Compounds and methods for treating central nervous system disorders

Abstract

Described herein are isolated peptides, compositions comprising the isolated peptides, and methods of treating central nervous system disorders using such peptides or compositions.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 536,009, filed August 31, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention generally relates to the field of treatment for central nervous system disorders. More specifically, this invention relates to treatment using small peptides. Summary of the Invention

[0003] On the one hand, this article provides the isolated peptide of formula (I): (I), Or its pharmaceutically acceptable salt, wherein: R 1 It is a C1-C6 alkyl group; and R 2 Each group is independently selected from H, polyethylene glycol, fatty acids, and the extended half-life fraction.

[0004] On the other hand, this article provides a isolate peptide comprising the amino acid sequence LRP. Or derived from amino acid sequence LRP Composition, in which P It is 2-methylproline.

[0005] On the other hand, this article provides a separate peptide comprising or consisting of the amino acid sequence of KKLRP (SEQ ID NO: 1).

[0006] On the other hand, this article provides an isolated peptide comprising or consisting of the amino acid sequence of AKKLRP (SEQ ID NO: 2).

[0007] In some embodiments, the peptide further comprises PEGylation, biotinylation, or one or more halogens, or a combination of two or more thereof. In some embodiments, the peptide further comprises N-terminal carboxylation, C-terminal amidation, C-terminal benzylation, or a combination of two or more thereof. In some embodiments, the peptide is cyclized.

[0008] On the other hand, this article provides pharmaceutical compositions comprising the peptides described herein and at least one pharmaceutically acceptable excipient.

[0009] On the other hand, this document provides a method for treating a central nervous system disorder in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the peptide or composition described herein. In some embodiments, the central nervous system disorder is selected from autism spectrum disorder, bipolar disorder, rigidity, depression, post-traumatic stress disorder (PTSD), encephalitis, epilepsy / seizures, locked-in syndrome, meningitis, migraine, multiple sclerosis, myelopathy, neurodegenerative diseases, schizophrenia, obsessive-compulsive disorder, tic disorders, and any combination thereof. In some embodiments, the central nervous system disorder is Alzheimer's disease.

[0010] On the other hand, this article provides a method for treating Ferenc McDermid syndrome in subjects in need, the method comprising administering to the subject a therapeutically effective amount of the peptide or composition described herein.

[0011] On the other hand, this article provides a method for treating depression in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the peptide or composition described herein.

[0012] On the other hand, this article provides a method for treating post-traumatic stress disorder (PTSD) in subjects in need, the method comprising administering to the subject a therapeutically effective amount of the peptide or composition described herein.

[0013] On the other hand, this article provides a method for treating neurodevelopmental disorders in subjects in need, the method comprising administering to the subject a therapeutically effective amount of the peptide or composition described herein. In some embodiments, the neurodevelopmental disorder is selected from intellectual disability, autism spectrum disorder, motor disorder, tic disorder, traumatic brain injury, Down syndrome, attention deficit hyperactivity disorder, schizophrenia, schizophrenic-type disorder, hypogonadotropic hypogonadism syndrome, fetal alcohol spectrum disorder, and Minamata disease caused by mercury, or any combination thereof. In some embodiments, the autism spectrum disorder is classic autism or autism disorder; Asperger's syndrome; childhood disintegrative disorder; pervasive developmental disorder unclassified (PDD-NOS); Fragile X syndrome; Rett syndrome; Kanner syndrome; or Phelan-McDermid syndrome. In some embodiments, the motor disorder is developmental coordination disorder or stereotyped motor disorder. Attached Figure Description

[0014] Figure 1 The results of the Porsolt forced swimming test using compound A (KKLRP (SEQ ID NO: 1)), compound B (AKKLRP (SEQ ID NO: 2)) or the medium are presented.

[0015] Figure 2 , Figure 3 and Figure 4 Compounds A, B, and C (LRP) were shown respectively. , where P It is 2-methylproline) in in vitro The efficacy of increasing intracellular calcium levels was altered. Data conformed to a three-factor log agonist versus dose-response function, and reported EC50 values. 50 The value was significantly different from zero at the P<.05 level.

[0016] Figure 5A The competition between different concentrations of the unlabeled control compound or compound C and the labeled control compound (1 nM) for binding to recombinant IGF2R immobilized on 96-well plates was demonstrated. Each condition had N = 4 to 7 wells. IGF2R activity was measured in HEK cells expressing hIGF2R via calcium activation using Fluo-8. Control compound = PKKLRP (SEQ ID NO:3). Figure 5B The activity of IGF2R in HEK expressing hIGF2R was demonstrated by calcium activation via Fluo-8. P<0.05 Student t test, 2 tails, comparing the control compound and compound C at a fixed concentration.

[0017] Figure 6A , Figure 6B and Figure 6C Showing rats in vivo Electrophysiological test results. Compound C (1 mg / kg PO; 1 hr after administration) showed postsynaptic (fEPSP) activity. Figure 6A ) and presynaptic (paired pulse) Figure 6B Both compounds enhanced synaptic strength. Compound C also simultaneously enhanced qEEG α power ( Figure 6C ).

[0018] Figure 7A and Figure 7B The study showcases body movement recording and ultrasound vocalization during 24-hour home cage recordings of paired adult male SD rats. N = 7 to 8 cages / pair per group. Figure 7A The circadian rhythm amplitude was calculated by comparing the average activity, mediator (mean 20.5 ± SEM 3.4), and compound C (activity % change from light out to light on 47.1 ± 2.3) before and 6 hours after lights out. Figure 7B 24hr aversion / Total USV call rate. P<.05 Media and control student t test.

[0019] Figure 8A and Figure 8B Novel object recognition and Y-maze tests were demonstrated in mice. Adult male wild-type and 5XFAD heterozygous mice were administered compound C (0.01 to 10 mg / kg PO; administered by gavage) or sterile saline medium (10 mg / ml) 1 hour before exposure to familiar objects in a spontaneous alternating Y-maze test and a NOR test (24 hr retention test after administration), with N = 6 mice per group. P<.05 Dunnett post-hoc testing and media 5XFAD. Detailed Implementation

[0020] Various embodiments are described below. It should be noted that the specific embodiments are not intended to be an exhaustive description or a limitation on the broader aspects discussed herein. One aspect described in connection with a specific embodiment is not necessarily limited to the described embodiment and can be practiced with any other embodiments.

[0021] As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is a use of a term that is not clear to those skilled in the art, “about” will mean at most positive or negative 10% of the particular term, taking into account the context in which the term is used.

