and / or norepinephrine levels and / or modulation of TNF-α, including inflammatory diseases or conditions, schizophrenia or psychosis, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis (ALS)), gastrointestinal diseases or disorders (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., drug use disorder, polysubstance use disorder, substance use disorder, such as alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction (e.g., opioids, e.g., morphine, heroin, oxycodone, or fentanyl; cocaine; or benzodiazepines, e.g., diazepam, alprazolam, or clonazepam), seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE) (e.g., atypical MDE), depression in the presence of a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or ALS), cognitive impairment, COVID-19-associated cognitive impairment, and / or Methods of treating a subject suffering from or at risk of depression, ADHD, autism spectrum disorder, pervasive developmental disorder, pervasive developmental disorder not otherwise specified (also referred to as atypical autism), multiple sclerosis, post-traumatic stress disorder (PTSD), sleep disorder (e.g., insomnia, daytime fatigue, or REM sleep behavior disorder), and methods of improving sleep are provided, comprising administering to a subject in need thereof a peptide or salt thereof, peptide conjugate or salt thereof, or pharmaceutical composition (collectively, herein conveniently referred to as "compounds and compositions of the present disclosure") described herein. In some embodiments, the subject has elevated TNF-α levels.

[0006] In a further aspect, the disclosure provides compounds and compositions of the disclosure for use in the methods of treatment described herein.

[0007] In a further aspect, the present disclosure provides the use of the compounds and compositions of the present disclosure in the manufacture of a medicament for treating a subject having or at risk of developing a disease or condition disclosed herein.

[0008] Exemplary features of methods of treatment, compounds and compositions for use in the methods of treatment, and uses are described in Section 6.4 and in numbered embodiments 1-461, below. [Brief description of the drawings]

[0009] 5. Brief description of the drawings [Figure 1-1] 1A-1G show neurotransmitter levels in mouse prefrontal cortex before and after oral administration of LSSTQAQQSY (SEQ ID NO: 2) (Example 1). Figure 1A: histamine; Figure 1B: norepinephrine; Figure 1C: GABA; Figure ID: glutamate; Figure IE: glycine; Figure 1F: dopamine; Figure 1G: serotonin. [Figure 1-2] 1A-1G show neurotransmitter levels in mouse prefrontal cortex before and after oral administration of LSSTQAQQSY (SEQ ID NO: 2) (Example 1). Figure 1A: histamine; Figure 1B: norepinephrine; Figure 1C: GABA; Figure ID: glutamate; Figure IE: glycine; Figure 1F: dopamine; Figure 1G: serotonin. [Figure 1-3] 1A-1G show neurotransmitter levels in mouse prefrontal cortex before and after oral administration of LSSTQAQQSY (SEQ ID NO: 2) (Example 1). Figure 1A: histamine; Figure 1B: norepinephrine; Figure 1C: GABA; Figure ID: glutamate; Figure IE: glycine; Figure 1F: dopamine; Figure 1G: serotonin. [Figure 1-4]1A-1G show neurotransmitter levels in mouse prefrontal cortex before and after oral administration of LSSTQAQQSY (SEQ ID NO: 2) (Example 1). Figure 1A: histamine; Figure 1B: norepinephrine; Figure 1C: GABA; Figure ID: glutamate; Figure IE: glycine; Figure 1F: dopamine; Figure 1G: serotonin.

[0010] [Figure 2-1] Figures 2A-2G show neurotransmitter levels in the mouse striatum before and after oral administration of LSSTQAQQSY (SEQ ID NO: 2) (Example 1). Figure 2A: histamine; Figure 2B: norepinephrine; Figure 2C: GABA; Figure 2D: glutamate; Figure 2E: glycine; Figure 2F: dopamine; Figure 2G: serotonin. [Figure 2-2] Figures 2A-2G show neurotransmitter levels in the mouse striatum before and after oral administration of LSSTQAQQSY (SEQ ID NO: 2) (Example 1). Figure 2A: histamine; Figure 2B: norepinephrine; Figure 2C: GABA; Figure 2D: glutamate; Figure 2E: glycine; Figure 2F: dopamine; Figure 2G: serotonin. [Figure 2-3] Figures 2A-2G show neurotransmitter levels in the mouse striatum before and after oral administration of LSSTQAQQSY (SEQ ID NO: 2) (Example 1). Figure 2A: histamine; Figure 2B: norepinephrine; Figure 2C: GABA; Figure 2D: glutamate; Figure 2E: glycine; Figure 2F: dopamine; Figure 2G: serotonin. [Figure 2-4] Figures 2A-2G show neurotransmitter levels in the mouse striatum before and after oral administration of LSSTQAQQSY (SEQ ID NO: 2) (Example 1). Figure 2A: histamine; Figure 2B: norepinephrine; Figure 2C: GABA; Figure 2D: glutamate; Figure 2E: glycine; Figure 2F: dopamine; Figure 2G: serotonin.

[0011] [Diagram 3]FIG. 3 shows plasma TNF-α levels after administration of lipopolysaccharide and the peptide LSSTQAQQSY (SEQ ID NO: 2) (Example 2).

[0012] [Figure 4] Figure 4 shows the latency of step-down inhibitor avoidance test in mice (n=10, mean±SEM) (Example 5). **P<0.01 vs. model group, *P<0.05 vs. model group (t-test for paired comparison).

[0013] [Diagram 5] FIG. 5 shows that the AVPR1A / AVPR2 inhibitor conivaptan blocks LSSTQAQQSY (SEQ ID NO:2) activity in the tail suspension test (Example 6).

[0014] [Figure 6] FIG. 6 shows that low doses of the AVPR1A / AVPR2 inhibitor conivaptan block LSSTQAQQSY (SEQ ID NO:2) activity in the tail suspension test (Example 6).

[0015] [Figure 7] FIG. 7 shows that the AVPR2 inhibitor tolvaptan does not block LSSTQAQQSY (SEQ ID NO: 2) activity in the tail suspension assay (Example 6).

[0016] [Figure 8] FIG. 8 shows that nerivaptan, an AVPR1A / B inhibitor, blocks LSSTQAQQSY (SEQ ID NO:2) activity in the tail suspension assay (Example 6).

[0017] [Figure 9] FIG. 9 shows the effect of doses of 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) versus placebo on the overall results of the PHQ-9 questionnaire (Example 7).

[0018] [Figure 10] FIG. 10 shows the effect of doses of 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) versus placebo on the CogState Detection Test (DET) of psychomotor function (Example 7).

[0019] [Figure 11] FIG. 11 shows the effect of doses of 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) versus placebo on the CogState Groton Maze Learning Test (GMLT) of executive function (Example 7).

[0020] [Figure 12] FIG. 12 shows the effect of doses of 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) versus placebo on the CogState Identification Test (IDN) of attention (Example 7). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] 6. Detailed Description 6.1 Definition A "conservative amino acid substitution" refers to an amino acid residue that is replaced with an amino acid residue that has a similar side chain. Families of amino acid residues that have similar side chains have been defined in the art. These families include amino acids that have basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan). In certain embodiments, all amino acid substitutions are conservative when compared to SEQ ID NO:42.

[0022] As used herein, the term "negative symptom" refers to a defect in a subject's ability to perform normal functions. For example, examples of negative symptoms in subjects suffering from schizophrenia include asociality, anhedonia, allogy, affective flattening, apathy, amotivation, blunted affect, anergy, depression, low mood, and cognitive impairment. Negative symptoms, such as one or more of the above-mentioned negative symptoms, can also be experienced by subjects suffering from other diseases, such as subjects with neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, or ALS). Common negative symptoms in such subjects include anhedonia, apathy, depression, and cognitive impairment.

[0023] As used herein, a "non-motor symptom" of Parkinson's disease refers to a symptom that is not related to movement. Non-motor symptoms include, for example, cognitive symptoms (e.g., mood changes, depression, anxiety, panic attacks, tiredness, confusion, and slowed thinking), sensory symptoms (e.g., numbness, restlessness, pain, chest discomfort, and anosmia), and autonomic symptoms (e.g., feeling hot / cold, bladder problems, sweating, abdominal discomfort, constipation, salivation, frequent and / or urinary urges), and erectile dysfunction.

[0024] As used herein, the terms "treat", "treatment", and "treating" refer to a reduction or amelioration of the progression or severity of one or more symptoms (preferably one or more discernible symptoms) of a disease, disorder, or condition resulting from administration of a compound or composition of the disclosure. In specific embodiments, the terms "treat", "treatment", and "treating" refer to an improvement in at least one measurable physical parameter of a disease, disorder, or condition. In other embodiments, the terms "treat", "treatment", and "treating" refer to slowing the progression of one or more symptoms of a disease, disorder, or condition.

[0025] 6.2 Peptides and peptide conjugates Peptides that may be used in the compositions and methods of the present disclosure are 5-15 amino acids in length and have the amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F). In certain embodiments, the peptide is 5-8, 6-10, 7-11, 8-12, 9-13, 10-14, 11-15, or 12-15 amino acids in length. Exemplary peptides and salts thereof are described in Section 6.2.1.

[0026] Peptide conjugates and salts thereof may also be used in the compositions and methods of the present disclosure. The peptide conjugates include a peptide moiety that is conjugated to one or more (e.g., 1, 2, or 3) conjugate moieties. The peptide moiety may be 5 to 15 amino acids in length and may have the amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F. In certain embodiments, the peptide moiety is 5-8, 6-10, 7-11, 8-12, 9-13, 10-14, 11-15, or 12-15 amino acids in length. Exemplary peptide conjugates and salts thereof are described in Section 6.2.2.

[0027] 6.2.1 Peptides The peptide and salts thereof that may be used in the compositions and methods of the present disclosure have the amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F). When embodiments described herein refer to a "peptide", it should be understood that the embodiment encompasses the peptide itself, as well as salts of said peptides, unless otherwise required by context, even though the embodiment may not explicitly recite the expression "or a salt thereof" or the like.

[0028] The peptides can be 5-15 amino acids (i.e., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids) in length. In some embodiments, the peptides are 5 amino acids in length, in other embodiments, the peptides are 6 amino acids in length, in other embodiments, the peptides are 7 amino acids in length, in other embodiments, the peptides are 8 amino acids in length, in other embodiments, the peptides are 9 amino acids in length, in other embodiments, the peptides are 10 amino acids in length, in other embodiments, the peptides are 11 amino acids in length, in other embodiments, the peptides are 12 amino acids in length, in other embodiments, the peptides are 13 amino acids in length, in other embodiments, the peptides are 14 amino acids in length, in other embodiments, the peptides are 15 amino acids in length.

[0029] Peptides generally have the amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1). Thus, in some embodiments, the peptide comprises or consists of the amino acid sequence SSTQA (SEQ ID NO:5). In other embodiments, the peptide comprises or consists of the amino acid sequence STQAQ (SEQ ID NO:6). In other embodiments, the peptide comprises or consists of the amino acid sequence TQAQQ (SEQ ID NO:7). In other embodiments, the peptide comprises or consists of the amino acid sequence QAQQS (SEQ ID NO:8). In other embodiments, the peptide comprises or consists of the amino acid sequence AQQSW (SEQ ID NO:9). In other embodiments, the peptide comprises or consists of the amino acid sequence AQQSF (SEQ ID NO:10). In other embodiments, the peptide comprises or consists of the amino acid sequence LSSTQ (SEQ ID NO:11). In other embodiments, the peptide comprises or consists of the amino acid sequence AQQSY (SEQ ID NO:12).

[0030] In certain aspects, the peptide has the amino acid sequence LSSTQAQQSX 1(SEQ ID NO:1). Thus, in some embodiments, the peptide comprises or consists of the amino acid sequence LSSTQA (SEQ ID NO:13). In other embodiments, the peptide comprises or consists of the amino acid sequence SSTQAQ (SEQ ID NO:14). In other embodiments, the peptide comprises or consists of the amino acid sequence STQAQQ (SEQ ID NO:15). In other embodiments, the peptide comprises or consists of the amino acid sequence TQAQQS (SEQ ID NO:16). In other embodiments, the peptide comprises or consists of the amino acid sequence QAQQSY (SEQ ID NO:17). In other embodiments, the peptide comprises or consists of the amino acid sequence QAQQSW (SEQ ID NO:18). In other embodiments, the peptide comprises or consists of the amino acid sequence QAQQSF (SEQ ID NO:19). In other embodiments, the peptide comprises or consists of the amino acid sequence WLSSTQ (SEQ ID NO:20). In other embodiments, the peptide comprises or consists of the amino acid sequence AQQSYW (SEQ ID NO:21).

[0031] In another aspect, the peptide has the amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1). Thus, in some embodiments, the peptide comprises or consists of the amino acid sequence LSSTQAQ (SEQ ID NO:22). In other embodiments, the peptide comprises or consists of the amino acid sequence SSTQAQQ (SEQ ID NO:23). In other embodiments, the peptide comprises or consists of the amino acid sequence STQAQQS (SEQ ID NO:24). In other embodiments, the peptide comprises or consists of the amino acid sequence TQAQQSY (SEQ ID NO:25). In other embodiments, the peptide comprises or consists of the amino acid sequence TQAQQSW (SEQ ID NO:26). In other embodiments, the peptide comprises or consists of the amino acid sequence TQAQQSF (SEQ ID NO:27).

[0032] In yet another aspect, the peptide has the amino acid sequence LSSTQAQQSX 1(SEQ ID NO:1). Thus, in some embodiments, the peptide comprises or consists of the amino acid sequence LSSTQAQQ (SEQ ID NO:28). In other embodiments, the peptide comprises or consists of the amino acid sequence SSTQAQQS (SEQ ID NO:29). In other embodiments, the peptide comprises or consists of the amino acid sequence STQAQQSY (SEQ ID NO:30). In other embodiments, the peptide comprises or consists of the amino acid sequence STQAQQSW (SEQ ID NO:31). In other embodiments, the peptide comprises or consists of the amino acid sequence STQAQQSF (SEQ ID NO:32).

[0033] In yet a further aspect, the peptide has the amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1). Thus, in some embodiments, the peptide comprises or consists of the amino acid sequence SSTQAQQSW (SEQ ID NO:33). In other embodiments, the peptide comprises or consists of the amino acid sequence SSTQAQQSF (SEQ ID NO:34). In other embodiments, the peptide comprises or consists of the amino acid sequence LSSTQAQQS (SEQ ID NO:35). In other embodiments, the peptide comprises or consists of the amino acid sequence SSTQAQQSY (SEQ ID NO:36).

[0034] In yet a further aspect, the peptide has the amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) and is 10, 11, 12, 13, 14, or 15 amino acids in length. In some embodiments, the peptide comprises or consists of the amino acid sequence LSSTQAQQSY (SEQ ID NO:2). In other embodiments, the peptide comprises or consists of the amino acid sequence LSSTQAQQSW (SEQ ID NO:3). In other embodiments, the peptide comprises or consists of the amino acid sequence LSSTQAQQSF (SEQ ID NO:4).

[0035] In another embodiment, the peptide comprises or consists of LSSTQAQQSYW (SEQ ID NO: 38). In another embodiment, the peptide comprises or consists of WLSSTQAQQSY (SEQ ID NO: 39). In another embodiment, the peptide comprises or consists of WLSSTQAQQSYW (SEQ ID NO: 40). In another embodiment, the peptide comprises or consists of ESFFLSSTQAQQSY (SEQ ID NO: 41).

[0036] Peptides that are 6 to 15 amino acids in length (i.e., peptides that are 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in length) can include, for example, an amino acid sequence identified in one of the embodiments described above (i.e., a sequence having at least 5, 6, 7, 8, 9, or 10 contiguous amino acids from SEQ ID NO:1) and one or more amino acids naturally adjacent to the sequence LSSTQAQQSY (SEQ ID NO:2) in the soybean storage protein β-conglycinin. For example, a peptide that includes the amino acid sequence LSSTQ (SEQ ID NO:11) and is 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in length can include an amino acid sequence N-terminal to the LSSTQ (SEQ ID NO:11) sequence that corresponds to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids N-terminal to LSSTQAQQSY (SEQ ID NO:2) in the sequence of β-conglycinin. As another example, a peptide that includes the amino acid sequence AQQSY (SEQ ID NO: 12) and is 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in length can include an amino acid sequence C-terminal to AQQSY (SEQ ID NO: 12) that corresponds to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids C-terminal to LSSTQAQQSY (SEQ ID NO: 2) in the sequence of β-conglycinin.

[0037] NKPGRFESFFLSSTQAQQSX 1 LQGFSKNILE (where X 1is Y, W, or F) (SEQ ID NO: 42) is flanked by 10 amino acids at each of the N-terminus and C-terminus of the β-conglycinin sequence, LSSTQAQQSX 1 (SEQ ID NO: 1). Thus, the first 10 amino acids in SEQ ID NO: 42 represent the 10 amino acids N-terminal to LSSTQAQQSY (SEQ ID NO: 2) in the β-conglycinin sequence, and the last 10 amino acids in SEQ ID NO: 42 represent the 10 amino acids C-terminal to LSSTQAQQSY (SEQ ID NO: 2) in the β-conglycinin sequence.

[0038] In certain aspects, the sequence of the peptides used in the compositions and methods of the disclosure is derived from SEQ ID NO: 42. Thus, the disclosure provides a peptide that is 5-15 amino acids in length and comprises or consists of 5-15 contiguous amino acids from SEQ ID NO: 42, with the proviso that said peptide has the amino acid sequence LSSTQAQQSX 1 It contains at least 5 consecutive amino acids from (SEQ ID NO:1).

[0039] Peptides having sequence variations relative to SEQ ID NO: 42 are also contemplated herein. Thus, in other embodiments, the peptide may have an amino acid sequence that includes one or more amino acid substitutions compared to an amino acid sequence consisting of 5 to 15 contiguous amino acids from SEQ ID NO: 42, provided that the peptide does not have the unsubstituted amino acid sequence LSSTQAQQSX. 1 (SEQ ID NO: 1). The maximum number of amino acid substitutions that a given peptide may have relative to the sequence of 5-15 consecutive amino acids in SEQ ID NO: 42 may vary depending on the length of the peptide, ranging from 1 amino acid substitution for a peptide that is 6 amino acids long to 10 amino acid substitutions for a peptide that is 15 amino acids long, provided that the peptide does not contain the unsubstituted amino acid sequence LSSTQAQQSX 1(SEQ ID NO: 1). Acceptable amino acid substitutions include, but are not limited to, substitutions with conservative amino acids and / or amino acid analogs.

[0040] Preferably, a peptide having one or more amino acid substitutions compared to the corresponding sequence in SEQ ID NO:42 has one, two, three, four, five or more conservative amino acid substitutions compared to the corresponding amino acid in SEQ ID NO:42.

[0041] In some embodiments, a peptide has an amino acid with an aromatic side chain (e.g., phenylalanine, tryptophan, or tyrosine) at the N-terminus and / or C-terminus of the peptide. In some embodiments, a peptide of the present disclosure has an amino acid with an aromatic side chain at the C-terminus but not at the N-terminus. In some embodiments, the peptide has a tryptophan at the C-terminus.

[0042] Peptides having amino acid substitutions compared to their counterparts in SEQ ID NO:42 may contain one or more amino acid analogs (e.g., 1, 2, 3, 4, or 5 amino acid analogs). Generally, as used herein, amino acid refers to the naturally occurring L-stereoisomer, and in some embodiments, each of the amino acids in the peptide is the naturally occurring L-stereoisomer. Amino acid analog refers to the D-stereoisomer or non-natural amino acids. For example, non-natural amino acids include, but are not limited to: Azetidine carboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tertiary butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid and thioproline.

[0043] The peptides may be entirely L-amino acids, entirely D-amino acids, or a mixture of L- and D-amino acids. Peptides that are entirely L-amino acids are preferred. Peptides that contain two or more asymmetric carbon atoms may be in any form, a mixture of enantiomers or diastereomers in any ratio.

[0044] The peptide may be in the form of a salt, preferably containing a pharma- ceutically acceptable counterion (e.g., chloride, sulfate, citrate, phosphate, acetate, sodium, potassium, calcium, magnesium). The peptide salt may be an acid or base addition salt. Exemplary acids that may be used to make acid addition salts include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid, citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid. In some embodiments, the peptide is in the form of a hydrochloride salt. Exemplary bases that may be used to make base addition salts include sodium hydroxide, potassium hydroxide, alkali metal bases (e.g., lithium hydroxide, calcium hydroxide) and alkaline earth metal salt bases (e.g., magnesium hydroxide). Additional acids and bases that can be used to make pharma- ceutically acceptable salts are described in Stahl and Wermuth, eds., 2008, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Verlag Helvetica Chimica Acta, Zurich, Switzerland, the contents of which are incorporated by reference herein in their entirety.

[0045] The peptides are obtained according to methods known in the art, for example, by liquid phase peptide synthesis or solid phase peptide synthesis (for example, as described in Benoiton, N., 2006, Chemistry of Peptide Synthesis, CRC Press, Baca Raton, FL; Howl, J., ed., 2005, Peptide Synthesis and Applications, Humana Press, Totowa, NJ; Chan and White, ed., 2000, Fmoc Solid Phase Synthesis: A Practical Approach, Oxford University Press, Oxford, UK). Custom peptide synthesis is also commercially available from many suppliers (for example, ABI Scientific (Sterling, VA); AnaSpec (Freemont CA); Pepscan, (Lelystad, Netherlands), Neo Scientific (Cambridge, MA); Sigma-Aldrich (St. Louis, MO)).

[0046] 6.2.2 Peptide conjugates Peptide conjugates and salts thereof that can be used in the compositions and methods of the present disclosure include peptide moieties and conjugate moieties. Conjugation of conjugate moieties to peptides can provide, for example, improved aqueous solubility, improved stability, and reduced clearance compared to unconjugated peptides (Hamley, 2014, Biomacromolecules 15:1543-1559). Thus, peptide conjugates can be more suitable as therapeutic agents in some cases compared to their unconjugated counterparts. Exemplary peptide moieties are described in Section 6.2.2.1, and exemplary conjugate moieties are described in Section 6.2.2.2. When an embodiment described herein refers to a "peptide conjugate," it should be understood that the embodiment includes the peptide conjugate itself, as well as salts of the peptide conjugate, even if the embodiment may not explicitly recite the expression "or a salt thereof" or the like, unless otherwise required by context. It should be further understood that the term "peptide conjugate", as used herein, does not encompass peptides whose amino acid sequence corresponds to a contiguous amino acid sequence found in a naturally occurring peptide or protein, where a portion of said amino acid sequence is optionally referred to as the "peptide portion" and another portion of said peptide sequence is optionally referred to as the "conjugate portion".

[0047] 6.2.2.1 Peptide moiety The peptide portion has the amino acid sequence LSSTQAQQSX 1 The peptide moiety has an amino acid sequence that includes or consists of at least 5 consecutive amino acids from (SEQ ID NO:1). The peptide moiety is linked (i.e., covalently linked) to one or more conjugate moieties (e.g., 1, 2, 3, 4, or 5 conjugate moieties). The peptides described in Section 6.2.1 and WO 2018 / 047852 (the contents of which are incorporated by reference in their entirety) can be used as peptide moieties.

[0048] 6.2.2.2 Combined part The peptide conjugate comprises one or more conjugate moieties (e.g., 1, 2, 3, 4, or 5 conjugate moieties) attached to the peptide moiety. The conjugate moiety may be attached to the N-terminal amino acid, the C-terminal amino acid, an amino acid that is neither the N-terminal nor the C-terminal amino acid, or a combination thereof. For example, the peptide conjugate may comprise one conjugate moiety. Preferably, the conjugate moiety is either attached to the N-terminal amino acid of the peptide moiety or to the C-terminal amino acid of the peptide moiety. As another example, the peptide conjugate may comprise two conjugate moieties, one of which is preferably attached to the N-terminal amino acid of the peptide moiety and the other of which is preferably attached to the C-terminal amino acid of the peptide moiety.

[0049] In embodiments in which the peptide conjugate comprises multiple conjugate moieties, each of the conjugate moieties may be the same, some of the conjugate moieties may be the same and others may be different, or all of the conjugate moieties may be different. For example, a peptide conjugate having two conjugate moieties may have two identical conjugate moieties. Alternatively, a peptide conjugate having two conjugate moieties may have two different conjugate moieties. As another example, a peptide conjugate having three conjugate moieties may have three identical conjugate moieties, three different conjugate moieties, or two identical conjugate moieties and one different conjugate moiety.

[0050] A conjugate moiety can be attached to a peptide moiety, for example, at one of the amino acid side chains, the backbone, the N-terminal amino group, or the C-terminal carboxylic acid group of the peptide moiety. For example, a conjugate moiety can be attached to an amino acid side chain to form a chemically modified amino acid (e.g., methionine sulfoxide, methionine sulfone, S-(carboxymethyl)-cysteine, S-(carboxymethyl)-cysteine ​​sulfoxide, and S-(carboxymethyl)-cysteine ​​sulfone). Other side chain modifications include acylation of lysine ε-amino group, N-alkylation of arginine, histidine, or lysine, and alkylation of carboxylic acid group of glutamic acid or aspartic acid. A conjugate moiety can be attached to the peptide backbone, for example, to a nitrogen atom in the backbone (e.g., a methyl conjugate moiety can be introduced into the backbone of a peptide conjugate by using N-methyl amino acid to synthesize the peptide). A conjugate moiety can be attached to the N-terminal amino group of the peptide moiety, for example, to provide an N-terminus with an N-lower alkyl, N-di-lower alkyl, or N-acyl modification. A conjugate moiety can be attached to the C-terminal carboxy group, for example, to provide a peptide conjugate with an amide, lower alkyl amide, dialkyl amide, or lower alkyl ester at the C-terminus of the conjugate. Lower alkyl refers to a C 1 -C 4 It means alkyl.

[0051] Exemplary conjugate moieties that can be used in the peptide conjugates include polymers, amine groups (e.g., amino (-NH 2 ), alkylamino and dialkylamino), acyl groups (e.g., formyl or acetyl), alkyl groups (e.g., C 1 -C 4 alkyl), phosphate groups, lipids and sugars.

[0052] In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise a polymer. Exemplary polymers that may be used as conjugate moieties include polyethylene glycol, polyvinylpyrrolidone, polylactic-co-glycolic acid, N-(2-hydroxypropyl) methacrylamide copolymer, polyglutamic acid, and polysaccharides. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise polyethylene glycol. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise polyvinylpyrrolidone. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise polylactic-co-glycolic acid. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise N-(2-hydroxypropyl) methacrylamide copolymer. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise a polyglutamic acid, In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise a polysaccharide.

[0053] In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include an amine group. Exemplary amine groups include amino (-NH 2 ), alkylamino, and dialkylamino groups. The alkyl groups include, for example, C 1 -C 4In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include an amino group. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include an alkylamino group. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include a dialkylamino group.

[0054] In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include an acyl group. Exemplary acyl groups include formyl and acetyl groups. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include a formyl group. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include an acetyl group.

[0055] In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include an alkyl group. In exemplary embodiments, the alkyl group is a lower alkyl group (e.g., methyl or ethyl). In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include a methyl group. In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include an ethyl group.

[0056] In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include a phosphate group attached to the side chain of, for example, serine, threonine, or tyrosine.

[0057] In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate comprise a lipid.

[0058] In some embodiments, at least one, more than one, or all of the conjugate moieties in the peptide conjugate include a sugar.

[0059] In some embodiments, the peptide conjugate comprises one or more of the peptide modifications described in PCT International Publication Nos. WO 2016 / 140277A1 or WO 2018 / 047852, the contents of which are incorporated by reference in their entireties.

[0060] Processes for attaching conjugate moieties to peptide moieties are known in the art and can be used to obtain the peptide conjugates described herein (e.g., Basle et al., 2010, Chemistry & Biology 17:213-227; Benoiton, N., 2006, Chemistry of Peptide Synthesis, CRC Press, Boca Raton, FL; Ernst and Leumann, eds., 1995, Modem Synthetic Methods, Verlag Helvetica Chimica Acta, Basel, Switzerland; Hamley, 2014, Biomacromolecules 15:1543” 1559; Lundblad, R., 1995, Techniques in Protein Modification, CRC Press, Boca Raton, FL). Custom synthesis of peptide conjugates is also commercially available from a number of suppliers (e.g., ABI Scientific (Sterling, VA); AnaSpec (Freemont CA); Pepscan, (Lelystad, Netherlands), Neo Scientific (Cambridge, MA); Sigma-Aldrich (St. Louis, MO), which provide a variety of peptides with N-terminal conjugate moieties (e.g., acetyl, formyl, fatty acids, and alkylamino groups), C-terminal conjugate moieties (e.g., amide, alkylamino, and alkyl groups), fatty acid conjugated peptides, polyethylene glycol conjugated peptides, and phosphate conjugate moieties (e.g., including phosphoserine, phosphothreonine, or phosphotyrosine).

[0061] The peptide conjugate may preferably be in the form of a salt containing a pharma- ceutically acceptable counterion (e.g., chloride, sulfate, citrate, phosphate, acetate, sodium, potassium, calcium, magnesium). The salt of the peptide conjugate may be an acid addition salt or a base addition salt. Exemplary acids that may be used to make acid addition salts include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid, citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid. Exemplary bases that may be used to make base addition salts include sodium hydroxide, potassium hydroxide, alkali metal bases (e.g., lithium hydroxide, calcium hydroxide), and alkaline earth metal salt bases (e.g., magnesium hydroxide). Additional acids and bases that can be used to make pharma- ceutically acceptable salts are described in Stahl and Wermuth, eds., 2008, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Verlag Helvetica Chimica Acta, Zurich, Switzerland, the contents of which are incorporated by reference herein in their entirety.

[0062] 6.3 Pharmaceutical Compositions In some aspects, the present disclosure provides a pharmaceutical composition comprising the peptide as described in section 6.2, its pharmaceutically acceptable salt, peptide conjugate, or its pharmaceutically acceptable salt.The pharmaceutical composition is preferably formulated for oral administration.The pharmaceutical composition can be prepared according to standard methods in the art (e.g., as described in Allen et al., eds., 2012, Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, London, UK).

[0063] In some aspects, the disclosure provides for the use of a peptide, a pharma- ceutically acceptable salt thereof, peptide conjugate, or a pharma- ceutically acceptable salt thereof as described in Section 6.2 in the manufacture of a medicament (e.g., a medicament for treating a subject having or at risk of having a disease or condition described in Section 6.4).