[0022] In the context of describing elements (especially in the context of the following claims), the terms “a”, “an”, “the”, and similar references should be interpreted as covering both singular and plural forms, unless otherwise indicated herein or explicitly contradicted by the context. Unless otherwise indicated herein, descriptions of value ranges herein are intended only as a way of individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if individually described herein. All methods described herein may be performed in any suitable order unless otherwise stated herein or explicitly contradicted by the context. Unless otherwise stated, any and all instances or exemplary language provided herein ( For example The use of "such as" is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of the claims. No language in this specification should be construed as indicating that any non-claimed element is necessary.

[0023] As used herein, the term "peptide" refers to a polymer of amino acid residues linked by amide bonds, which may optionally be chemically modified to achieve desired properties. The term "amino acid residue" includes, but is not limited to, amino acid residues contained in the group consisting of: alanine (Ala or A), cysteine ​​(Cys or C), aspartic acid (Asp or D), glutamic acid (Glu or E), phenylalanine (Phe or F), glycine (Gly or G), histidine (His or H), isoleucine (Ile or I), lysine (Lys or K), leucine (Leu or L), methionine (Met or M), asparagine (Asn or N), proline (Pro or P), glutamine (Gln or Q), arginine (Arg or R), serine (Ser or S), threonine (Thr or T), valine (Val or V), tryptophan (Trp or W), and tyrosine (Tyr or Y) residues. The term "amino acid residue" may also include non-natural amino acids or residues contained in the group consisting of: homocysteine, 2-aminoadipic acid, N-ethyl-L-asparagine, 3-aminoadipic acid, hydroxylysine, β-alanine, β-amino-propionic acid, allohydroxylysine, 2-aminobutyric acid, 3-hydroxyproline, 2-methylproline, 4-aminobutyric acid, 4-hydroxyproline, piperidine-3-carboxylic acid, 6-aminohexanoic acid, isodesin, 2-aminoheptanoic acid, alloleucine, 2-aminoisobutyric acid, N-methylglycine, 3-aminoisobutyric acid, N-methylisoleucine, 2-aminopimelic acid, 6-N-methyllysine, 2,4-diaminobutyric acid, N-methylvaline, despinatin, n-valine, 2,2'-diaminopimelic acid, n-leucine, 2,3-diaminopropionic acid, ornithine, and N-ethylglycine. Typically, the amide bond of a peptide is formed by an amino group on one amino acid backbone and a carboxyl group on another amino acid backbone.

[0024] "Pharmaceutical acceptable" means that the material is not biologically or otherwise undesirable. For example This material can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting harmfully with any other component of the composition containing it. When the term "pharmaceutical acceptable" is used to refer to a pharmaceutical carrier or excipient, it generally means that the carrier or excipient has met the standards required for toxicological and manufacturing testing, or that the carrier or excipient is included in the Inactive Ingredient Guide developed by the U.S. Food and Drug Administration.

[0025] As used herein, “subject” means an animal, such as a mammal (including humans), that has been or will be the subject of treatment, observation, or experimentation. Unless otherwise stated, “subject” and “patient” may be used interchangeably. Mammals include, but are not limited to, mice, rodents, rats, apes, humans, livestock, dogs, cats, racing animals, and pets. The methods described herein can be used for human therapeutics and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0026] The terms "therapeutic effective dose" and "effective dose" are used interchangeably and refer to the dose administered to a patient requiring such treatment at one or more doses. For example When administered to humans, the amount of a compound sufficient to achieve the therapeutic effect as defined below. The effective therapeutic amount will vary depending on the patient, the disease being treated, the patient's weight and / or age, the severity of the disease, or the method of administration determined by a qualified prescriber or caregiver.

[0027] The term “treatment / treating” means the application of the compounds disclosed herein for the purpose of: (i) delaying the onset of a disease, i.e. preventing or delaying the development of clinical symptoms of the disease; (ii) inhibiting the disease, i.e. preventing the development of clinical symptoms; and / or (iii) alleviating the disease, i.e. causing the reduction of clinical symptoms or their severity.

[0028] As used herein, “half-life extension” means any portion that extends the half-life of the compound disclosed herein in a subject. Examples of half-life extensions include, but are not limited to, polymers (such as polyethylene glycol (PEG) portions), fatty acids, peptides, glycosylation compounds, starches (such as hydroxyethyl starch), heparin, isotope labeling (such as deuterium), and prodrug portions.

[0029] As used herein, “fatty acid” refers to a straight-chain or branched saturated or unsaturated (including monounsaturated, diunsaturated, and polyunsaturated) carboxylic acid or its residues having, for example, 4 to 24 carbon atoms. Examples of fatty acids include, but are not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, benzyl acid, myristone acid, palmitoleic acid, saponin acid, oleic acid, transoleic acid, isoleic acid, linoleic acid, translinoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.

[0030] This disclosure also covers isotopically labeled compounds of this disclosure, which are identical to the compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. For example, compounds disclosed herein may have one or more H atoms substituted with deuterium.

[0031] "Prodrug" refers to a compound, including derivatives of the compounds disclosed herein, having a cleavable group and being converted into the pharmaceutically active compounds of the present invention by solvation or under physiological conditions. Examples of such prodrugs include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Prodrugs also include acid derivatives, such as esters prepared, for example, by reaction of a parent acid with a suitable alcohol, or amides, or acid anhydrides, or mixed acid anhydrides prepared by reaction of a parent acid compound with a substituted or unsubstituted amine.

[0032] When listing a range of values, the aim is to cover every value and subrange within that range. For example, “C1-C6 alkyl” is intended to cover C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0033] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbons with 1-6, 1-4, or 1 to 3 carbon atoms, referred to herein as C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl, etc.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this invention, representative illustrative methods and materials are described herein.

[0035] Central nervous system diseases Central nervous system disorders are neurological conditions that affect the structure or function of the brain or spinal cord, which together form the central nervous system (CNS). CNS disorders include neurodegenerative diseases and neurodevelopmental disorders.

[0036] Neurodegenerative diseases Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose function and eventually die over time. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, and progressive supranuclear palsy.

[0037] Neurodevelopmental disorders Neurodevelopmental disorders are deficits primarily associated with the function of the nervous system and brain. Non-restrictive examples include autism spectrum disorders.

[0038] One in 59 children in the United States is diagnosed with autism spectrum disorder (ASD). Phelan-McDermead syndrome (PMS) is an etiologically defined form of ASD caused by loss of function of the Shank3 gene and is estimated to account for up to 2% of ASD diagnoses. Currently, there are no disease-modifying treatments for either ASD or PMS. The various clinical and developmental symptoms of PMS and ASD can be managed with varying degrees of success through a range of costly interventions. The development of therapies for ASD is extremely challenging due to its significant etiological heterogeneity. However, drug development for etiologically defined subtypes of ASD, such as PMS, is feasible and could pave the way for treatments for other forms of autism.

[0039] Given the high prevalence of ASD diagnosis in the general population, and the fact that over 80% of these diagnoses occur concurrently with other developmental, neurological, genetic, and psychiatric diagnoses, the economic and social burden of this disorder is enormous. The estimated annual cost for a child with ASD in the United States ranges from $11.5 to $60.9 billion (Lavelle). et al. , Pediatrics, (2014), 133(3):e520-529; Buescher et al. , JAMA Pediatr., (2014), 168(8):721-728). The median annual medical expenditure for children and adolescents with ASD is 8.0 to 10.0 times that of their normally developing peers.

[0040] Phelan-McDermid syndrome is a rare and complex neurodevelopmental disorder characterized by overall developmental delay, varying degrees of intellectual disability (ID), speech deficit or delay, ASD, epilepsy, sensory processing, attention and motor deficits, hypotonia, regression, brain abnormalities, mild malformation features, feeding and gastrointestinal problems, and a range of other comorbid clinical symptoms (Drapeau). et al. , eNeuro, (2018), 5(3): ENEURO.0046-18.2018; Harony-Nicolas et al. , J. Child. Neurol., (2015), 30(14):1861-1870; Kolevzon et al. , Mol. Autism, (2014), 5(1):54). In fact, PMS is one of the most common and penetrating single-gene causes of autism and ID, accounting for up to 2% of ASD cases (Leblond , Mol. Autism, (2014), 5(1):54). et al. , PLoS Genet., (2014), 10(9):e1004580). Therefore, the development of the first effective pharmacological treatment for PMS will have an impact on the management of PMS and possibly ASD.

[0041] peptides In one respect, this article provides a separate peptide consisting of the amino acid sequence of KKLRP (SEQ ID NO: 1).

[0042] On the other hand, this article provides a separated peptide consisting of the amino acid sequence of AKKLRP (SEQ ID NO: 2).

[0043] On the other hand, this paper provides the isolated peptide of formula (I): (I), Or its pharmaceutically acceptable salt, wherein: R 1 It is a C1-C6 alkyl group; and R 2 Each group is independently selected from H, polyethylene glycol, fatty acids, and the extended half-life fraction.

[0044] In some embodiments, R 1 It is a C1-C4 alkyl group. For example, R 1 It is a methyl group.

[0045] In some embodiments, R 2 It is H. In some embodiments, R 2 Choose the group consisting of free H, polyethylene glycol, and fatty acids.

[0046] On the other hand, this article provides LRP The isolated peptide is composed of an amino acid sequence, in which P It is 2-methylproline. LRP It is also referred to in this paper as Leu-Arg-2-methyl-Pro-NH2 and has the following chemical structure: .

[0047] In some embodiments, the peptides disclosed herein comprise both D- and L-amino acids. In some embodiments, the peptides disclosed herein comprise only L-amino acids.

[0048] In some embodiments, the peptides disclosed herein are cyclized. In some embodiments, the peptides disclosed herein are non-cyclized.

[0049] In some embodiments, the peptides disclosed herein further include modifications at the N-terminus, C-terminus, or both. For example, in one embodiment, the peptide further includes an acyl group (such as, but not limited to, an acetyl group) at the N-terminus. In another embodiment, the peptide further includes an amide group at the C-terminus. In some embodiments, the peptides disclosed herein further comprise PEGylation, biotinylation, or one or more halogens, or a combination of two or more of these. In some embodiments, the peptides disclosed herein further comprise N-terminal carboxylation, C-terminal amidation, C-terminal benzylation, or a combination of two or more of these.

[0050] In some embodiments, the peptides disclosed herein include any form of peptide having substantially homology with SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a peptide that is “substantially homologous” to SEQ ID NO: 1 or SEQ ID NO: 2 is about 50% homologous, more preferably about 70% homologous, even more preferably about 80% homologous, more preferably about 90% homologous, even more preferably about 95% homologous, even more preferably about 99% homologous.

[0051] As is known in the art, the “similarity” between two peptides is determined by comparing the amino acid sequence of one polypeptide and its conserved amino acid substitutions with the sequence of a second polypeptide. A variant is defined as a peptide sequence that differs from the original sequence, preferably with less than 40% of the residues differing from the original sequence in each fragment of interest, more preferably less than 25% of the residues differing from the original sequence in each fragment of interest, even more preferably less than 10% of the residues differing from the original protein sequence in each fragment of interest, and most preferably differing from the original protein sequence by only a few residues in each fragment of interest, while simultaneously being sufficiently homologous to the original sequence to retain the functionality of the original sequence and / or the ability to stimulate stem cell differentiation into osteoblast lineages. The present invention includes amino acid sequences that are at least 60%, 65%, 70%, 72%, 74%, 76%, 78%, 80%, 90%, or 95% similar to or identical to the original amino acid sequence. The degree of identity between two peptides is determined using computer algorithms and methods well known to those skilled in the art. The identity between two amino acid sequences is preferably determined by using the BLASTP algorithm [BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md. 20894, Altschul, S., et al., J.Mol. Biol. 215: 403-410 (1990)].

[0052] In some embodiments, the peptides disclosed herein are variants containing one or more deletions relative to a reference amino acid sequence. A “deletion” refers to a change in the amino acid or nucleotide sequence that results in the absence of one or more amino acid residues or nucleotides relative to the reference sequence. A deletion removes at least one amino acid residue or nucleotide. Deletions may include internal deletions or terminal deletions (e.g., N-terminal or C-terminal truncation of a reference polypeptide or 5'-terminal or 3'-terminal truncation of a reference polynucleotide).

[0053] In some embodiments, the peptides disclosed herein are variants of fragments comprising a reference amino acid sequence. A “fragment” is a portion of an amino acid sequence or polynucleotide that is identical in sequence to the reference sequence but shorter in length. A fragment may comprise at most the full length of the reference sequence, minus at least one nucleotide / amino acid residue. For example, a fragment may comprise 5 to 1000 consecutive nucleotide or consecutive amino acid residues of a reference polynucleotide or reference polypeptide, respectively. In some embodiments, a fragment may comprise at least 3 or 4 consecutive amino acid residues of a reference peptide, respectively. Fragments may preferably be selected from certain regions of a molecule. The term “at least one fragment” encompasses a full-length polynucleotide or full-length polypeptide.