[0064] 6.4 Treatment Method The compounds and compositions of the present disclosure can be used to treat or prevent a variety of diseases, disorders and conditions. The present disclosure provides therapeutic uses for the compounds and compositions disclosed herein, including for treating diseases, disorders and conditions amenable to treatment with vagus nerve stimulation and / or modulation of histamine and / or norepinephrine levels and / or modulation of the inflammatory cytokine TNF-α.

[0065] In some aspects, the present disclosure provides a method for treating a subject suffering from or at risk of an inflammatory condition, comprising administering to the subject a compound or composition of the present disclosure in an amount effective to treat the subject. As will be appreciated by those skilled in the art, a variety of conditions have an inflammatory aspect and can be considered inflammatory conditions (e.g., inflammatory bowel disease, rheumatoid arthritis, and schizophrenia).

[0066] In some aspects, the present disclosure provides a method for treating a subject suffering from or at risk of suffering from schizophrenia or psychosis, comprising administering to the subject a compound or composition of the present disclosure in an amount effective to treat the subject. In some embodiments, the subject suffers from schizophrenia. In some embodiments, the subject exhibits psychotic behavior.

[0067] Schizophrenia is characterized by positive symptoms (e.g., delusions and hallucinations), negative symptoms, mood abnormalities, and cognitive deficits, often resulting in severe functional impairment (Yasui-Furukori, 2012, Drug Des Devel Therapy 6:107-115). Treatment can include, for example, improving or slowing the progression of one or more negative symptoms of schizophrenia or psychosis. Negative symptoms include asociality, anhedonia, allopathic, affective flattening, apathy, amotivation, blunted affect, anergy, apathy, depression, low mood, and cognitive impairment. The cognitive impairment can be, for example, a deficit in verbal working memory, spatial working memory, verbal fluency, verbal learning, or a combination thereof. Negative symptoms, and changes in such symptoms, can be measured using a variety of scales and scores, such as the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987, Schizophr Bull. 13(2):261-76), the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1982, Arch Gen Psychiatry 39(7):784-8), the Personal and Social Performance (PSP) scale (Morosini et al., 2000, Acta Psychiatr Scand. 101(4):323-9), and the Clinical Global Impression Improvement (CGI-I) scale (Busner & Targum, 2007, Psychiatry (Edgmont). 4(7):28-37), and the Clinical Global Impression Severity (CGI-S) scale (Busner & Targum, 2007, Psychiatry (Edgmont). 4(7):28-37).Treating a subject with a compound or composition of the present disclosure can include improving or slowing the worsening of one or more negative symptoms as measured by one or more of these scales or scores, or portions thereof.

[0068] In another aspect, the present disclosure provides a method for treating a subject suffering from a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis (ALS)), comprising administering to the subject a compound or composition of the present disclosure in an amount effective to treat the subject. The treatment may include improving or slowing the progression of one or more negative symptoms of the neurodegenerative disease (e.g., antisociality, anhedonia, allopathic, affective flattening, apathy, amotivation, blunted affect, anergy, depression, low mood, and cognitive impairment). Negative symptoms, and changes in such symptoms, may be assessed by various scales and scores (e.g., those described in the previous paragraph).

[0069] In some aspects, the present disclosure provides a method for treating a subject suffering from Parkinson's disease, comprising administering to the subject a compound or composition of the present disclosure in an amount effective for treating the subject.The treatment can include improving or slowing the progression of one or more non-motor symptoms of Parkinson's disease.The non-motor symptoms of Parkinson's disease include sensory symptoms (e.g., numbness, restlessness, pain, chest discomfort, anosmia), cognitive symptoms (e.g., mood changes, depression, anxiety, panic attacks, fatigue, confusion, slow thinking), and autonomic symptoms (e.g., hot / cold, bladder problems, sweating, abdominal discomfort, constipation, drooling (drooling or excessive salivation), frequent and / or urgent urination, erectile dysfunction) (see, for example, Barone et al., 2009, Mov Disord. 24(11):1641-9). Non-motor symptoms, and changes in such symptoms, can be assessed by various scales and scores, such as the Non-motor symptoms Scale (NMSS) (Chaudhuri et al., 2007, Movement Disorders 22(13):1901-11), the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) non-motor symptoms score (Goetz et al., International Parkinson and Movement Disorder Society, updated 13 August 2019; www.movementdisorders.org / MDS-Files1 / PDFs / MDS-UPDRS_English__FINAL.pdf), and the Fatigue Severity Scale (FSS) score (Krupp et al., 1989, Arch Neurol.46(10):1121-3), Beck's Depression Inventory II (BDI-II) score (Beck, Steer, & Brown, 1996), Beck Anxiety Inventory (BAI) score (Beck et al., 1988, J Consult Clin Phychol. 56(6):893-7), Montreal Cognitive Assessment (MoCA) score (Nasreddine et al., 2005, J Am GeriatrSoc. 53(4):695-9), scores on the Cogstate test(s) (cogstate.com), Clinical Global Impression Improvement (CGI-I) overall score or non-motor symptoms score (Busner & Targum, 2007, Psychiatry (Edgmont). 4(7):28-37), Clinical Global Impression Severity (CGI-S) overall or non-motor symptoms score (Busner & Targum, 2007, Psychiatry (Edgmont). 4(7):28-37), and the Parkinson's Disease Questionnaire-39 (PDQ-39) (Jenkinson et al., 1997, Age Ageing.26(5):353-7). The Cogstate test includes the following computerized cognitive assessments: Behavioral Pattern Separation Object test; Continuous Paired Associate Learning Test; Face Name Associative Memory Exam; Groton Maze Learning Test; Identification Test; International Daily Symbol Substitution Tests (medicine or symbol); International Shopping List Test; One Back Test; One Card Learning Test; Sustained Attention Test; Sustained Attention to Response Test; and Two Back Test.

[0070] In another aspect, the disclosure provides a method for treating a subject suffering from a gastrointestinal disease or condition, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0071] In another aspect, the disclosure provides a method for treating a subject suffering from irritable bowel syndrome, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0072] In another aspect, the disclosure provides a method for treating a subject suffering from inflammatory bowel disease, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0073] In another aspect, the disclosure provides a method for treating a subject suffering from ulcerative colitis, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0074] In another aspect, the disclosure provides a method for treating a subject suffering from Crohn's disease, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0075] In another aspect, the disclosure provides a method for treating a subject suffering from constipation, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0076] In another aspect, the disclosure provides a method for treating a subject suffering from pain, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0077] In another aspect, the disclosure provides a method for treating a subject suffering from visceral pain, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0078] In another aspect, the disclosure provides a method for treating a subject suffering from rheumatoid arthritis, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0079] In another aspect, the disclosure provides a method for treating a subject suffering from a migraine headache, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0080] In another aspect, the disclosure provides a method for treating a subject suffering from a headache, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0081] In another aspect, the disclosure provides a method for treating a subject suffering from substance abuse (e.g., a substance use disorder such as a drug use disorder, a polysubstance use disorder, an alcohol use disorder, a nicotine use disorder, or a tobacco use disorder), comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject. In some embodiments, the subject has a substance use disorder. In some embodiments, the subject has a polysubstance use disorder. In some embodiments, the subject has an alcohol use disorder. In some embodiments, the subject has a nicotine use disorder. In some embodiments, the subject has a tobacco use disorder.

[0082] In another aspect, the present disclosure provides a method for treating a subject suffering from drug addiction, comprising administering to the subject a compound or composition of the present disclosure in an amount effective for treating the subject.Examples of drug addiction include opioid addiction, such as addiction to morphine, heroin, oxycodone or fentanyl; cocaine addiction; and benzodiazepine addiction (such as addiction to diazepine, alprazolam or clonazepa).

[0083] In another aspect, the present disclosure provides a method for treating a subject suffering from a seizure disorder, comprising administering to the subject a compound or composition of the present disclosure in an amount effective to treat the subject. In some embodiments, the seizure disorder is epilepsy. In some embodiments, the seizure disorder is orphan epilepsy (see, for example, Perucca et al., 2020, Lancet 19:544-556).

[0084] In another aspect, the disclosure provides a method for treating a subject suffering from major depressive disorder, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0085] In another aspect, the disclosure provides a method for treating a subject suffering from atypical depression, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0086] In another aspect, the disclosure provides a method for treating a subject suffering from a major depressive episode (MDE) (e.g., atypical MDE), comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0087] In another aspect, the present disclosure provides a method for treating a subject suffering from depression in the presence of a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or ALS), comprising administering to the subject a compound or composition of the present disclosure in an amount effective to treat the subject. Depression in subjects with neurodegenerative diseases is typically resistant to traditional antidepressant treatments (Hussain et al., 2020, Gureus 12(11): e11613).

[0088] In another aspect, the disclosure provides a method for treating a subject suffering from treatment-resistant depression, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0089] In another aspect, the disclosure provides a method for treating a subject suffering from a cognitive disorder, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0090] In another aspect, the present disclosure provides a method for treating a subject suffering from Alzheimer's disease, comprising administering to the subject a compound or composition of the present disclosure in an amount effective to treat the subject. In another aspect, the present disclosure provides a method for treating a subject suffering from COVID-19 associated cognitive impairment and / or depression, comprising administering to the subject a compound or composition of the present disclosure in an amount effective to treat the subject.

[0091] In another aspect, the disclosure provides a method for treating a subject suffering from ADHD, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0092] In another aspect, the disclosure provides a method for treating a subject suffering from an autism spectrum disorder, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0093] In another aspect, the disclosure provides a method for treating a subject suffering from a pervasive developmental disorder (e.g., Asperger's syndrome or Rett's syndrome), comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0094] In another aspect, the disclosure provides a method for treating a subject suffering from a pervasive developmental disorder not otherwise specified, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0095] In another aspect, the disclosure provides a method for treating a subject suffering from multiple sclerosis, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0096] In another aspect, the disclosure provides a method for treating a subject suffering from PTSD, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0097] In another aspect, the disclosure provides a method for treating a subject suffering from a sleep disorder, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0098] In another aspect, the disclosure provides a method for treating a subject suffering from insomnia, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0099] In another aspect, the disclosure provides a method for treating a subject suffering from daytime fatigue, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0100] In another aspect, the disclosure provides a method for treating a subject suffering from REM sleep behavior disorder, comprising administering to the subject a compound or composition of the disclosure in an amount effective to treat the subject.

[0101] In another aspect, the disclosure provides a method for improving sleep in a subject, the method comprising administering to the subject a compound or composition of the disclosure in an amount effective to improve sleep in the subject.

[0102] In another aspect, the present disclosure provides a method for improving cognitive function in a subject, comprising administering to the subject a compound or composition of the present disclosure in an amount effective to improve cognitive function. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0103] In another aspect, the disclosure provides a method for improving mood in a subject, comprising administering to the subject a compound or composition of the disclosure in an amount effective to improve mood. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0104] In another aspect, the disclosure provides a method for improving or slowing the deterioration of a subject's overall Patient Health Questionnaire-9 (PHQ-9) score, comprising administering to the subject a compound or composition of the disclosure in an amount effective to improve or slow the deterioration of the subject's overall PHQ-9 score. The subject can be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0105] In another aspect, the disclosure provides a method for improving or slowing the deterioration of a subject's score on one or more of the PHQ-9 questions (e.g., PHQ-9 questions 1, 2, 3, or 6), the method comprising administering to the subject a compound or composition of the disclosure in an amount effective to improve or slow the deterioration of the subject's score on the PHQ-9 questions.

[0106] In another aspect, the present disclosure provides a method for improving or slowing the deterioration of one or more of a subject's CogState Groton Maze Test (GMLT), CogState Discrimination Test (IDN), or CogState One-Card Test (OCL) results, comprising administering to the subject a compound or composition of the present disclosure in an amount effective to improve or slow the deterioration of the subject's results on the GMLT, IDN, and / or OCL. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0107] In another aspect, the present disclosure provides a method for improving or slowing the deterioration of at least one of alpha band power or gamma band power of an electroencephalogram (EEG) of a subject. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0108] In some embodiments of the methods described herein, the subject has elevated TNF-α levels, e.g., relative to a reference range obtained from a healthy subject. For example, in some embodiments, a subject with elevated TNF-α levels has a serum TNF-α level of greater than 5.6 pg / ml, e.g., as measured by a sandwich immunoassay (e.g., Eurofins Viracor TNF-α serum test; www.eurofins-viracor.com / clinical / test-menu / 1220-tnf-alpha-tnf-a-serum).

[0109] The subject of the methods described herein is preferably a mammal, such as a human or a domesticated pet (e.g., cat, dog). The subject can be of any age, but is preferably an adult (e.g., a human subject that is 18 years or older, 25 years or older, 35 years or older, 45 years or older, 55 years or older, etc.). In some embodiments, the subject is an elderly person (e.g., a human subject that is 65 years or older, 70 years or older, 75 years or older, or 80 years or older).

[0110] The compounds and pharmaceutical compositions containing them can be administered orally, topically, rectally, or parenterally. Oral administration is preferred. The method of administration can vary depending on the condition and the age of the subject.

[0111] Suitable daily dosages of the compounds may range from 0.005 mg / kg to 500 mg / kg of body weight per day (e.g., 0.005 mg / kg to 100 mg / kg, 0.005 mg / kg to 30 mg / kg, 0.005 mg / kg to 1 mg / kg, 0.01 mg / kg to 30 mg / kg, 0.01 mg / kg to 3 mg / kg, 0.01 mg / kg to 1 mg / kg, 0.02 mg / kg to 5 mg / kg, 0.02 mg / kg to 2 mg / kg, 0.02 mg / kg to 1 mg / kg). Alternatively, the compound may be administered in a fixed dose ranging from 0.1 mg to 50 g (e.g., 0.1 mg to 10 g, 0.1 mg to 3 g, 0.1 mg to 100 mg, 0.1 mg to 1 mg, 0.3 mg to 3 g, 0.3 mg to 100 mg, 20 mg to 2 g, 20 mg to 1 g, 0.5 g to 2 g, 0.5 g to 1 g, or 1 g to 2 g) per day. For administration of a pharmaceutical composition, an amount of the pharmaceutical composition containing an amount of the compound within one of the aforementioned ranges may be administered. Exemplary daily doses of the compounds described herein (e.g., the peptide LSSTQAQQSY (SEQ ID NO: 2) or a salt thereof) include 60 mg / day, 180 mg / day, and 540 mg / day. The daily dose may be administered as a single dose (e.g., a single dose of 60 mg, 180 mg, or 540 mg) or multiple doses. EXAMPLES

[0112] 7. Working Example 7.1 Example 1: LSSTQAQQSY (SEQ ID NO:2) Brain Microdialysis Study Studies were conducted to determine the CNS neurotransmitter responses elicited by oral administration of the peptide LSSTQAQQSY (SEQ ID NO:2).

[0113] Male C57BI / 6 mice were instrumented with microdialysis probes in the prefrontal cortex (which regulates sensory processing, memory, and emotion) or striatum (required for behavioral reinforcement by natural rewards). Animals were orally administered a single 3 mg / kg dose of peptide or vehicle. Brain dialysate samples were collected pre-dose and every 30 min for 4 h after dosing. Dopamine, norepinephrine, serotonin, histamine, glutamate, GABA, and glycine concentrations in the dialysate samples were determined by HPLC-MS.

[0114] The results are shown in Figures 1A to 1G and Figures 2A to 2G.