[0054] In some embodiments, the peptides disclosed herein are variants containing one or more insertions or additions relative to a reference sequence. The terms “insertion” and “addition” refer to a change in amino acid or sequence resulting in the addition of one or more amino acid residues. An insertion or addition may refer to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0055] The peptides disclosed herein can be variants containing one or more non-natural amino acids, formed through post-translational modification or by introducing one or more non-natural amino acids during translation or chemical synthesis. Various methods are available for introducing non-natural amino acids during protein translation.

[0056] The peptides disclosed herein may comprise one or more variants selected from: halogens, optional C1-C3 alkyl substituents (further optionally substituted with one or more halogen or amino (NH2) groups or combinations thereof), optional hydroxyl substituents, optional amino (NH2) group substituents, and optional omission of one or more of the alkyl, hydroxyl, or amino groups. Variants comprising one or more halogens may include at least one radioisotope halogen, such as 18-fluoro. In some embodiments, the variant has proline substituted with 2-methylproline.

[0057] The peptides of this invention can be synthesized using any techniques known to those skilled in the art and by methods as disclosed herein. Methods for synthesizing the disclosed peptides may include the chemical synthesis of proteins or peptides, expression of peptides using standard molecular biology techniques, and / or isolation of proteins or peptides from natural sources. The disclosed peptides thus synthesized may be subject to further chemical and / or enzymatic modifications. Various methods for the commercial preparation of peptides and polypeptides are known to those skilled in the art.

[0058] In unrestricted instances, LRP (where P) (It is 2-methylproline) prepared as shown in Scheme 1.

[0059] Option 1.

[0060]

[0061] The peptides of this invention can be prepared alternatively by recombinant methods or by cleavage from longer polypeptides. The composition of the peptides can be confirmed by amino acid analysis or sequencing.

[0062] The peptides of this invention are capable of post-translational modifications. For example, post-translational modifications falling within the scope of this invention include signal peptide cleavage, glycosylation, acetylation, isoprenelation, proteolysis, myristoylation, protein folding, and proteolytic processing. Some modification or processing events require the introduction of additional biological mechanisms. For example, processing events such as signal peptide cleavage and core glycosylation can be examined by adding canine microsomal membrane or Xenopus laevis egg extract to a standard translation reaction (US Patent No. 6,103,489).

[0063] The peptides disclosed herein can be modified to include non-amino acid moieties. Modifications may include, but are not limited to, carboxylation (e.g., N-terminal carboxylation via the addition of a dicarboxylic acid (such as glutaric acid, succinic acid, adipic acid, and 4,4-dimethylglutaric acid) having 4-7 straight-chain or branched carbon atoms), amidation (e.g., C-terminal amidation via the addition of an amide or a substituted amide (such as an alkylamide or dialkylamide), polyethylene glycolation (e.g., N-terminal or C-terminal polyethylene glycolation via the addition of polyethylene glycol), acylation (e.g., O-acylation (ester), N-acylation (amide), S-acylation (thioester)), acetylation (e.g., adding an acetyl group at the N-terminus or lysine residue of a protein), formylation, and biological... Acrylation, esterification (e.g., attachment of lipoic acid, C8 functional group), myristylation (e.g., attachment of myristic acid, C14 saturated acid), palmitoylation (e.g., attachment of palmitic acid, C16 saturated acid), alkylation (e.g., addition of an alkyl group, such as adding a methyl group at a lysine or arginine residue or attaching a methyl group to the peptide backbone), isopreneation or isopentenylation (e.g., addition of isoprene-like groups, such as farnesol or geraniylgeraniol), C-terminal amidation, glycosylation (e.g., adding a glycosyl group to asparagine, hydroxylysine, serine, or threonine to form a glycoprotein), and benzylation (e.g., using a benzyl group to replace a hydrogen atom). In some embodiments, proline is replaced by a 2-amino-thiophene-3-carboxylic acid ester (Nadimpally). et al. (ChemistrySelect, (2017), 3594-3596). In some embodiments, the benzene ring on the selected amino acid residue is modified to include one or more fluorine atoms. In another embodiment, at least one fluorine atom is 18-fluoro.

[0064] Composition In some embodiments, the peptides described herein are formulated as pharmaceutically acceptable compositions when combined with at least one pharmaceutically acceptable carrier and / or excipient. Such pharmaceutically acceptable carriers and / or excipients are non-toxic and do not interfere with the active ingredient (…). For exampleThe efficacy of the peptides disclosed herein. The exact nature of the pharmaceutically acceptable carriers and / or excipients depends on the route of administration. The compositions can be formulated for any pharmaceutically acceptable route of administration, such as, for example, oral, parenteral, pulmonary, topical, rectal, nasal, vaginal administration, or via an implantable receptacle. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection. The compositions disclosed herein can be formulated into solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, and aerosols.

[0065] In pharmaceutical dosage forms, the peptides disclosed herein may be administered in the form of pharmaceutically acceptable salts (such as, but not limited to, acetates) and / or their salts or their free base forms, or as pharmaceutically acceptable solvates, or the peptides may be used alone or appropriately in combination, as well as in combination with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way intended to limit the scope of the invention.

[0066] For oral administration, liquid or solid dosage forms may be used. Some non-limiting examples of oral dosage forms include tablets, gelatin capsules, pills, lozenges, elixirs, suspensions, syrups, rice paper capsules, chewing gum, etc. Peptides may be mixed with suitable drug carriers (media) or excipients as understood by those skilled in the art. Non-limiting examples of carriers and excipients include starch, milk, sugar, certain types of clay, gelatin, lactic acid, stearic acid or its salts, including magnesium or calcium stearate, talc, vegetable fats or oils, gums, and glycols.

[0067] For systemic, intrathecal, local, intranasal, subcutaneous, or transdermal administration, formulations of peptides suitable for the methods of this invention can utilize conventional diluents, carriers, or excipients. wait Formulations may contain one or more of the following: stabilizers, surfactants (such as nonionic, ionic, anionic, cationic, or amphoteric surfactants), and optionally salts and / or buffers. The peptide may be delivered in solution or in a reconstituted lyophilized form.

[0068] In some embodiments, the stabilizer may be, for example, an amino acid, such as glycine, or an oligosaccharide, such as sucrose, a tetrasaccharide, lactose, or dextran. Alternatively, the stabilizer may be a sugar alcohol, such as mannitol, sorbitol, xylitol, or a combination thereof. In some embodiments, the stabilizer or combination of stabilizers constitutes about 0.1% to about 10% of the weight of the formulation, or any percentage between these two values.