[0115] Statistically significant changes in histamine and norepinephrine in the prefrontal cortex were observed. No significant changes were observed in other neurotransmitters in the prefrontal cortex or in all evaluated neurotransmitters in the striatum.

[0116] 7.2 Example 2: Inhibition of inflammation by LSSTQAQQSY (SEQ ID NO: 2) Vagus nerve stimulation has been reported to suppress lipopolysaccharide (LPS)-induced increases in serum levels of the proinflammatory cytokine TNF-α (see, e.g., Tarnawski et al., 2018, Front. Immunol. 9:2648; Komegae et al., 2018, Brain Behav Immun. 73:441-449). Since the peptide LSSTQAQQSY (SEQ ID NO:2) is believed to act via the vagus nerve, the ability of the peptide to suppress TNF-α after LPS injection was evaluated.

[0117] Mice were administered LPS at a dose of 10 μg / kg (ip). The peptide LSSTQAQQSY (SEQ ID NO: 2) was administered twice to the mice at 0.3 mg / kg, 3 mg / kg, or 10 mg / kg (po), 2.5 and 3.5 hours after LPS administration. Blood was collected 4 hours after LPS administration. Plasma levels of TNF-α were subsequently measured by ELISA.

[0118] The results are shown in Figure 3. A trend towards TNF-α suppression was observed in animals administered the peptide after in vivo challenge with LPS, indicating an anti-inflammatory effect of the peptide.

[0119] 7.3 Example 3: Phase 2 Study in Subjects with Schizophrenia (Prospective) A Phase 2, 4-week randomized placebo-controlled crossover trial with the peptide LSSTQAQQSY (SEQ ID NO:2) is conducted in subjects with schizophrenia with predominantly negative symptoms and cognitive deficits.

[0120] The study will have a 4-week treatment period (with a 7-day washout between treatment periods) comparing the peptide with a placebo.

[0121] The study population included men and women, aged 18-65 years, with schizophrenia (DSM-5 / SCID-5-CT) with predominantly negative symptoms and cognitive deficits.

[0122] The primary outcome measure was the mean change from baseline in the Positive and Negative Syndrome Scale (PANSS) negative symptom factor score.

[0123] Secondary outcome measures include the mean change from baseline in the negative symptom assessment (SANS) score; personal and social performance (PSP) total score; PANSS total score; PANSS factor score; PANSS subscale score; Clinical Global Impression-Improvement (CGI-I) total and negative symptom assessment score and Clinical Global Impression-Improvement Severity (CGI-S) total and negative symptom assessment score.Secondary outcome measures also include the percentage of participants who have a response as assessed by the PANSS negative symptom factor score; CGI-I total and negative symptom assessment score; CGI-S total and negative symptom assessment score.

[0124] Exploratory outcome measures will include brain activity and cognitive-behavioral task performance using a combination of functional magnetic resonance imaging (fMRI), arterial spin labeling (ASL-MRI), and population PK utilizing a memory activation task.

[0125] Treatment with the peptide ameliorates or slows the progression of one or more negative symptoms and / or cognitive deficits in subjects with schizophrenia that predominantly involves negative symptoms and cognitive deficits.

[0126] 7.4 Example 4: Phase 2 Study in Subjects with Parkinson's Disease and Predominantly Non-Motor Symptoms (Prospective) A Phase 2, 6-week randomized, placebo-controlled crossover trial is conducted with the peptide LSSTQAQQSY (SEQ ID NO: 2) in subjects with predominantly non-motor Parkinson's disease.

[0127] The study will have a 6 week treatment period (with a 7 day washout between treatment periods) comparing the peptide with a placebo.

[0128] The study population included men and women, aged 40 years or older, with predominantly non-motor Parkinson's disease (DSM-5 / ICD-10).

[0129] The primary outcome measure was the mean change from baseline in the Non-Motor Symptom Scale (NMSS) score.

[0130] Secondary outcome measures include non-motor symptoms (e.g., Part I, cognition, depression, anxiety, fatigue) of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS); motor symptoms (e.g., MDS-UPDRS, Parts II, III, IV); Fatigue Severity Scale (FSS) score; Beck Depression Inventory II (BDI-II) score; Beck Anxiety Inventory (BAI) score; Montreal Cognitive Assessment (MoCA) score; Cogstate score; CGI-I global and non-motor symptom rating score; CGI-S global and non-motor symptom rating score; mean change from baseline in the Parkinson's Disease Questionnaire-39 (PDQ-39). Exploratory outcome measures include brain activity and cognitive-behavioral task performance using a combination of functional magnetic resonance imaging (fMRI), arterial spin labeling (ASL-MRI), and population PK utilizing a memory activation task.

[0131] Treatment with the peptide ameliorates or slows the progression of one or more non-motor symptoms in subjects with predominantly non-motor Parkinson's disease.

[0132] 7.5 Example 5: Effect of LSSTQAQQSY (SEQ ID NO: 2) on Scopolamine-Induced Memory Impairment in Mice 7.5.1 Materials 7.5.1.1 Animals Male ICR mice (4-5 weeks old) were used in the study.

[0133] 7.5.1.2 Drugs The above peptide LSSTQAQQSY (SEQ ID NO: 2) and donepezil hydrochloride were used as test drugs.

[0134] 7.5.1.3 Test equipment The test was carried out in a step-down suppression avoidance device with dimensions of 12 cm x 2 cm x 18 cm in each chamber (Model: YLS-3T, Shandong Yiyan Technology Co., LTD., China). The bottom of each chamber was covered with a copper grid that could be electrified. A rubber platform was placed in the right corner of each chamber.

[0135] 7.5.2 Method 7.5.2.1 Drug Administration Male ICR mice in each group were treated with vehicle, donepezil hydrochloride (1.5mg / kg), and the above peptide LSSTQAQQSY (SEQ ID NO:2) (0.3mg / kg, 10mg / kg) by oral gavage once a day for 21 days. Two hours after the last administration, scopolamine hydrobromide (2mg / kg) was injected intraperitoneally to induce memory impairment.

[0136] 7.5.2.2 Fauna Fifty male ICR mice were divided into five groups (10 mice per group) according to average body weight, as detailed in Table 1. [Table 1]

[0137] 7.5.2.3 Process downtime prevention evaluation Training period: Mice were intraperitoneally injected with scopolamine hydrobromide solution at a dose of 2mg / kg for model, donepezil hydrochloride and LSSTQAQQSY (SEQ ID NO:2) groups, while mice in vehicle group were intraperitoneally injected with the same volume of 0.9% NaCl solution. 30 minutes after the injection of scopolamine hydrobromide solution, the mice were placed into the step-down chamber for 5 minutes to adapt, and then the mice received foot shock (82v voltage at 2mA current) during the training session. The mice could freely jump on and off the rubber stand during the shock.

[0138] Evaluation period: 24 hours after the training period, the mice were placed on the rubber platform and evaluated for 5 minutes. The latency of the first jump from the platform to the copper grid was observed and counted, and the latency in seconds was analyzed to evaluate memory improvement.

[0139] 7.5.2.4 Statistical analysis All results are presented as mean ± SEM, and data differences between groups were analyzed by t-test using the GraphPad Prism 8 statistical package (GraphPad Software Inc., San Diego, CA, USA) for paired comparisons. P < 0.05 was considered statistically significant.

[0140] 7.5.3 Results The latency in the model group was significantly shorter than that in the vehicle group (P<0.01). The latency in the positive control group, 1.5 mg / kg donepezil hydrochloride group, was significantly longer than that in the model group (P<0.01). The 0.3 mg / kg and 10 mg / kg peptide treatment groups all prolonged their latency, which was significantly different from the model group (P<0.05). The results are shown in FIG. 4. These results indicate that LSSTQAQQSY (SEQ ID NO: 2) improved memory impairment induced by scopolamine in mice, indicating that LSSTQAQQSY (SEQ ID NO: 2) and related peptides have the potential to treat cognitive impairment associated with Alzheimer's disease and other diseases.

[0141] 7.6 Example 6: LSSTQAQQSY (SEQ ID NO:2) Target Characterization Several screens were performed to characterize the molecular target of LSSTQAQQSY (SEQ ID NO:2). Initial screens included Trp channels (TRPA1, TRPV1), nutrient and metabolite sensing GPCRs (FFAR1, FFAR2, FFAR3, FFAR4, GPR119, CaS, GPR142, GPBAR1 and LPA5) and taste receptors; a genome-wide binding-based screen of all cell surface expressed receptors (about 6K receptors); and a large-scale screen of 168 GPCRs for agonist or antagonist activity. Initial screens were negative or provided non-reproducible hits.

[0142] Subsequently, a more universal and more sensitive GPCR screening strategy was used. In the screen, three possible targets were identified: GNRHR, AVPR1A, and AVPR2. Tests were then performed to identify and confirm the targets.

[0143] The effect of LSSTQAQQSY (SEQ ID NO: 2) was found to be blocked by the AVPR1A / AVPR2 inhibitor conivaptan in the tail suspension test (TST) (see WO 2016 / 140277). This suggests that the primary target of LSSTQAQQSY (SEQ ID NO: 2) is either AVPR1A or AVPR2 (Figures 5-6). The effect of LSSTQAQQSY (SEQ ID NO: 2) was found not to be blocked by the AVPR2 inhibitor tolvaptan (Figure 7). This suggests that the primary target of the peptide is not AVPR2. The effect of LSSTQAQQSY (SEQ ID NO: 2) was also found to be blocked by the AVPR1A / B inhibitor nerivaptan (Figure 8). This suggests that the primary target of the peptide is AVPR1A.

[0144] The test results are summarized in Table 2. [Table 2]

[0145] 7.7 Example 7: Mood and Cognition Improvement in Healthy Subjects in a Phase 1a / 1b Study A Phase 1a / 1b, randomized, placebo-controlled, crossover study of the peptide LSSTQAQQSY (SEQ ID NO: 2) was conducted in healthy subjects. The study population included men and women in good health.

[0146] The single ascending dose (SAD) group included four cohorts receiving 60 mg / day (cohorts SAD1 and SAD2), 180 mg / day (cohort SAD3), or 540 mg / day (cohort SAD4) of the peptide or placebo. The multiple ascending dose (MAD) group included three cohorts receiving 60 mg / day (cohort MAD1), 180 mg / day (cohort MAD2), or 540 mg / day (cohort MAD3) of the peptide or placebo for 7 days. All doses were administered orally.

[0147] 7.7.1. Results 7.7.1.1. Safety A few members of each cohort experienced mild adverse effects (generally gastrointestinal upset or throat irritation). Vital signs, electrocardiogram (ECG) data, and physical examinations were normal in all participants throughout the study.

[0148] 7.7.1.2. Patient Questionnaire The Patient Health Questionnaire-9 (PHQ-9), a standard questionnaire for assessing depression severity, was administered to subjects in cohorts MAD1-MAD3 approximately 4 hours after each of the placebo and peptide administration periods. Each of the nine questions asks the subject to what extent in the past two weeks he or she has had the following: [Table 3]

[0149] Each question is answered on a 0 to +3 scale (0 being never, +1 being several days, +2 being more than half a day, and +3 being almost every day).

[0150] Whether the peptides produced improvement above placebo in each PHQ-9 question was assessed.

[0151] Preliminary data indicate that administration of the peptides resulted in improvements in measures of mood, depression, sleep, consciousness, and / or alertness in cohort MAD3 (improvements in responses to PHQ-9 questions 1-3 and 6, overall PHQ-9 score summarized in Figure 9).

[0152] CogState Subjects in cohorts MAD1-MAD3 also underwent cognitive assessments (CogState Ltd., Melbourne, Vic., Australia): 1) Detection Test (DET), assessing psychomotor function; 2) Groton Maze Learning Test (GMLT), assessing executive function; 3) Discrimination Test (IDN), assessing attention; and 4) One Card Learning Test (OCL), assessing visual learning. Cognitive assessments were performed essentially simultaneously with administration of the PHQ-9 questionnaire to the subjects. It was qualitatively determined whether the peptides produced improvements over placebo in the four cognitive assessments.

[0153] Preliminary data indicates that the peptide has no significant effect on psychomotor function in healthy subjects (Figure 10). Preliminary data further indicates positive trends in GMLT (Figure 11), IDN (Figure 12), and OCL (not shown) after several days of treatment.

[0154] In conclusion, preliminary data from the study indicate that treatment with the peptide improved executive function, attention, and visual learning in the subjects.

[0155] 7.7.1.4. Alpha and Gamma Electroencephalography (EEG) Bands The different bands observed in the EEG are generally associated with different states of mental activity, as summarized in the following table: [Table 4]

[0156] Across the MAD cohort, quantitative EEG (qEEG) was recorded for some subjects immediately prior to administration of the final dose (day 7), as well as approximately 1, 2, 4, 8, and 12 hours after administration of the final dose. Power in each band was recorded immediately prior to administration of the first dose (day 10 provided a baseline (100%) against which post-dose EEG band power was normalized).

[0157] Preliminary data from the MAD1 cohort, each dose of which contained 60 mg of the peptide, showed a marked increase in alpha band power, from approximately 80% of baseline before administration of the final dose to approximately 150% of baseline just 1 hour after the final dose. Alpha band power changed from approximately 120% to approximately 200% by approximately 12 hours after the final dose. Gamma band power similarly increased from approximately 100-110% of baseline before administration of the final dose to approximately 140% of baseline 1 hour after the final dose, remaining above approximately 125% of baseline for 8 hours.

[0158] Preliminary data from the MAD2 cohort, each dose of which contained 180 mg of the peptide, also showed a significant increase in power in the alpha and gamma bands. Alpha band power increased from approximately 110% of baseline before the administration of the final dose to approximately 150% of baseline 2 hours after the final dose and remained above 110% of baseline until approximately 12 hours after the final dose. Gamma band power increased from approximately 100-110% of baseline before the administration of the final dose to approximately 125% of baseline 1 hour after the final dose and remained above 150% of baseline until approximately 12 hours after the final dose.

[0159] Preliminary data from the MAD3 cohort, each dose of which contained 540 mg of the above peptides, showed a decrease in alpha band power from approximately 100% of baseline prior to administration of the final dose to approximately 70-80% of baseline from 1-12 hours after administration of the final dose.

[0160] In summary, preliminary data from the studies indicate that treatment with the peptide at doses of 60 mg / day or 180 mg / day increases power in the alpha and gamma EEG bands, indicative of a state of relaxed awareness and focus.