[0069] In some embodiments, the surfactant is a nonionic surfactant, such as polysorbate. Some examples of suitable surfactants include polysorbate (… For example (Tween 20, Tween 80); polyethylene glycol or polyoxyethylene polyoxypropylene glycol, such as about 0.001% (w / v) to about 10% (w / v) of Pluronic F-68 or any percentage between these two values.

[0070] The salt or buffer can be any salt or buffer, such as, for example, sodium chloride or sodium / potassium phosphate, respectively. In some embodiments, the buffer maintains the pH of the pharmaceutical composition in the range of about 5.5 to about 7.5 or any pH between these two values. The salt and / or buffer can also be used to maintain osmotic pressure at a level suitable for administration to humans or animals. In some embodiments, the salt or buffer is present at a substantially isotonic concentration of about 150 mM to about 300 mM.

[0071] Formulations of peptides that can be used in the methods of the present invention may additionally contain one or more conventional additives. Some non-limiting examples of such additives include solubilizers, such as glycerol; antioxidants, such as benzalkonium chloride (a mixture of quaternary ammonium compounds, referred to as "quats"), benzyl alcohol, chlorhexidine, or chlorobutanol; anesthetics, such as morphine derivatives; or isotonic agents. wait As described above. As an additional precaution against oxidation or other spoilage, the pharmaceutical composition may be stored under nitrogen in vials sealed with impermeable stoppers.

[0072] The amount of any single excipient in the composition will vary depending on the function of the excipient, the dosage requirements of the active agent component, and the specific needs of the composition. However, typically the amount of excipient present in the composition is from about 1% to about 99% by weight, from about 5% to about 98% by weight, or from about 15% to about 95% by weight. Generally, the amount of excipient present in the compositions of this disclosure is selected from the following: at least about 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or even 95% by weight.

[0073] On the other hand, this document provides formulations for intravenous, intramuscular, subcutaneous, or intranasal administration, comprising, substantially comprising, or consisting of the peptides disclosed herein and at least one pharmaceutically acceptable excipient. In some embodiments, the formulation is for intravenous administration. In some embodiments, the formulation is for intramuscular administration. In some embodiments, the formulation is for subcutaneous administration. In some embodiments, the formulation is for intranasal administration.

[0074] One or more additional active agents may be applied sequentially or simultaneously with the peptides disclosed herein. In some embodiments, the peptides disclosed herein and one or more additional active agents are applied in a single composition. Non-limiting examples of additional active agents include sodium chloride and carboxymethyl cellulose.

[0075] In some embodiments, the peptides disclosed herein may be administered to patients at effective doses ranging from about 0.1 mg / kg to about 500 mg / kg per day. This includes doses of 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, and 180 mg / kg per day. 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 or 500 mg / kg.

[0076] Typically, the therapeutically effective doses of the peptides disclosed herein range from about 0.1 mg / day to 500 mg / day, about 1 mg / day to 25 mg / day, about 3 mg / day to 15 mg / day, about 3 mg / day to 20 mg / day, about 30 mg / day to 720 mg / day, about 60 mg / day to 600 mg / day, or about 100 mg / day to 480 mg / day or more in total daily doses. In some embodiments, the therapeutically effective amount of the peptides disclosed herein ranges from about 1 mg / day to 240 mg / day, about 30 mg / day to 240 mg / day, about 30 mg / day to 200 mg / day, about 30 mg / day to 120 mg / day, about 1 mg / day to 120 mg / day, about 50 mg / day to 150 mg / day, about 60 mg / day to 150 mg / day, about 60 mg / day to 120 mg / day, or about 60 mg / day to 100 mg / day, administered as a single dose or multiple doses. In some embodiments, multiple doses include doses administered twice, three times, or four times daily.

[0077] In some embodiments, the therapeutically effective amount of the peptides disclosed herein is at least 0.1 mg / day, at least 0.5 mg / day, at least 1 mg / day, at least 5 mg / day, at least 10 mg / day, at least 15 mg / day, at least 20 mg / day, at least 30 mg / day, at least 40 mg / day, at least 50 mg / day, at least 60 mg / day, at least 70 mg / day, at least 80 mg / day, at least 90 mg / day, at least 100 mg / day, at least 110 mg / day, at least 120 mg / day, at least 130 mg / day, at least 140 mg / day, at least 150 mg / day, at least 160 mg / day, at least 170 mg / day, at least 180 mg / day, at least 190 mg / day, at least 200 mg / day, at least 225 mg / day, at least 250 mg / day, at least 275 mg / day, at least 300 mg / day, at least 325 mg / day, at least 350 mg / day. mg / day, at least 375 mg / day, at least 400 mg / day, at least 425 mg / day, at least 450 mg / day, at least 475 mg / day, or at least 500 mg / day.

[0078] Of course, the dosage can be changed based on the patient's age, weight, susceptibility, symptoms, or the efficacy of the compound.

[0079] The peptides and compositions disclosed herein can be used to prepare formulations and medicaments for treating depression, central nervous system disorders, or neurodevelopmental disorders. In some embodiments, the peptides and compositions disclosed herein are used to prepare formulations and medicaments for treating autism spectrum disorders. In some embodiments, the peptides and compositions disclosed herein are used to prepare formulations and medicaments for treating Phelan-McDermid syndrome.

[0080] method On the other hand, this document provides a method for treating a central nervous system disorder in a subject in need, the method comprising, substantially comprising, or comprising comprising administering to the subject a therapeutically effective amount of the peptide or composition disclosed herein. In some embodiments, the central nervous system disorder is selected from autism spectrum disorder, bipolar disorder, rigidity, depression, post-traumatic stress disorder (PTSD), encephalitis, epilepsy / seizures, locked-in syndrome, meningitis, migraine, multiple sclerosis, myelopathy, neurodegenerative disease, schizophrenia, obsessive-compulsive disorder, and tic disorders, or any combination thereof. In some embodiments, the central nervous system disorder is Alzheimer's disease.

[0081] On the other hand, this article provides a method for treating central nervous system disorders in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a separated peptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0082] On the other hand, this article provides a method for treating central nervous system disorders in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a separated peptide consisting of the amino acid sequence of KKLRP (SEQ ID NO: 1).

[0083] On the other hand, this article provides a method for treating central nervous system disorders in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a peptide consisting of the amino acid sequence of AKKLRP (SEQ ID NO: 2).

[0084] On the other hand, this article provides a method for treating central nervous system disorders in subjects in need, the method comprising, substantially comprising, or consisting of: administering to the subject a therapeutically effective amount of LRP. A peptide composed of an amino acid sequence, wherein P It is 2-methylproline.

[0085] On the other hand, this document provides a method for treating neurodevelopmental disorders in a subject in need, the method comprising, substantially comprising, or comprising comprising administering to the subject a therapeutically effective amount of the peptide or composition disclosed herein. In some embodiments, the neurodevelopmental disorder is selected from intellectual disability, autism spectrum disorder, motor disorder, tic disorder, traumatic brain injury, Down syndrome, attention deficit hyperactivity disorder, schizophrenia, schizophrenic disorder, hypogonadotropic hypogonadism syndrome, fetal alcohol spectrum disorder, and mercury-induced Minamata disease, or any combination thereof.

[0086] On the other hand, this article provides a method for treating neurodevelopmental disorders in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a separated peptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0087] On the other hand, this article provides a method for treating neurodevelopmental disorders in subjects in need, the method comprising, substantially consisting of, or consisting of: administering to the subject a therapeutically effective amount of a separated peptide consisting of the amino acid sequence of KKLRP (SEQ ID NO:1).

[0088] On the other hand, this article provides a method for treating neurodevelopmental disorders in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a peptide consisting of the amino acid sequence of AKKLRP (SEQ ID NO:2).

[0089] On the other hand, this article provides a method for treating neurodevelopmental disorders in subjects in need, the method comprising, substantially consisting of, or consisting of: administering a therapeutically effective amount of LRP to the subject. A peptide composed of an amino acid sequence, wherein P It is 2-methylproline.

[0090] In some embodiments, autism spectrum disorder is classic autism or autism disorder; Asperger's syndrome; childhood disintegrative disorder; pervasive developmental disorder unclassified (PDD-NOS); Fragile X syndrome; Ritter syndrome; Kanner syndrome; or Phelan-McDermid syndrome.

[0091] In some embodiments, the movement disorder is a developmental coordination disorder or a stereotyped movement disorder.

[0092] On the other hand, this document provides a method for treating autism spectrum disorder in a subject of need, the method comprising, substantially comprising, or comprising comprising administering to the subject a therapeutically effective amount of the peptide or composition disclosed herein. In some embodiments, the autism spectrum disorder is classic autism or autism disorder. In some embodiments, the autism spectrum disorder is Asperger's syndrome. In some embodiments, the autism spectrum disorder is childhood disintegrative disorder. In some embodiments, the autism spectrum disorder is pervasive developmental disorder unclassified (PDD-NOS). In some embodiments, the autism spectrum disorder is Fragile X syndrome. In some embodiments, the autism spectrum disorder is Rett syndrome. In some embodiments, the autism spectrum disorder is Kanner syndrome. In some embodiments, the autism spectrum disorder is Phelan-McDermid syndrome.

[0093] On the other hand, this article provides a method for treating autism spectrum disorder in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a separated peptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0094] On the other hand, this article provides a method for treating autism spectrum disorder in subjects in need, the method comprising, substantially comprising, or comprising administering to the subject a therapeutically effective amount of a separated peptide consisting of the amino acid sequence of KKLRP (SEQ ID NO:1).

[0095] On the other hand, this article provides a method for treating autism spectrum disorder in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a peptide consisting of the amino acid sequence of AKKLRP (SEQ ID NO: 2).

[0096] On the other hand, this article provides a method for treating autism spectrum disorder in subjects in need, which includes, substantially consists of, or consists of, administering a therapeutically effective dose of LRP to the subject. A peptide composed of an amino acid sequence, wherein P It is 2-methylproline.

[0097] On the other hand, this article provides a method for treating Ferenc McDermid syndrome in subjects in need, the method comprising, substantially comprising, or consisting of administering to the subject a therapeutically effective amount of the peptide or composition disclosed herein.

[0098] On the other hand, this article provides a method for treating Ferenc-McDermid syndrome in subjects in need, which includes, substantially consists of, or consists of administering to the subject a therapeutically effective amount of the isolated peptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0099] On the other hand, this article provides a method for treating Ferenc McDermid syndrome in subjects in need, comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a separated peptide consisting of the amino acid sequence of KKLRP (SEQ ID NO: 1).

[0100] On the other hand, this article provides a method for treating Feren-McDermid syndrome in subjects in need, comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a peptide consisting of the amino acid sequence of AKKLRP (SEQ ID NO: 2).

[0101] On the other hand, this article provides a method for treating Ferenc-McDermid syndrome in subjects in need, which includes, substantially consists of, or comprises: administering a therapeutically effective dose of LRP to the subject. A peptide composed of an amino acid sequence, wherein P It is 2-methylproline.

[0102] On the other hand, this article provides a method for treating depression in subjects in need, the method comprising, substantially comprising, or consisting of administering to the subject a therapeutically effective amount of a peptide or a composition described herein.

[0103] On the other hand, this article provides a method for treating depression in subjects in need, which includes, substantially consists of, or consists of administering to the subject a therapeutically effective amount of a separated peptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0104] On the other hand, this article provides a method for treating depression in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a separated peptide consisting of the amino acid sequence of KKLRP (SEQ ID NO: 1).

[0105] On the other hand, this article provides a method for treating depression in subjects in need, the method comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a peptide consisting of the amino acid sequence of AKKLRP (SEQ ID NO: 2).

[0106] On the other hand, this article provides a method for treating depression in subjects in need, which includes, substantially consists of, or comprises: administering to the subject a therapeutically effective dose of LRP. A peptide composed of an amino acid sequence, wherein P It is 2-methylproline.

[0107] On the other hand, this article provides a method for treating post-traumatic stress disorder (PTSD) in subjects in need, the method comprising, substantially comprising, or consisting of administering to the subject a therapeutically effective amount of the peptide or composition disclosed herein.

[0108] On the other hand, this article provides a method for treating post-traumatic stress disorder (PTSD) in subjects in need, comprising, substantially consisting of, or consisting of, administering to the subject a therapeutically effective amount of a separated peptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0109] On the other hand, this article provides a method for treating post-traumatic stress disorder (PTSD) in subjects in need, comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a separated peptide consisting of the amino acid sequence of KKLRP (SEQ ID NO: 1).

[0110] On the other hand, this article provides a method for treating post-traumatic stress disorder (PTSD) in subjects in need, comprising, substantially consisting of, or consisting of administering to the subject a therapeutically effective amount of a peptide consisting of the amino acid sequence of AKKLRP (SEQ ID NO: 2).

[0111] On the other hand, this article provides a method for treating post-traumatic stress disorder (PTSD) in subjects in need, which includes, substantially consists of, or comprises: administering a therapeutically effective dose of LRP to the subject. A peptide composed of an amino acid sequence, in which It is 2-methylproline.