[0161] 8. Specific embodiments, citations of references While various specific embodiments have been illustrated and described, it will be understood that changes may be made therein without departing from the spirit and scope of the present disclosure. The present disclosure is exemplified by the numbered embodiments set forth below. 1. (a) an inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease or ALS), a gastrointestinal disease or disorder (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., a substance use disorder such as drug use disorder, polysubstance use disorder, alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction, seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, depression in the presence of a neurodegenerative disease, cognitive impairment, COVID-19-associated cognitive impairment, and and / or treating a subject suffering from or at risk for depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, a sleep disorder (e.g., insomnia, daytime fatigue, or REM sleep behavior disorder); (b) improving sleep in a subject; or (c) improving cognition in a subject, optionally wherein with respect to (a)-(c), the subject has elevated TNF-α levels, the method comprising administering to the subject an effective amount of a peptide or a pharma- ceutical acceptable salt thereof, optionally wherein the peptide or a pharma-ceutical acceptable salt thereof is administered orally, wherein the peptide comprises: a. is 5 to 15 amino acids in length; and b. Amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F), method. 2. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of SSTQA (SEQ ID NO:5). 3. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of STQAQ (SEQ ID NO:6). 4. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of TQAQQ (SEQ ID NO: 7). 5. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of QAQQS (SEQ ID NO:8). 6. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of AQQSW (SEQ ID NO:9). 7. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of AQQSF (SEQ ID NO: 10). 8. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQ (SEQ ID NO:11). 9. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of AQQSY (SEQ ID NO: 12). 10. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQA (SEQ ID NO: 13). 11. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of SSTQAQ (SEQ ID NO: 14). 12. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of STQAQQ (SEQ ID NO: 15). 13. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of TQAQQS (SEQ ID NO: 16). 14. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of QAQQSY (SEQ ID NO: 17). 15. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of QAQQSW (SEQ ID NO: 18). 16. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of QAQQSF (SEQ ID NO: 19). 17. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of WLSSTQ (SEQ ID NO: 20). 18. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of AQQSYW (SEQ ID NO:21). 19. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQAQ (SEQ ID NO: 22). 20. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of SSTQAQQ (SEQ ID NO: 23). 21. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of STQAQQS (SEQ ID NO: 24). 22. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of TQAQQSY (SEQ ID NO: 25). 23. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of TQAQQSW (SEQ ID NO: 26). 24. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of TQAQQSF (SEQ ID NO: 27). 25. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQAQQ (SEQ ID NO: 28). 26. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of SSTQAQQS (SEQ ID NO: 29). 27. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of STQAQQSY (SEQ ID NO: 30). 28. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of STQAQQSW (SEQ ID NO:31). 29. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of STQAQQSF (SEQ ID NO: 32). 30. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of SSTQAQQSW (SEQ ID NO: 33). 31. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of SSTQAQQSF (SEQ ID NO: 34). 32. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQAQQS (SEQ ID NO: 35). 33. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of SSTQAQQSY (SEQ ID NO: 36). 34. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQAQQSY (SEQ ID NO: 2). 35. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQAQQSW (SEQ ID NO: 3). 36. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQAQQSF (SEQ ID NO: 4). 37. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of LSSTQAQQSYW (SEQ ID NO: 38). 38. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of WLSSTQAQQSY (SEQ ID NO: 39). 39. The method of embodiment 1, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof comprises or consists of WLSSTQAQQSYW (SEQ ID NO: 40). 40. The method of any one of embodiments 1-9, wherein the peptide is 5 amino acids in length. 41. The method of any one of embodiments 1-18, wherein the peptide is 6 amino acids in length. 42. The method of any one of embodiments 1-24, wherein the peptide is 7 amino acids in length. 43. The method of any one of embodiments 1-29, wherein the peptide is 8 amino acids in length. 44. The method of any one of embodiments 1-33, wherein the peptide is 9 amino acids in length. 45. The method of any one of embodiments 1-36, wherein the peptide is 10 amino acids in length. 46. ​​The method of any one of embodiments 1-38, wherein the peptide is 11 amino acids in length. 47. The method of any one of embodiments 1 to 39, wherein the peptide is 12 amino acids in length. 48. The method of any one of embodiments 1 to 39, wherein the peptide is 13 amino acids in length. 49. The method of any one of embodiments 1 to 39, wherein the peptide is 14 amino acids in length. 50. The method of any one of embodiments 1 to 39, wherein the peptide is 15 amino acids in length. 51. (a) an inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease or ALS), a gastrointestinal disease or disorder (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., a substance use disorder such as drug use disorder, polysubstance use disorder, alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction, a seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, depression in the presence of a neurodegenerative disease, cognitive impairment, COVID-19-associated cognitive impairment and / or depression, ADHD, autism spectrum disorder. (b) treating a subject suffering from or at risk for a sleep disorder (e.g., insomnia, daytime fatigue, or REM sleep behavior disorder); (b) improving sleep in a subject; or (c) improving cognition in a subject, optionally wherein with respect to (a)-(c), the subject has elevated TNF-α levels, the method comprising administering to the subject an effective amount of a peptide conjugate or a pharmacologic agent ... a. is 5 to 15 amino acids in length; and b. Amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F), method. 52. The method of embodiment 51, wherein the peptide moiety is a peptide as described in any one of embodiments 2 to 50. 53. The method of embodiment 51 or embodiment 52, wherein at least one of the one or more conjugate moieties comprises a polymer, an amino group, an acyl group, an alkyl group, a phosphate group, a lipid, or a sugar. 54. The method of embodiment 53, wherein at least one of the one or more conjugate moieties comprises a polymer. 55. The method of embodiment 54, wherein the polymer comprises polyethylene glycol, polyvinylpyrrolidone, polylactic-co-glycolic acid, N-(2-hydroxypropyl) methacrylamide copolymer, polyglutamic acid, or a polysaccharide. 56. The method of any one of embodiments 51-55, wherein at least one of the one or more conjugate moieties comprises an amine group. 57. The method of embodiment 56, wherein the amine group is an amino group, an alkylamino group, or a dialkylamino group. 58. The method of any one of embodiments 51-57, wherein at least one of the one or more conjugate moieties comprises an acyl group. 59. The method of embodiment 58, wherein the acyl group is a formyl group or an acetyl group. 60. The method of any one of embodiments 51-59, wherein at least one of the one or more conjugate moieties comprises an alkyl group. 61. The method of embodiment 60, wherein the alkyl group is a methyl group or an ethyl group. 62. The method of any one of embodiments 51-61, wherein at least one of the one or more conjugate moieties comprises a phosphate group. 63. The method of any one of embodiments 51-62, wherein at least one of the one or more conjugate moieties comprises a lipid. 64. The method of any one of embodiments 51-63, wherein at least one of the one or more conjugate moieties comprises a sugar. 65. The method of any one of embodiments 51-64, comprising a single conjugate moiety. 66. The method of embodiment 65, wherein the conjugate moiety is attached to the N-terminal amino acid of the peptide moiety. 67. The method of embodiment 65, wherein the conjugate moiety is attached to the C-terminal amino acid of the peptide moiety. 68. The method of any one of embodiments 51-67, comprising more than one conjugate moiety. 69. The method of embodiment 68, wherein all of the conjugate moieties are the same. 70. The method of embodiment 68, wherein not all of the conjugate moieties are the same. 71. The method of embodiment 68, wherein all of the conjugate moieties are different. 72. The method of embodiment 68, comprising a conjugate moiety attached to the N-terminal amino acid of the peptide moiety and a conjugate moiety attached to the C-terminal amino acid of the peptide moiety. 73. The method of embodiment 72, wherein the conjugate moiety attached to the N-terminal amino acid of the peptide moiety is the same as the conjugate moiety attached to the C-terminal amino acid of the peptide moiety. 74. The method of embodiment 72, wherein the conjugate moiety attached to the N-terminal amino acid of the peptide moiety is different from the conjugate moiety attached to the C-terminal amino acid of the peptide moiety. 75. The method of any one of embodiments 1-74, wherein the subject is suffering from or at risk of schizophrenia or psychosis. 76. The method of embodiment 75, wherein the subject is suffering from schizophrenia. 77. The method of any one of embodiments 75-76, wherein the subject exhibits psychotic behavior. 78. The method of any one of embodiments 75-77, wherein the treating step comprises ameliorating or slowing the progression of one or more negative symptoms of schizophrenia or psychosis. 79. The method of embodiment 78, wherein the one or more negative symptoms comprise antisociality, anhedonia, allogy, affective flattening, apathy, amotivation, blunted affect, anergy, apathy, depression, decreased mood, cognitive impairment, or a combination thereof. 80. The method of embodiment 79, wherein the one or more negative symptoms include antisocial. 81. The method of embodiment 79 or embodiment 80, wherein the one or more negative symptoms comprises anhedonia. 82. The method of any one of embodiments 79-81, wherein the one or more negative symptoms include allogeneic. 83. The method of any one of embodiments 79-82, wherein the one or more negative symptoms include affective flattening. 84. The method of any one of embodiments 79-83, wherein the one or more negative symptoms comprise apathy. 85. The method of any one of embodiments 79-84, wherein the one or more negative symptoms comprise loss of motivation. 86. The method of any one of embodiments 79-85, wherein the one or more negative symptoms comprise blunted affect. 87. The method of any one of embodiments 79-86, wherein the one or more negative symptoms include anergy. 88. The method of any one of embodiments 79-87, wherein the one or more negative symptoms comprise apathy. 89. The method of any one of embodiments 79-88, wherein the one or more negative symptoms comprises depression. 90. The method of any one of embodiments 79-89, wherein the one or more negative symptoms comprise decreased mood. 91. The method of any one of embodiments 79-90, wherein the one or more negative symptoms include cognitive impairment. 92. The method of any one of embodiments 75-91, wherein the treating step comprises improving or slowing the progression of a cognitive deficit in the subject, optionally wherein the cognitive deficit comprises a deficit in verbal working memory, spatial working memory, verbal fluency, verbal learning, or a combination thereof. 93. The method of any one of embodiments 75-92, wherein the treating step comprises improving or slowing the deterioration of the subject's Positive and Negative Syndrome Scale (PANSS) negative symptom factor score. 94. The method of any one of embodiments 75 to 93, wherein the treating step comprises improving or slowing the deterioration of the subject's Assessment of Negative Symptoms (SANS) score scale. 95. The method of any one of embodiments 75-94, wherein the treating step comprises improving or slowing the deterioration of the subject's Personal and Social Performance (PSP) total score. 96. The method of any one of embodiments 75 to 95, wherein the treating step comprises improving or slowing the deterioration of the subject's PANSS total score. 97. The method of any one of embodiments 75-96, wherein the treating step comprises improving or slowing the deterioration of one or more of the subject's PANSS factor scores. 98. The method of any one of embodiments 75-97, wherein the treating step comprises improving or slowing the worsening of one or more of the subject's PANSS subscale scores. 99. The method of any one of embodiments 75-98, wherein the treating step comprises improving or delaying the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) overall score. 100. The method of any one of embodiments 75-99, wherein the treating step comprises improving or slowing the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) Negative Symptoms rating score. 101. The method of any one of embodiments 75 to 100, wherein the treating step comprises improving or slowing the worsening of the subject's Clinical Global Improvement Index-Severity (CGI-S) global score. 102. The method of any one of embodiments 75 to 101, wherein the treating step comprises improving or slowing the worsening of the subject's Clinical Global Improvement Index-Severity (CGI-S) negative symptom score. 103. The method of any one of embodiments 1 to 74, wherein the subject is suffering from a neurodegenerative disease. 104. The method of embodiment 103, wherein the subject is suffering from Parkinson's disease. 105. The method of embodiment 103, wherein the subject is suffering from Alzheimer's disease. 106. The method of embodiment 103, wherein the subject is suffering from ALS. 107. The method of any one of embodiments 103-106, wherein the treating step comprises ameliorating or slowing the progression of one or more negative symptoms of the neurodegenerative disease. 108. The method of embodiment 107, wherein the one or more negative symptoms comprise antisociality, anhedonia, allogy, affective flattening, apathy, amotivation, blunted affect, anergy, apathy, depression, decreased mood, cognitive impairment, or a combination thereof. 109. The method of embodiment 108, wherein the one or more negative symptoms include antisocial. 110. The method of embodiment 108 or embodiment 109, wherein the one or more negative symptoms comprises anhedonia. 111. The method of any one of embodiments 108-110, wherein the one or more negative symptoms include allogeneic. 112. The method of any one of embodiments 108-111, wherein the one or more negative symptoms include affective flattening. 113. The method of any one of embodiments 108-112, wherein the one or more negative symptoms include apathy. 114. The method of any one of embodiments 108-113, wherein the one or more negative symptoms comprise loss of motivation. 115. The method of any one of embodiments 108-114, wherein the one or more negative symptoms comprise apathy. 116. The method of any one of embodiments 108-115, wherein the one or more negative symptoms include anergy. 117. The method of any one of embodiments 108-116, wherein the one or more negative symptoms include apathy. 118. The method of any one of embodiments 108-117, wherein the one or more negative symptoms comprises depression. 119. The method of any one of embodiments 108-118, wherein the one or more negative symptoms include decreased mood. 120. The method of any one of embodiments 108-119, wherein the one or more negative symptoms include cognitive impairment. 121. The method of any one of embodiments 1-74, wherein the subject is suffering from Parkinson's disease. 122. The method of embodiment 121, wherein the treating step comprises ameliorating or slowing the progression of one or more non-motor symptoms of Parkinson's disease in the subject. 123. The method of embodiment 122, wherein the one or more non-motor symptoms include a sensory symptom, a cognitive symptom, an autonomic symptom, or a combination thereof. 124. The method of embodiment 123, wherein the one or more non-motor symptoms include one or more sensory symptoms. 125. The method of embodiment 124, wherein the one or more sensory symptoms comprise numbness, restlessness, pain, chest discomfort, anosmia, or a combination thereof. 126. The method of any one of embodiments 123-125, wherein the one or more non-motor symptoms include one or more cognitive symptoms. 127. The method of embodiment 126, wherein the one or more cognitive symptoms comprise mood changes, depression, anxiety, panic attacks, fatigue, confusion, slowed thinking, or a combination thereof. 128. The method of any one of embodiments 123-127, wherein the one or more non-motor symptoms include one or more autonomic symptoms. 129. The method of embodiment 128, wherein the one or more autonomic symptoms comprise hot / cold sensation, bladder problems, sweating, abdominal discomfort, constipation, salivation, frequent and / or urinary urge, erectile dysfunction, or a combination thereof. 130. The method of any one of embodiments 122-129, wherein the one or more non-motor symptoms comprise cognitive deficits and / or impairment, depression, anxiety, fatigue, apathy, or a combination thereof. 131. The method of any one of embodiments 121-130, wherein the treating step comprises improving or slowing the deterioration of the subject's Non-Motor Symptom Scale (NMSS) score. 132. The method of any one of embodiments 121-131, wherein the treating step comprises improving or slowing the deterioration of the subject's MDS-UPDRS non-motor symptom score. 133. The method of any one of embodiments 121-132, wherein the treating step comprises improving or slowing the worsening of the subject's Fatigue Severity Scale (FSS) score. 134. The method of any one of embodiments 121-133, wherein the treating step comprises improving or slowing the worsening of the subject's Beck Depression Inventory II (BDI-II) score. 135. The method of any one of embodiments 121-134, wherein the treating step comprises improving or slowing the deterioration of the subject's Beck Anxiety Inventory (BAI) score. 136. The method of any one of embodiments 121-135, wherein the treating step comprises improving or slowing the deterioration of the subject's Montreal Cognitive Assessment (MoCA) score. 137. The method of any one of embodiments 121-136, wherein the treating step comprises improving or slowing the deterioration of the subject's score on one or more Cogstate tests. 138. The method of any one of embodiments 121-137, wherein the treating step comprises improving or slowing the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) overall score. 139. The method of any one of embodiments 121-138, wherein the treating step comprises improving or slowing the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) non-motor symptom score. 140. The method of any one of embodiments 121-139, wherein the treating step comprises improving or slowing the worsening of the subject's Clinical Global Improvement Index-Severity (CGI-S) global score. 141. The method of any one of embodiments 121 to 140, wherein the treating step comprises improving or slowing the worsening of the subject's Clinical Global Improvement Severity (CGI-S) non-motor symptom score. 142. The method of any one of embodiments 121-141, wherein the treating step comprises improving or slowing the deterioration of the subject's Parkinson's Disease Questionnaire-39 (PDQ-39) score. 143. The method of any one of embodiments 1-74, wherein the subject is suffering from a gastrointestinal disease or disorder. 144. The method of any one of embodiments 1-74, wherein the subject is suffering from irritable bowel syndrome. 145. The method of any one of embodiments 1-74, wherein the subject is suffering from inflammatory bowel disease. 146. The method of any one of embodiments 1-74, wherein the subject is suffering from ulcerative colitis. 147. The method of any one of embodiments 1-74, wherein the subject is suffering from Crohn's disease. 148. The method of any one of embodiments 1-74, wherein the subject is suffering from constipation. 149. The method of any one of embodiments 1-74, wherein the subject is suffering from pain. 150. The method of any one of embodiments 1-74, wherein the subject is suffering from visceral pain. 151. The method of any one of embodiments 1-74, wherein the subject is suffering from rheumatoid arthritis. 152. The method of any one of embodiments 1-74, wherein the subject is suffering from migraine headache. 153. The method of any one of embodiments 1-74, wherein the subject is suffering from a headache. 154. The method of any one of embodiments 1-74, wherein the subject is suffering from substance abuse. 155. The method of any one of embodiments 1-74, wherein the subject suffers from a substance use disorder, and optionally the substance use disorder is a drug use disorder, a polysubstance use disorder, an alcohol use disorder, a nicotine use disorder, or a tobacco use disorder. 156. The method of any one of embodiments 1-74, wherein the subject is suffering from drug addiction. 157. The method of embodiment 156, wherein the subject suffers from opioid addiction (e.g., morphine, heroin, oxycodone, or fentanyl). 158. The method of embodiment 156, wherein the subject is suffering from cocaine addiction. 159. The method of embodiment 156, wherein the subject is suffering from benzodiazepine addiction (e.g., diazepam, alprazolam, or clonazepam). 160. The method of any one of embodiments 1-74, wherein the subject suffers from a seizure disorder. 161. The method of embodiment 160, wherein the seizure disorder is epilepsy. 162. The method of embodiment 161, wherein the epilepsy is sporadic epilepsy. 163. The method of any one of embodiments 1-74, wherein the subject is suffering from major depressive disorder. 164. The method of any one of embodiments 1-74, wherein the subject is suffering from atypical depression. 165. The method of any one of embodiments 1-74, wherein the subject is suffering from a major depressive episode (MDE) (e.g., atypical MDE). 166. The method of any one of embodiments 1-74, wherein the subject is suffering from treatment-resistant depression. 167. The method of any one of embodiments 1-74, wherein the subject is suffering from depression in the presence of a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease). 168. The method of embodiment 167, wherein the subject is suffering from depression in the presence of Parkinson's disease. 169. The method of embodiment 167, wherein the subject is suffering from depression in the presence of Alzheimer's disease. 170. The method of embodiment 167, wherein the subject is suffering from depression in the presence of ALS. 171. The method of any one of embodiments 1-74, wherein the subject suffers from a cognitive disorder. 172. The method of embodiment 171, wherein the cognitive impairment is mild cognitive impairment. 173. The method of any one of embodiments 1 to 74, wherein the subject is suffering from COVID-19-associated cognitive impairment and / or depression. 174. The method of any one of embodiments 1-74, wherein the subject is suffering from Alzheimer's disease. 