[0112] The invention, which has been generally described therein, will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to limit the invention.

[0113] Example animal Adult male Sprague-Dawley (SD) rats (2-3 months old) were purchased from Harlan (USA) for the Porsolt forced swimming test. The rats were housed in plexiglass cages with poplar wood bedding, maintaining a 12:12 light:dark cycle (lights on at 5 AM), and were allowed to swim freely throughout the study. random Drinking Purina laboratory feed (USA) and tap water. All experiments were approved by the Animal Care and Use Committee of Sai Life Sciences (India).

[0114] Example 1. Porsolt Forced Swimming Test Porsolt forced swimming test according to Burgdorf et al. The procedure was performed as described in (Neuropsychopharmacology, (2013),38(5):729-742). Rats were administered compound A (KKLRP (SEQ ID NO: 1)), compound B (AKKLRP (SEQ ID NO: 2)), or 0.9% sterile saline medium (1 ml / kg, intravenous injection). Injection was performed via the lateral tail vein, and rats were tested 1 hour post-administration. Animals were placed in transparent glass tubes 46 cm high x 20 cm in diameter, filled to 30 cm with tap water (23 ± 1°C), for 15 min on day 1 (acclimation) and 5 min on subsequent test days. The water was changed after each subsequent animal was treated. Animals were videotaped, and the videotapes were scored offline by blinded experimenters, ensuring high inter-evaluator reliability (Pearson correlation coefficient >.9). Floating time (in seconds) is defined as the minimum effort required to keep the animal’s head above water, and dives (occurrences) are recorded when the animal’s entire body is submerged in water and its head is facing the bottom of the tank.

[0115] like Figure 1 As shown, in the Porsolt test of rats 1 hour after IV injection, both compound A and compound B reduced the floating time [F (2, 9) = 46.72, P<.001; Dunnett multiple comparison test: AP < .001 for mediator and compound, and BP < .001 for mediator and compound. Each group consisted of N = 4 male rats aged 2 to 3 months.

[0116] Example 2. Calcium imaging method.

[0117] Primary cortical cultures (E18 rats) were seeded into 96-well plates, and intracellular calcium in dendritic cells was measured at 21 DIV using a high-content confocal microscope (ImageXpress, Meigu Molecular Instruments) (using Fluo-8 dye, Abcam). Measurements were performed immediately before drug administration and again 1 hour after administration, and changes in fractions were analyzed. Compound A was obtained ( Figure 2 Compound B Figure 3 ) and compound C ( Figure 4 The results showed that the control compound (PKKLRP (SEQ ID NO: 3)) exhibited EC... 50 = 5 nM.

[0118] Example 3. IGF2R binding assay The recombinant c-terminal HIS-labeled IGF2R (R&D) system was coupled to clear copper-coated 96-well plates (Thermo, USA). Various concentrations of unlabeled IGF2 or IGFBP2 (Thermo, USA) or compound C were co-incubated with a biotinylated control compound (PKKLRP (SEQ ID NO: 3)) (1 nM) on a track-controlled shaker at room temperature for 30 min. Non-specific binding was determined by co-incubation with 10 mM of the unlabeled control compound. The plates were then washed three times in sample buffer tris HCl (10 mM). The samples were then co-incubated with streptavidin-HRP (1:1000, Sigma, USA), and binding was observed after washing using TMB and stop solution (HCl). Absorbance was quantified at 440 nM using a plate reader (Meigu Molecular Instruments, USA). Results are shown in [Table data would be inserted here]. Figure 5A .

[0119] IGF2R activity assays were performed entirely in accordance with Burgdorf standards. et al. The procedure was performed as described in (Mol. Psychiatry, (2023) 28(3):1101-1111, PMID: 36481930). In short, HEK cell lines expressing hIGF2-R were treated with different concentrations of compound C, and intercellular calcium was measured using an ImageXpress (molecular device) with a fluo-8, measured by subtracting the pre-drug level from the calcium signal 1 hour after administration. The results are shown in... Figure 5B .

[0120] The data were averaged over the repetitions and fitted to a log (agonist) versus response (three parameters) model (GraphPadPrism, USA).

[0121] Example 4. Rats in vivo Electrophysiology Rats were anesthetized with isoflurane (5% induction and 2% to 3% maintenance; total duration 15 to 20 min) and cranial screws were implanted for recording cortical electroencephalography (EEG) (Pinnacle, USA), as well as intracranial medial prefrontal cortex (MPFC) and periaqueductal gray matter (PAG) recording and stimulation (bipolar) with insulated stainless steel electrodes. Animals were given 7 days to recover before the start of the test. EEG signals were captured via a tethered system (AM Systems, USA). Data were acquired at 10 kHz using an AM Systems (USA) amplifier with high-pass (0.1 Hz) and low-pass (100 kHz) filters and digitized using Data Wave (A-MSystems, USA) acquisition software. Data were analyzed using Brain Products Analyzer 2 software (Germany).

[0122] In vivo study of excitatory synaptic strength (fEPSPS) For field potential studies, field potentials induced by shocks (10 µA, 70 µs, every 30 seconds) simulated using bipolar electrodes in layers 2 to 3 and 4 of the MPFC were recorded, and the initial slope after stimulation artifacts was quantified. Excitation field potential measurements were performed using single-shock induced fEPSPs. Paired-pulse facilitation measurements were performed using two shock pairs spaced 50 ms apart, and paired-pulse facilitation was calculated by the ratio of the second to the first fEPSP. Normalized α power was calculated using FFT (Brain Vision Analyzer, Germany). The test results for compound C are shown in... Figure 6A , Figure 6B and Figure 6C .

[0123] Example 5. Home cage motion recorder and ultrasonic sound generator. Male 2-3 month old SD rats were administered compound C (1 mg / kg PO) or sterile saline medium (1 ml / kg PO) according to Burgdorf guidelines. et al. The description of (Sleep, (2019), 42(10):zsz135) describes the collection of home cage motion recorder and ultrasonic vocalization data. The circadian rhythm amplitude was calculated by comparing mean activity, mediator (mean 20.5 ± SEM 3.4), and compound C (change in activity % from light-off to light-on, 47.1 ± 2.3) 6 hours before and after lights-off—see [link to full text]. Figure 7A Additionally, the 24-hour aversion / total USV call rate was calculated as a measure of negative impact. Figure 7B ).

[0124] Example 6. New Object Recognition (NOR) and Y-maze Test Novel object recognition and Y-maze tests in 5XFAD mice (- / +) and wild-type controls were performed in full accordance with Burgdorf standards. wait people The study was conducted as described in (Mol. Psychiatry, (2023) 28(3):1101-1111, PMID: 36481930). NOR test (working memory): In short, mice were acclimatized to an empty NOR region for one hour each day for the first three days of the learning test. During the learning test, mice were allowed to explore two identical objects (e.g., A1 and A2) for 10 minutes. This was followed by a 24-hour interval between tests, after which the mice were returned to their home cages. During the retention test, mice were allowed to explore both the familiar object (A) and the new object (e.g., B) from the learning test. Y-maze (long-term memory): In short, mice were placed in a Y-maze and allowed to enter any of the three arms for 7 minutes. The order of entry into the arms was recorded, and spontaneous alternation was analyzed. Alternating scores were given for each group of three consecutive choices when there was no repeated input. The discrimination index (DI) for both the Y-maze [(alternating entry - non-alternating entry) / total entries] and the NOR [(time spent exploring new objects - time spent exploring familiar objects) / total exploration time] tests was calculated. One hour prior to training for the Y-maze and NOR tests, animals were administered compound C (0.01 to 10 mg / kg PO) or sterile saline medium (10 ml / kg PO). Mean and SEM values ​​from wild-type (N=6), medium 5XFAD (n=6), and compound C 5XFAD (n=6) mice were used for statistical analysis (Graphpad Prism, USA). Results are shown in... Figure 8A and Figure 8B .

[0125] Although certain embodiments have been described and illustrated, it should be understood that changes and modifications may be made therein by those skilled in the art without departing from the broader aspects of the invention as defined in the following claims.

[0126] The embodiments described illustratively herein may be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” “containing,” etc., should be read broadly without limitation. Furthermore, the terms and expressions used herein have been used as descriptive rather than limiting terms and are not intended to exclude any equivalent forms of the features shown and described or portions thereof in the use of such terms and expressions; however, it is recognized that various modifications are possible within the scope of the claimed invention. Additionally, the phrase “consistently composed of” will be understood to include those elements specifically described and additional elements that do not materially affect the essential and novel features of the claimed invention. The phrase “consisting of” excludes any unspecified elements.

[0127] This disclosure is not limited to the specific embodiments described herein. Many modifications and variations of the technology of this invention can be made without departing from the spirit and scope of the invention, as will be apparent to those skilled in the art. In addition to those listed herein, functionally equivalent methods and combinations within the scope of this disclosure will be apparent to those skilled in the art based on the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terms of the appended claims and the full scope of their equivalents. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, or compositions, which are of course subject to variation. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0128] Furthermore, when features or aspects of this disclosure are described in accordance with the Markush group, those skilled in the art will recognize that this disclosure is also described in accordance with any individual member or subgroup of the Markush group.

[0129] As those skilled in the art will understand, for any and all purposes, particularly in providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily considered sufficiently descriptive and such that the same scope can be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily decomposed into a lower third, a middle third, and an upper third, etc. As those skilled in the art will also understand, all language such as “at most,” “at least,” “greater than,” “less than,” etc., includes the listed numbers and refers to a scope that can subsequently be decomposed into subscopes as discussed above. Finally, as those skilled in the art will understand, a scope includes each individual member.

[0130] All publications, patent applications, published patents, and other documents mentioned in this specification are incorporated herein by reference as if each individual publication, patent application, published patent, or other document were specifically and individually indicated as being incorporated herein by reference in its entirety. Where a definition contained in the text incorporated by reference contradicts a definition in this disclosure, the definition contained in the text incorporated by reference shall be excluded.

[0131] Other embodiments are set forth in the appended claims.

Claims

1. A separated peptide of formula (I): (I)， Or its pharmaceutically acceptable salt, wherein R 1 It is a C1-C6 alkyl group; and R 2 Each group is independently selected from H, polyethylene glycol, fatty acids, and the extended half-life fraction.

2. A method for obtaining LRPs based on amino acid sequences The isolated peptides consist of P It is 2-methylproline.

3. A separate peptide consisting of the amino acid sequence of KKLRP (SEQ ID NO: 1).

4. A separate peptide consisting of the amino acid sequence of AKKLRP (SEQ ID NO: 2).

5. The peptide according to any one of claims 1 to 4, further comprising PEGylation, biotinylation, or one or more halogens, or a combination of two or more of them.

6. The peptide according to any one of claims 1 to 5, further comprising N-terminal carboxylation, C-terminal amidation, C-terminal benzylation, or a combination of two or more thereof.

7. The peptide according to any one of claims 1 to 6, wherein the peptide is cyclized.

8. A pharmaceutical composition comprising a peptide according to any one of claims 1 to 7 and at least one pharmaceutically acceptable excipient.

9. A method for treating a central nervous system disorder in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a peptide according to any one of claims 1 to 7 or a composition according to claim 8.

10. The method of claim 9, wherein the central nervous system disorder is selected from autism spectrum disorder, bipolar disorder, rigidity, depression, post-traumatic stress disorder (PTSD), encephalitis, epilepsy / seizures, locked-in syndrome, meningitis, migraine, multiple sclerosis, myelopathy, neurodegenerative diseases, schizophrenia, obsessive-compulsive disorder, tic disorders, and any combination thereof.

11. The method of claim 10, wherein the central nervous system symptom is Alzheimer's disease.

12. A method for treating Ferenc-McDermid syndrome in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the peptide according to any one of claims 1 to 7 or the composition according to claim 8.

13. A method for treating depression in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a peptide according to any one of claims 1 to 7 or a composition according to claim 8.

14. A method for treating post-traumatic stress disorder (PTSD) in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the peptide according to any one of claims 1 to 7 or the composition according to claim 8.

15. A method for treating a neurodevelopmental disorder in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a peptide according to any one of claims 1 to 7 or a composition according to claim 8.

16. The method of claim 15, wherein the neurodevelopmental disorder is selected from intellectual disability, autism spectrum disorder, motor disorder, tic disorder, traumatic brain injury, Down syndrome, attention deficit hyperactivity disorder, schizophrenia, schizophrenic disorder, hypogonadotropic hypogonadism syndrome, fetal alcohol spectrum disorder, and mercury-induced Minamata disease, or any combination thereof.

17. The method of claim 16, wherein the autism spectrum disorder is classic autism or autism disorder; Asperger's syndrome; childhood disintegrative disorder; pervasive developmental disorder unclassified (PDD-NOS); Fragile X syndrome; Ritter syndrome; Kanner syndrome; or Phelan-McDermid syndrome.

18. The method of claim 16, wherein the motor disorder is a developmental coordination disorder or a stereotyped motor disorder.

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