175. The method of any one of embodiments 1-74, wherein the subject is suffering from ADHD. 176. The method of any one of embodiments 1-74, wherein the subject suffers from an autism spectrum disorder. 177. The method of any one of embodiments 1-74, wherein the subject suffers from a pervasive developmental disorder (optionally Asperger's syndrome or Rett's syndrome). 178. The method of any one of embodiments 1-74, wherein the subject suffers from atypical autism. 179. The method of any one of embodiments 1-74, wherein the subject is suffering from multiple sclerosis. 180. The method of any one of embodiments 1-74, wherein the subject is suffering from PTSD. 181. The method of any one of embodiments 1-74, wherein the subject suffers from a sleep disorder. 182. The method of any one of embodiments 1-74, wherein the subject suffers from insomnia. 183. The method of any one of embodiments 1-74, wherein the subject suffers from daytime fatigue. 184. The method of any one of embodiments 1-74, wherein the subject suffers from REM sleep behavior disorder. 185. The method of any one of embodiments 1-74, wherein the treating step comprises improving sleep in the subject. 186. The method of any one of embodiments 1 to 185, wherein the subject has elevated TNF-α levels. 187. The method of any one of embodiments 1-186, wherein the treating step comprises improving or slowing the deterioration of the subject's overall Patient Health Questionnaire-9 (PHQ-9) score, optionally wherein the subject is not afflicted with a condition described in (a) or is a healthy subject. 188. The method of any one of embodiments 1-187, wherein the treating step comprises improving or slowing the deterioration of the subject's score on one or more of the PHQ-9 questions, optionally wherein the subject is not afflicted with a condition listed in (a) or is a healthy subject. 189. The method of embodiment 188, wherein the treating step comprises improving or slowing the deterioration of the subject's score on one or more of questions 1, 2, 3, or 6 of the PHQ-9. 190. The method of any one of embodiments 1-189, wherein the treating step comprises improving or slowing the deterioration of the subject's score in one or more of the CogState Groton Maze Test (GMLT), the CogState Discrimination Test (SDN), or the CogState One Card Test (OCL), optionally wherein the subject is not afflicted with a condition set forth in (a) or is a healthy subject. 191. The method of any one of embodiments 1-190, wherein the treating step comprises improving or slowing the deterioration of at least one of alpha band power or gamma band power of the subject's electroencephalogram (EEG), optionally wherein the subject is not afflicted with a condition set forth in (a) or is a healthy subject. 192. The method of any one of embodiments 1-191, wherein the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 50 mg / day to about 750 mg / day or about 60 mg / day to about 540 mg / day, optionally at a dose of 60 mg / day, 180 mg / day, or 540 mg / day. 193. The method of any one of embodiments 1-192, wherein the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is administered from once over a period of about 4 days to about 7 times over a period of about 10 days. 194. The method of any one of embodiments 1-192, wherein about 60 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is administered once over a period of about 4 days. 195. The method of any one of embodiments 1-192, wherein about 180 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is administered once over a period of about 4 days. 196. The method of any one of embodiments 1-192, wherein about 540 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is administered once over a period of about 4 days. 197. The method of any one of embodiments 1-192, wherein about 60 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is administered about 7 times over a period of about 10 days. 198. The method of any one of embodiments 1-192, wherein about 180 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is administered about 7 times over a period of about 10 days. 199. The method of any one of embodiments 1-192, wherein about 540 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is administered about 7 times over a period of about 10 days. 200. (a) In the presence of an inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease or ALS), a gastrointestinal disease or disorder (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., a substance use disorder such as drug use disorder, polysubstance use disorder, alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction, a seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, a neurodegenerative disease, (b) improving sleep in a subject; or (c) improving cognition in a subject, optionally wherein with respect to (a)-(c), the subject has elevated TNF-α levels, and wherein the peptide is: a. is 5 to 15 amino acids in length; and b. Amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F), Optionally, the method includes orally administering the peptide or a pharma- ceutically acceptable salt thereof. A peptide or a pharma- ceutically acceptable salt thereof. 201. The peptide or a pharma- ceutically acceptable salt thereof for use in embodiment 200, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof is LSSTQAQQSY (SEQ ID NO: 2), LSSTQAQQSW (SEQ ID NO: 3), or LSSTQAQQSF (SEQ ID NO: 4). 202. The peptide or a pharma- ceutically acceptable salt thereof for use in embodiment 201, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof is LSSTQAQQSY (SEQ ID NO: 2). 203. The peptide for use in embodiment 200, wherein the peptide is a peptide described in any one of embodiments 2 to 50, or a pharma- ceutically acceptable salt thereof. 204. (a) an inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or ALS), a gastrointestinal disease or disorder (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., a substance use disorder such as drug use disorder, polysubstance use disorder, alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction, a seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, depression in the presence of a neurodegenerative disease, cognitive impairment, COVID-19-related 1. A peptide conjugate or a pharma- ceutically acceptable salt thereof for use in a method of treating a subject suffering from or at risk for cognitive impairment and / or depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, a sleep disorder (e.g., insomnia, daytime fatigue, or REM sleep behavior disorder); (b) improving sleep in a subject; or (c) improving cognition in a subject, optionally wherein with respect to (a)-(c), the subject has elevated TNF-α levels, and wherein the peptide conjugate comprises a peptide moiety linked to a conjugate moiety, and wherein the peptide moiety is: a. is 5 to 15 amino acids in length; and b. Amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F), Optionally, the method includes orally administering the peptide conjugate or a pharma- ceutically acceptable salt thereof. A peptide conjugate or a pharma- ceutically acceptable salt thereof. 205. The peptide conjugate for use in embodiment 204, or a pharma- ceutically acceptable salt thereof, wherein the peptide moiety is a peptide described in any one of embodiments 2 to 50. 206. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from or is at risk of having schizophrenia or psychosis. 207. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 206, wherein the subject suffers from schizophrenia. 208. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 206 or embodiment 207, wherein the subject exhibits psychotic behavior. 209. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 208, wherein the treating step comprises ameliorating or slowing the progression of one or more negative symptoms of schizophrenia or psychosis. 210. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 209, wherein the one or more negative symptoms comprise antisociality, anhedonia, allo- gy, affective flattening, apathy, amotivation, blunted affect, anergy, apathy, depression, decreased mood, cognitive impairment, or a combination thereof. 211. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 210, wherein said one or more negative symptoms include antisocial. 212. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 211, wherein the one or more negative symptoms comprises anhedonia. 213. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 212, wherein the one or more negative symptoms include allogeneic. 214. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 213, wherein the one or more negative symptoms include affective flattening. 215. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 214, wherein the one or more negative symptoms comprise apathy. 216. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 215, wherein the one or more negative symptoms include loss of motivation. 217. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 216, wherein the one or more negative symptoms include apathy. 218. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 217, wherein the one or more negative symptoms comprises anergy. 219. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 218, wherein the one or more negative symptoms include apathy. 220. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 219, wherein the one or more negative symptoms comprises depression. 221. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 220, wherein the one or more negative symptoms comprises decreased mood. 222. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 210 to 221, wherein the one or more negative symptoms comprises cognitive impairment. 223. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 222, wherein the treating step comprises ameliorating or slowing the progression of one or more cognitive deficits in the subject, optionally wherein the cognitive deficits comprise deficits in verbal working memory, spatial working memory, verbal fluency, verbal learning, or a combination thereof. 224. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 223, wherein the treating step comprises improving or delaying the worsening of the subject's Positive and Negative Syndrome Scale (PANSS) negative symptom factor score. 225. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 224, wherein the treating step comprises improving or delaying the worsening of the subject's SANS score scale. 226. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 225, wherein the treating step comprises improving or delaying the deterioration of the subject's total personal and social performance (PSP) score. 227. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 226, wherein the treating step comprises improving or delaying the worsening of the subject's PANSS total score. 228. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 227, wherein the treating step comprises improving or slowing the worsening of one or more of the subject's PANSS factor scores. 229. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 228, wherein the treating step comprises improving or slowing the worsening of one or more of the subject's PANSS subscale scores. 230. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 229, wherein the treating step comprises improving or delaying the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) overall score. 231. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 230, wherein the treating step comprises improving or delaying the worsening of the subject's Clinical Global Impression-Improvement (CGI-I) Negative Symptoms rating score. 232. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 206 to 231, wherein the treating step comprises improving or delaying the worsening of the subject's Clinical Global Improvement Index-Severity (CGI-S) global score. 233. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 206 to 232, wherein the treating step comprises improving or delaying the worsening of the subject's Clinical Global Improvement Severity (CGI-S) negative symptom score. 234. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200 to 203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204 to 205, wherein the subject suffers from a neurodegenerative disease. 235. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 234, wherein the subject is suffering from Parkinson's disease. 236. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 234, wherein the subject is suffering from Alzheimer's disease. 237. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 234, wherein the subject is suffering from ALS. 238. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 234 to 237, wherein the treating step comprises ameliorating or slowing the progression of one or more negative symptoms of the neurodegenerative disease. 239. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 238, wherein the one or more negative symptoms comprise antisociality, anhedonia, allo- gy, affective flattening, apathy, amotivation, blunted affect, anergy, apathy, depression, decreased mood, cognitive impairment, or a combination thereof. 240. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 239, wherein the one or more negative symptoms include antisocial. 241. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 239 or 240, wherein the one or more negative symptoms comprises anhedonia. 242. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 241, wherein the one or more negative symptoms include allo- gy. 243. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 242, wherein the one or more negative symptoms include affective flattening. 244. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 243, wherein the one or more negative symptoms comprises apathy. 245. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 244, wherein the one or more negative symptoms include loss of motivation. 246. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 245, wherein the one or more negative symptoms comprises apathy. 247. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 246, wherein the one or more negative symptoms comprises anergy. 248. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 247, wherein the one or more negative symptoms comprise apathy. 249. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 248, wherein the one or more negative symptoms comprises depression. 250. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 249, wherein the one or more negative symptoms comprises decreased mood. 251. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 239 to 250, wherein the one or more negative symptoms comprises cognitive impairment. 252. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from Parkinson's disease. 253. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 252, wherein the treating step comprises ameliorating or slowing the progression of one or more non-motor symptoms of Parkinson's disease in the subject. 254. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 253, wherein the one or more non-motor symptoms include a sensory symptom, a cognitive symptom, an autonomic symptom, or a combination thereof. 255. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 254, wherein said one or more non-motor symptoms include one or more sensory symptoms. 256. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 255, wherein the one or more sensory symptoms comprise numbness, restlessness, pain, chest discomfort, anosmia, or a combination thereof. 257. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 254 to 256, wherein the one or more non-motor symptoms include one or more cognitive symptoms. 258. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 257, wherein the one or more cognitive symptoms comprise mood changes, depression, anxiety, panic attacks, fatigue, confusion, slowed thinking, or a combination thereof. 259. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 254 to 258, wherein the one or more non-motor symptoms include one or more autonomic symptoms. 260. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 259, wherein the one or more autonomic symptoms comprise hot / cold sensation, bladder problems, sweating, abdominal discomfort, constipation, salivation, frequent and / or urinary urge, erectile dysfunction, or a combination thereof. 261. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 253 to 260, wherein the one or more non-motor symptoms comprise cognitive deficits and / or cognitive impairment, depression, anxiety, fatigue, apathy, or a combination thereof. 262. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 261, wherein the treating step comprises improving or delaying the deterioration of the subject's Non-Motor Symptom Scale (NMSS) score. 263. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 262, wherein the treating step comprises improving or delaying the worsening of the subject's MDS-UPDRS non-motor symptom score. 264. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 263, wherein the treating step comprises improving or delaying the worsening of the subject's Fatigue Severity Scale (FSS) score. 265. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 264, wherein the treating step comprises improving or slowing the worsening of the subject's Beck Depression Inventory II (BDI-II) score. 266. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 265, wherein the treating step comprises improving or delaying the deterioration of the subject's Beck Anxiety Inventory (BAI) score. 267. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 266, wherein the treating step comprises improving or slowing the deterioration of the subject's Montreal Cognitive Assessment (MoCA) score. 268. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 252 to 267, wherein the treating step comprises improving or slowing the deterioration of the subject's score on one or more Cogstate tests. 269. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 252 to 268, wherein the treating step comprises improving or delaying the worsening of the subject's Clinical Global Impression-Improvement (CGI-I) overall score. 270. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 269, wherein the treating step comprises improving or delaying the worsening of the subject's Clinical Global Impression-Improvement (CGI-I) non-motor symptom score. 271. A peptide or a pharma- ceutically acceptable salt thereof, or a peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 252 to 270, wherein the treating step comprises improving or delaying the worsening of the subject's Clinical Global Improvement Index-Severity (CGI-S) global score. 272. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 271, wherein the treating step comprises improving or delaying the worsening of the subject's Clinical Global Improvement Severity (CGI-S) non-motor symptom score. 273. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in any one of embodiments 252 to 272, wherein the treating step comprises improving or slowing the worsening of the subject's Parkinson's Disease Questionnaire-39 (PDQ-39) score. 274. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from a gastrointestinal disease or disorder. 275. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from irritable bowel syndrome. 276. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from inflammatory bowel disease. 277. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from ulcerative colitis. 278. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from Crohn's disease. 279. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from constipation. 280. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject is suffering from pain. 281. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from visceral pain. 282. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from rheumatoid arthritis. 283. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from migraine. 284. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from a headache. 285. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from substance abuse. 286. The peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or the peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from a substance use disorder, and optionally the substance use disorder is a drug use disorder, a polysubstance use disorder, an alcohol use disorder, a nicotine use disorder, or a tobacco use disorder. 287. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from drug addiction. 288. The peptide or a pharma- ceutically acceptable salt thereof for use in embodiment 287, wherein the subject suffers from opioid addiction (e.g., morphine, heroin, oxycodone, or fentanyl). 289. The peptide or a pharma- ceutically acceptable salt thereof for use in embodiment 287, wherein the subject is suffering from cocaine addiction. 290. The peptide or a pharma- ceutically acceptable salt thereof for use in embodiment 287, wherein the subject suffers from benzodiazepine addiction (e.g., diazepam, alprazolam, or clonazepam). 291. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from a seizure disorder. 292. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 291, wherein said seizure disorder is epilepsy. 293. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 292, wherein said epilepsy is sporadic epilepsy. 294. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from major depressive disorder. 295. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from atypical depression. 296. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject is suffering from a major depressive episode (MDE) (e.g., atypical MDE). 297. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from treatment-resistant depression. 298. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from depression in the presence of a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease). 299. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 298, wherein the subject suffers from depression in the presence of Parkinson's disease. 300. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 298, wherein the subject suffers from depression in the presence of Alzheimer's disease. 301. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 298, wherein the subject suffers from depression in the presence of ALS. 302. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from a cognitive disorder. 303. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 302, wherein said cognitive impairment is mild cognitive impairment. 304. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200 to 203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204 to 205, wherein the subject suffers from COVID-19 associated cognitive impairment and / or depression. 305. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from Alzheimer's disease. 306. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from ADHD. 307. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from an autism spectrum disorder. 308. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from a pervasive developmental disorder, optionally Asperger's syndrome or Rett's syndrome. 309. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from atypical autism. 310. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from multiple sclerosis. 311. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from PTSD. 312. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from a sleep disorder. 313. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from insomnia. 314. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from daytime fatigue. 315. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the subject suffers from REM sleep behavior disorder. 316. A peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or a peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the treating step comprises improving sleep in a subject. 317. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 200 to 316, wherein the subject has elevated TNF-a levels. 318. The peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or the peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the treating step comprises improving or slowing the deterioration of the subject's overall Patient Health Questionnaire-9 (PHQ-9) score, optionally wherein the subject is not afflicted with a condition set forth in (a) or is a healthy subject. 319. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 318, wherein the treating step comprises improving or slowing the worsening of the subject's score on one or more of the questions of the PHQ-9. 320. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 319, wherein the treating step comprises improving or slowing the worsening of the subject's score on one or more of questions 1, 2, 3, or 6 of the PHQ-9. 321. The peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or the peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the treating step comprises improving or slowing the deterioration of the subject's score in one or more of the CogState Groton Maze Test (GMLT), the CogState Discrimination Test (IDN), or the CogState One-Card Test (OCL), optionally wherein the subject is not afflicted with a condition set forth in (a) or is a healthy subject. 322. The peptide or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 200-203, or the peptide conjugate or a pharma- ceutically acceptable salt thereof for use in any one of embodiments 204-205, wherein the treating step comprises improving or slowing the deterioration of at least one of alpha band power or gamma band power of the electroencephalogram (EEG) of the subject, optionally wherein the subject is not afflicted with a condition set forth in (a) or is a healthy subject. 323. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 200 to 322, wherein the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is provided in a dose of about 50 mg / day to about 750 mg / day or about 60 mg / day to about 540 mg / day, optionally 60 mg / day, 180 mg / day, or 540 mg / day. 324. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 200 to 323, wherein the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is provided for use from once over a period of about 4 days to about 7 times over a period of about 10 days. 325. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 200 to 323, wherein about 60 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is provided for one-time use over a period of about 4 days. 326. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 200 to 323, wherein about 180 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is provided for one-time use over a period of about 4 days. 327. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 200 to 323, wherein about 540 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is provided for one-time use over a period of about 4 days. 328. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 200 to 323, wherein about 60 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is provided for about 7 uses over a period of about 10 days. 329. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 200 to 323, wherein about 180 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is provided for use about 7 times over a period of about 10 days. 330. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 200 to 323, wherein about 540 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, is provided for use about 7 times over a period of about 10 days. 331. (a) In the presence of an inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or ALS), a gastrointestinal disease or disorder (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., a substance use disorder such as drug use disorder, polysubstance use disorder, alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction, a seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, a neurodegenerative disease, (b) improving sleep; or (c) use of a peptide or a pharmacologic acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of depression, cognitive impairment, COVID-19 associated cognitive impairment and / or depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, sleep disorders (e.g. insomnia, daytime fatigue, or REM sleep behavior disorder) in a subject, (b) improving sleep; or (c) improving cognition in a subject, optionally wherein with respect to (a)-(c), the medicament is formulated for administration to a subject with elevated TNF-α levels, and the peptide comprises: a. is 5 to 15 amino acids in length; and b. Amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F), Optionally, the medicament is formulated for oral administration. use. 332. The use of embodiment 331, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof is LSSTQAQQSY (SEQ ID NO: 2), LSSTQAQQSW (SEQ ID NO: 3), or LSSTQAQQSF (SEQ ID NO: 4). 333. The use of embodiment 332, wherein the amino acid sequence of the peptide or a pharma- ceutically acceptable salt thereof is LSSTQAQQSY (sequence number 2). 334. The use of embodiment 331, wherein the peptide is a peptide described in any one of embodiments 2 to 50. 335. (a) An inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or ALS), a gastrointestinal disease or disorder (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., a substance use disorder such as drug use disorder, polysubstance use disorder, alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction, seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, depression in the presence of a neurodegenerative disease, cognitive impairment, Alzheimer's disease, COVID-19, 2. Use of a peptide conjugate or a pharma- tically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of tumor necrosis factor-related cognitive impairment and / or depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, a sleep disorder (e.g., insomnia, daytime fatigue, or REM sleep behavior disorder); (b) to improve sleep; or (c) to improve cognition in a subject, optionally wherein with respect to (a)-(c), the medicament is formulated for administration to a subject having elevated TNF-α levels, and wherein the peptide conjugate comprises a peptide moiety linked to a conjugate moiety, and wherein the peptide moiety is: a. is 5 to 15 amino acids in length; and b. Amino acid sequence LSSTQAQQSX 1 (SEQ ID NO:1) (wherein X 1 is Y, W, or F), Optionally, the medicament is formulated for oral administration. use. 336. The use of embodiment 335, wherein the peptide moiety is a peptide described in any one of embodiments 2 to 50. 337. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from or at risk of schizophrenia or psychosis. 338. The use of embodiment 337, wherein the medicament is formulated for administration to a subject suffering from schizophrenia. 339. The use of embodiment 337 or embodiment 338, wherein the medicament is formulated for administration to a subject exhibiting psychotic behavior. 340. The use of any one of embodiments 337-339, wherein administration of said medicament to said subject ameliorates or slows the progression of one or more negative symptoms of schizophrenia or psychosis. 341. The use of embodiment 340, wherein the one or more negative symptoms comprise antisociality, anhedonia, allogy, affective flattening, apathy, amotivation, blunted affect, anergy, apathy, depression, decreased mood, cognitive impairment, or a combination thereof. 342. The use of embodiment 341, wherein the one or more negative symptoms include antisocial. 343. The use of any one of embodiments 341-342, wherein the one or more negative symptoms comprises anhedonia. 344. The use of any one of embodiments 341-343, wherein the one or more negative symptoms include allogeneic. 345. The use of any one of embodiments 341-344, wherein the one or more negative symptoms include affective flattening. 346. The use of any one of embodiments 341-345, wherein the one or more negative symptoms include apathy. 347. The use of any one of embodiments 341-346, wherein the one or more negative symptoms include loss of motivation. 348. The use of any one of embodiments 341-347, wherein the one or more negative symptoms include apathy. 349. The use of any one of embodiments 341-348, wherein the one or more negative symptoms include anergy. 350. The use of any one of embodiments 341-349, wherein the one or more negative symptoms include apathy. 351. The use of any one of embodiments 341-350, wherein the one or more negative symptoms comprises depression. 352. The use of any one of embodiments 341-351, wherein the one or more negative symptoms include decreased mood. 353. The use of any one of embodiments 341-352, wherein the one or more negative symptoms include cognitive impairment. 354. The use of any one of embodiments 337-353, wherein administration of the medicament to the subject ameliorates or slows the progression of a cognitive deficit in the subject, and optionally, the cognitive deficit comprises a deficit in verbal working memory, spatial working memory, verbal fluency, verbal learning, or a combination thereof. 355. The use of any one of embodiments 337-354, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Positive and Negative Syndrome Scale (PANSS) negative symptom factor score. 356. The use of any one of embodiments 337-355, wherein administration of the medicament to the subject improves or slows the deterioration of the subject's SANS score scale. 357. The use of any one of embodiments 337-356, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Personal and Social Performance (PSP) total score. 358. The use of any one of embodiments 337-357, wherein administration of the medicament to the subject improves or slows the deterioration of the subject's PANSS total score. 359. The use of any one of embodiments 337-358, wherein administration of the medicament to the subject improves or slows the deterioration of one or more of the subject's PANSS factor scores. 360. The use of any one of embodiments 337-359, wherein administration of the medicament to the subject improves or slows the deterioration of one or more of the subject's PANSS subscale scores. 361. The use of any one of embodiments 337-360, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) global score. 362. The use of any one of embodiments 337-361, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) Negative Symptoms rating score. 363. The use of any one of embodiments 337-362, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Clinical Global Improvement Severity (CGI-S) global score. 364. The use of any one of embodiments 337-363, wherein administering the medicament to the subject improves or delays the subject's Clinical Global Improvement Severity (CGI-S) negative symptom score. 365. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a neurodegenerative disease. 366. The use of embodiment 365, wherein the subject is suffering from Parkinson's disease. 367. The use of embodiment 365, wherein the subject is suffering from Alzheimer's disease. 368. The use of embodiment 365, wherein the subject is suffering from ALS. 369. The use of any one of embodiments 365-368, wherein the treating step comprises ameliorating or slowing the progression of one or more negative symptoms of the neurodegenerative disease. 370. The use of embodiment 369, wherein the one or more negative symptoms comprise antisociality, anhedonia, allogy, affective flattening, apathy, amotivation, blunted affect, anergy, apathy, depression, decreased mood, cognitive impairment, or a combination thereof. 371. The use of embodiment 370, wherein the one or more negative symptoms include antisocial. 372. The use of embodiment 370 or embodiment 371, wherein the one or more negative symptoms comprises anhedonia. 373. The use of any one of embodiments 370-372, wherein the one or more negative symptoms include allogeneic. 374. The use of any one of embodiments 370-373, wherein the one or more negative symptoms include affective flattening. 375. The use of any one of embodiments 370-374, wherein the one or more negative symptoms include apathy. 376. The use of any one of embodiments 370-375, wherein the one or more negative symptoms include loss of motivation. 377. The use of any one of embodiments 370-376, wherein the one or more negative symptoms include apathy. 378. The use of any one of embodiments 370-377, wherein the one or more negative symptoms include anergy. 379. The use of any one of embodiments 370-378, wherein the one or more negative symptoms include apathy. 380. The use of any one of embodiments 370-379, wherein the one or more negative symptoms comprises depression. 381. The use of any one of embodiments 370-380, wherein the one or more negative symptoms include decreased mood. 382. The use of any one of embodiments 370-381, wherein the one or more negative symptoms include cognitive impairment. 383. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from Parkinson's disease. 384. The use of embodiment 365, wherein administering the medicament to the subject ameliorates or slows the progression of one or more non-motor symptoms of Parkinson's disease in the subject. 385. The use of embodiment 384, wherein the one or more non-motor symptoms include a sensory symptom, a cognitive symptom, an autonomic symptom, or a combination thereof. 386. The use of embodiment 385, wherein the one or more non-motor symptoms include one or more sensory symptoms. 387. The use of embodiment 386, wherein the one or more sensory symptoms comprise numbness, restlessness, pain, chest discomfort, anosmia, or a combination thereof. 388. The use of any one of embodiments 384-387, wherein the one or more non-motor symptoms include one or more cognitive symptoms. 389. The use of embodiment 388, wherein the one or more cognitive symptoms comprise mood changes, depression, anxiety, panic attacks, fatigue, confusion, slowed thinking, or a combination thereof. 390. The use of any one of embodiments 384-389, wherein the one or more non-motor symptoms include one or more autonomic symptoms. 391. The use of embodiment 390, wherein the one or more autonomic symptoms comprise hot / cold sensation, bladder problems, sweating, abdominal discomfort, constipation, salivation, frequent and / or urinary urge, erectile dysfunction, or a combination thereof. 392. The use of any one of embodiments 384-391, wherein the one or more non-motor symptoms comprise cognitive deficits and / or impairment, depression, anxiety, fatigue, apathy, or a combination thereof. 393. The use of any one of embodiments 383-392, wherein administration of the medicament to the subject improves or slows the deterioration of the subject's Non-Motor Symptom Scale (NMSS) score. 394. The use of any one of embodiments 383-393, wherein administering the medicament to the subject improves or slows the deterioration of the subject's MDS-UPDRS non-motor symptom score. 395. The use of any one of embodiments 383-394, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Fatigue Severity Scale (FSS) score. 396. The use of any one of embodiments 383-395, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Beck Depression Inventory II (BDI-II) score. 397. The use of any one of embodiments 383-396, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Beck Anxiety Inventory (BAI) score. 398. The use of any one of embodiments 383-397, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Montreal Cognitive Assessment (MoCA) score. 399. The use of any one of embodiments 383-398, wherein administration of the medicament to the subject improves or slows the deterioration of the subject's score on one or more Cogstate tests. 400. The use of any one of embodiments 383-399, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) global score. 401. The use of any one of embodiments 383-400, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Clinical Global Impression-Improvement (CGI-I) non-motor symptom score. 402. The use of any one of embodiments 383-401, wherein administration of the medicament to the subject improves or slows the deterioration of the subject's Clinical Global Improvement Severity (CGI-S) global score. 403. The use of any one of embodiments 383-402, wherein administering the medicament to the subject improves or slows the deterioration of the subject's Clinical Global Improvement Severity (CGI-S) non-motor symptom score. 404. The use of any one of embodiments 383-403, wherein administering said medicament to said subject improves or slows the deterioration of said subject's Parkinson's Disease Questionnaire-39 (PDQ-39) score. 405. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a gastrointestinal disease or disorder. 406. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from irritable bowel syndrome. 407. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from inflammatory bowel disease. 408. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from ulcerative colitis. 409. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from Crohn's disease. 410. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from constipation. 411. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from pain. 412. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from visceral pain. 413. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from rheumatoid arthritis. 414. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a migraine headache. 415. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a headache. 416. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from substance abuse. 417. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a substance use disorder, and optionally the substance use disorder is a drug use disorder, a polysubstance use disorder, an alcohol use disorder, a nicotine use disorder, or a tobacco use disorder. 418. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from drug addiction. 419. The use of embodiment 418, wherein the subject suffers from opioid addiction (e.g., morphine, heroin, oxycodone, or fentanyl). 420. The use of embodiment 418, wherein the subject is suffering from cocaine addiction. 421. The use of embodiment 418, wherein the subject suffers from benzodiazepine addiction (e.g., diazepam, alprazolam, or clonazepam). 422. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a seizure disorder. 423. The use of embodiment 422, wherein the seizure disorder is epilepsy. 424. The peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, for use in embodiment 423, wherein said epilepsy is sporadic epilepsy. 425. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from major depressive disorder. 426. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from atypical depression. 427. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a major depressive episode (MDE) (e.g., atypical MDE). 428. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from treatment-resistant depression. 429. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from depression in the presence of a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease). 430. The use of embodiment 429, wherein the medicament is formulated for administration to a subject suffering from depression in the presence of Parkinson's disease. 431. The use of embodiment 429, wherein the medicament is formulated for administration to a subject suffering from depression in the presence of Alzheimer's disease. 432. The use of embodiment 429, wherein the medicament is formulated for administration to a subject suffering from depression in the presence of ALS. 433. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a cognitive disorder. 434. The use of embodiment 433, wherein the cognitive disorder is mild cognitive impairment. 435. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from COVID-19 associated cognitive impairment and / or depression. 436. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from Alzheimer's disease. 437. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from ADHD. 438. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from an autism spectrum disorder. 439. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a pervasive developmental disorder, optionally Asperger's syndrome or Rett's syndrome. 440. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from atypical autism. 441. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from multiple sclerosis. 442. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from PTSD. 443. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from a sleep disorder. 444. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from insomnia. 445. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from daytime fatigue. 446. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject suffering from REM sleep behavior disorder. 447. The use of any one of embodiments 331-336, wherein the medicament is formulated for administration to a subject in need of improved sleep. 448. The use of any one of embodiments 331-447, wherein the subject has elevated TNF-α levels. 449. The use of any one of embodiments 331-336, wherein administration of the medicament improves or slows the deterioration of the subject's overall Patient Health Questionnaire-9 (PHQ-9) score, optionally wherein the subject is not afflicted with a condition described in (a) or is a healthy subject, and optionally wherein the medicament is formulated for administration to a subject not afflicted with a condition described in (a) or a healthy subject. 450. The use of embodiment 449, wherein administration of the medicament improves or slows the deterioration of the subject's score on one or more of the questions of the PHQ-9. 451. The use of embodiment 450, wherein administration of the medicament improves or slows the deterioration of the subject's score on one or more of questions 1, 2, 3, or 6 of the PHQ-9. 452. The use of any one of embodiments 331-336, wherein administration of the medicament improves or slows the deterioration of the subject's score in one or more of the CogState Groton Maze Test (GMLT), the CogState Discrimination Test (IDN), or the CogState One-Card Test (OCL), optionally wherein the medicament is formulated for administration to a subject not suffering from a condition set forth in (a) or to a healthy subject. 453. The use of any one of embodiments 331-336, wherein administration of the medicament improves or slows the deterioration of at least one of alpha band power or gamma band power in the electroencephalogram (EEG) of the subject, optionally wherein the medicament is formulated for administration to a subject not suffering from a condition set forth in (a), or to a healthy subject. 454. The use of any one of embodiments 331 to 453, wherein the medicament is formulated to provide a dosage of about 50 mg to about 750 mg, or about 60 mg / day to about 540 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof. 455. The use of any one of embodiments 331-454, wherein the medicament is formulated to provide a dose of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, from 1 dose over a period of about 4 days to about 7 doses over a period of about 10 days. 456. The use of any one of embodiments 331-454, wherein the medicament is formulated to provide a dose of about 60 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, once over a period of about 4 days. 457. The use of any one of embodiments 331-454, wherein the medicament is formulated to provide a dose of about 180 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, once over a period of about 4 days. 458. The use of any one of embodiments 331-454, wherein the medicament is formulated to provide a dose of about 540 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, once over a period of about 4 days. 459. The use of any one of embodiments 331-454, wherein the medicament is formulated to provide a dose of about 60 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, about 7 times over a period of about 10 days. 460. The use of any one of embodiments 331-454, wherein the medicament is formulated to provide a dose of about 180 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, about 7 times over a period of about 10 days. 461. The use of any one of embodiments 331-454, wherein the medicament is formulated to provide a dose of about 540 mg / day of the peptide or a pharma- ceutically acceptable salt thereof, or the peptide conjugate or a pharma- ceutically acceptable salt thereof, about 7 times over a period of about 10 days.

[0162] 9. References All publications, patents, patent applications, and other documents cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated for all purposes. In that event, if there is any conflict between the teachings of one or more of the references incorporated herein and the present disclosure, the teachings of this specification are intended.

Claims

1. A composition comprising a peptide or a pharmaceutically acceptable salt thereof, The compositions may be used to treat (a) schizophrenia or psychosis, an inflammatory disease or disorder, a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or ALS), a gastrointestinal disease or disorder (e.g., irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., a substance use disorder such as drug use disorder, polysubstance use disorder, alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction, seizure disorder, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, or atopic dermatitis (PD). (b) treating a subject suffering from or at risk of antidepressant depression, depression in the presence of a neurodegenerative disease, cognitive impairment, COVID-19 associated cognitive impairment and / or depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, a sleep disorder (e.g., insomnia, daytime fatigue, or REM sleep behavior disorder); (b) improving sleep in a subject; or (c) improving cognition in a subject, optionally with respect to (a)-(c), wherein the subject has elevated TNF-α levels and the peptide is: a. 5 to 15 amino acids in length; and b. Amino acid sequence LSSTQAQQSX １ (SEQ ID NO: 1) (wherein X １ is Y, W, or F), composition.

2. 2. The composition of claim 1, wherein the amino acid sequence of the peptide or a pharmaceutically acceptable salt thereof is LSSTQAQQSY (SEQ ID NO: 2).

3. The composition of claim 1, wherein the composition is administered orally.

4. A composition comprising a peptide conjugate or a pharmaceutically acceptable salt thereof, comprising: The composition is for use in treating (a) schizophrenia or psychosis, an inflammatory disease or disorder, a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or ALS), a gastrointestinal disease or disorder (e.g., irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, or constipation), pain (e.g., visceral pain), rheumatoid arthritis, migraine, headache, substance abuse (e.g., a substance use disorder such as drug use disorder, polysubstance use disorder, alcohol use disorder, nicotine use disorder, or tobacco use disorder), drug addiction, a seizure disorder, major depressive disorder, atypical depression, a major depressive episode (MDE), treatment-resistant depression, a neurodegenerative disease, (b) treating a subject suffering from or at risk of depression, cognitive impairment, COVID-19 associated cognitive impairment and / or depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, a sleep disorder (e.g., insomnia, daytime fatigue, or REM sleep behavior disorder); (b) improving sleep in a subject; or (c) improving cognition in a subject, optionally with respect to (a)-(c), wherein the subject has elevated TNF-α levels, and the peptide conjugate comprises a peptide moiety conjugated to a conjugate moiety, and wherein the peptide moiety is: a. 5 to 15 amino acids in length; and b. Amino acid sequence LSSTQAQQSX １ (SEQ ID NO: 1) (wherein X １ is Y, W, or F), composition.

5. The composition of claim 4, wherein the composition is administered orally.

6. The composition of any one of claims 1 to 5, wherein the subject is suffering from or at risk of schizophrenia or psychosis.

7. The composition of claim 6 , wherein the subject is suffering from schizophrenia.

8. The composition of claim 6 , wherein the subject exhibits psychotic behavior.

9. 7. The composition of claim 6, wherein said treating comprises ameliorating or slowing the progression of one or more negative symptoms of schizophrenia or psychosis.

10. 10. The composition of claim 9, wherein the one or more negative symptoms comprise antisociality, anhedonia, allogia, affective flattening, apathy, loss of motivation, blunted affect, anergy, apathy, depression, decreased mood, cognitive impairment, or a combination thereof.

11. 7. The composition of claim 6, wherein said treating comprises improving or slowing the progression of a cognitive deficit in said subject, optionally wherein said cognitive deficit comprises a deficit in verbal working memory, spatial working memory, verbal fluency, verbal learning, or a combination thereof.

12. 6. The composition of any one of claims 1 to 5, wherein the subject is suffering from a neurodegenerative disease, and the neurodegenerative disease is optionally Parkinson's disease, Alzheimer's disease, or ALS.

13. 13. The composition of claim 12, wherein said treating comprises ameliorating or slowing the progression of one or more negative symptoms of said neurodegenerative disease.

14. 14. The composition of claim 13, wherein the one or more negative symptoms comprise antisociality, anhedonia, allogia, affective flattening, apathy, loss of motivation, blunted affect, anergy, apathy, depression, low mood, cognitive impairment, or a combination thereof.

15. The composition of any one of claims 1 to 5, wherein the subject is suffering from Parkinson's disease.

16. 16. The composition of claim 15, wherein said treating comprises improving or slowing the progression of one or more non-motor symptoms of Parkinson's disease in said subject.

17. 17. The composition of claim 16, wherein the one or more non-motor symptoms comprise a sensory symptom, a cognitive symptom, an autonomic symptom, or a combination thereof.

18. 18. The composition of claim 17, wherein the one or more sensory symptoms comprise numbness, restlessness, pain, chest discomfort, anosmia, or a combination thereof; the one or more cognitive symptoms comprise mood changes, depression, anxiety, panic attacks, fatigue, confusion, slowed thinking, or a combination thereof; and the one or more autonomic symptoms comprise hot / cold sensations, bladder problems, sweating, abdominal discomfort, constipation, salivation, frequent and / or urinary urges, erectile dysfunction, or a combination thereof.

19. 17. The composition of claim 16, wherein the one or more non-motor symptoms comprise cognitive deficits and / or impairment, depression, anxiety, fatigue, apathy, or a combination thereof.

20. The composition of any one of claims 1 to 5, wherein the subject is suffering from a gastrointestinal disease or disorder.

21. The composition of any one of claims 1 to 5, wherein the subject is suffering from irritable bowel syndrome.

22. The composition of any one of claims 1 to 5, wherein the subject is suffering from inflammatory bowel disease.

23. The composition of any one of claims 1 to 5, wherein the subject is suffering from Crohn's disease.

24. The composition of any one of claims 1 to 5, wherein the subject is suffering from constipation.

25. The composition of any one of claims 1 to 5, wherein the subject is suffering from pain.

26. The composition of any one of claims 1 to 5, wherein the subject is suffering from visceral pain.

27. The composition of any one of claims 1 to 5, wherein the subject is suffering from rheumatoid arthritis.

28. The composition of any one of claims 1 to 5, wherein the subject is suffering from a migraine headache.

29. The composition of any one of claims 1 to 5, wherein the subject is suffering from a headache.

30. The composition of any one of claims 1 to 5, wherein the subject is suffering from substance abuse.

31. 6. The composition of any one of claims 1 to 5, wherein the subject suffers from a substance use disorder, optionally wherein the substance use disorder is a drug use disorder, a polysubstance use disorder, an alcohol use disorder, a nicotine use disorder, or a tobacco use disorder.

32. 6. The composition of any one of claims 1 to 5, wherein the subject is suffering from a drug addiction, optionally wherein the drug addiction is an opioid addiction, a cocaine addiction, or a benzodiazepine addiction.

33. The composition of any one of claims 1 to 5, wherein the subject is suffering from a seizure disorder.

34. 34. The composition of claim 33, wherein the seizure disorder is epilepsy.

35. 34. The composition of claim 33, wherein the epilepsy is sporadic epilepsy.

36. The composition of any one of claims 1 to 5, wherein the subject is suffering from major depressive disorder.

37. The composition of any one of claims 1 to 5, wherein the subject is suffering from atypical depression.

38. The composition of any one of claims 1 to 5, wherein the subject is suffering from a major depressive episode (MDE) (e.g., atypical MDE).

39. The composition of any one of claims 1 to 5, wherein the subject is suffering from treatment-resistant depression.

40. The composition of any one of claims 1 to 5, wherein the subject is suffering from depression in the presence of a neurodegenerative disease.

41. The composition of any one of claims 1 to 5, wherein the subject is suffering from a cognitive disorder.

42. 42. The composition of claim 41, wherein the cognitive impairment is mild cognitive impairment.

43. The composition of any one of claims 1 to 5, wherein the subject is suffering from COVID-19 associated cognitive impairment and / or depression.

44. The composition of any one of claims 1 to 5, wherein the subject is suffering from Alzheimer's disease.

45. The composition of any one of claims 1 to 5, wherein the subject is suffering from ADHD.

46. The composition of any one of claims 1 to 5, wherein the subject suffers from an autism spectrum disorder.

47. 6. The composition of any one of claims 1 to 5, wherein the subject suffers from a pervasive developmental disorder, and optionally the pervasive developmental disorder is Asperger's syndrome or Rett's syndrome.

48. The composition according to any one of claims 1 to 5, wherein the subject suffers from atypical autism.

49. The composition of any one of claims 1 to 5, wherein the subject is suffering from multiple sclerosis.

50. The composition of any one of claims 1 to 5, wherein the subject is suffering from PTSD.

51. The composition of any one of claims 1 to 5, wherein the subject suffers from a sleep disorder.

52. The composition of any one of claims 1 to 5, wherein the subject is suffering from insomnia.

53. The composition of any one of claims 1 to 5, wherein the subject is suffering from daytime fatigue.

54. The composition of any one of claims 1 to 5, wherein the subject is suffering from REM sleep behavior disorder.

55. The composition of any one of claims 1 to 5, wherein the treating comprises improving sleep in a subject.

56. The composition according to any one of claims 1 to 5, characterized in that the composition is administered at a dose of about 50 mg / day to 750 mg / day or about 60 mg / day to about 540 mg / day of the peptide or pharmaceutically acceptable salt thereof, or peptide conjugate or pharmaceutically acceptable salt thereof.

57. 57. The composition of claim 56, wherein the dose is 60 mg / day, 180 mg / day, or 540 mg / day.

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