Neuromodulatory peptides

Abstract

The present disclosure provides, in part, compositions comprising neuromodulatory peptides and methods of using the same, e.g., to treat and / or ameliorate psychological, behavioral, and / or cognitive disorders.

Description

Attorney Docket No.: LACT-003PC / 121851-5003 NEUROMODULATORY PEPTIDES FIELD

[0001] The present disclosure relates to, in part, compositions comprising neuromodulatory peptides and methods of using the same. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The application claims the benefit of and priority to U.S. Provisional Application No.63 / 515,388, filed July 25, 2023, the entire contents of which is herein incorporated by reference. SEQUENCE LISTING

[0003] The instance application contains a sequence listing, which has been submitted in XML format via Patent Center. The contents of the XML file, named “LACT-003PC_Sequence_Listing.xml,” which was created on July 24, 2024, and is approximately 25,930 bytes in size, are incorporated herein by reference in their entirety. BACKGROUND

[0004] The nervous system is a highly-controlled system which functions to rapidly transmit signals via neurons and glial cells. It regulates a wide range of physiological functions such as appetite, sleep, body temperature, nociception, emotion, behavior, and memory. Neurological function is controlled, in part, by a series of signaling molecules, many of which are endogenous neuropeptides and peptide hormones. Many peptidic signaling transmitters exist as precursor proteins which are first synthesized in the cell and then digested, processed, and / or degraded by cellular proteases to produce the mature, bioactive peptides. These mature bioactive peptides are then secreted or otherwise exported from the cell, and then circulate to elicit their function on the nervous system.

[0005] Recently, experimentation has demonstrated that enzymatic digestion of food proteins produces peptides that can mimic the structure-function effects of endogenous peptides and peptide hormones. Food- derived peptides which mimic endogenous neuropeptides have grown interest for treating and modulating psychological, behavioral, and cognitive disorders. Relative to most biologics, such as antibodies, AAVs, and gene therapy vectors, neuropeptides exhibit low molecular weights and can more readily cross the blood- brain barrier. Although low molecular weight peptides derived can exhibit some level of behavioral or cognitive effect, they suffer from significant disadvantages as therapeutics. For example, food-derived peptides outside 1 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 of the gastrointestinal lumen tend to exhibit poor bioavailability, poor plasma half-life (T1 / 2on the order of minutes), and susceptibility to proteases, which delimit their therapeutic usefulness. Additionally, their purported therapeutic mechanisms are poorly understood.

[0006] There remains a need to develop peptides and peptide drugs that resemble endogenous neuropeptides and peptide hormones in that they can exhibit neuromodulatory effects, while addressing the shortcomings of food-derived peptides outside of the gastrointestinal lumen, especially for lower molecular weight peptides, such as poor bioavailability and poor half-life. SUMMARY

[0007] Accordingly, the present disclosure provides, in part, compositions of a peptide comprising a general formula I: R1-[F1Q1X1E1]y-R2(I), where F1is or comprises a phenylalanine, Q1is or comprises a glutamine, X1 is or comprises a serine, threonine, or a non-canonical amino acid, and E1 is or comprises a glutamate, and where at least one of R1, F1, Q1, X1, E1, and / or R2comprises one or more modifications.

[0008] In embodiments, the peptide is oriented amino-terminus to carboxy-terminus, or the peptide is oriented carboxy-terminus to amino-terminus. In embodiments, y is a whole number integer between 1 and 10. In embodiments, y is 1.

[0009] In embodiments, R1is or comprises a non-modified amino-terminus. In embodiments, R1is or comprises an amino-terminus comprising one or more modifications which comprise one or more chemical modifications. In embodiments, the one or more chemical modifications is or comprises one or more of acetylation, methylation, thiolation, glycosylation, prenylation, PEGylation, biotinylation, aminoethylation, halogenation, lipidation, myristylation, palmitoylation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine.

[0010] In embodiments, R1is or comprises an acetylated amino-terminus of F1. In embodiments, R1is or comprises a myristoylated amino-terminus of F1. In embodiments, R1 is or comprises a palymitoylated amino-terminus of F1.

[0011] In embodiments, R2 is or comprises a non-modified carboxy-terminus. In embodiments, R2 is or comprises a carboxy-terminus comprising one or more modifications which comprise one or more chemical modifications. In embodiments, the one or more chemical modification is or comprises one or more of amidated, acetylation, methylation, thiolation, glycosylation, prenylation, PEGylation, biotinylation, 2 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 aminoethylation, halogenation, lipidation, myristylation, palmitoylation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine.

[0012] In embodiments, R2 is or comprises an amidated carboxy-terminus of E1. In embodiments, R2 is or comprises an myristoylated carboxy-terminus. In embodiments, R2is or comprises a myristoylated D- lysine carboxy-terminus. In embodiments, R1 is or comprises a palymitoylated carboxy-terminus of E1. In embodiments, R2 is or comprises a palymitoylated D-lysine carboxy-terminus.

[0013] In embodiments, the modification comprises one or more non-canonical amino acids comprising sarcosine (N-methylglycine), hydroxyproline, homoserine, β-serine, homoglutamine, homoallylglycine, homopropargylglycine, azidohomoalanine, azidonorleucine, azidophenylalanine, acetylphenylalanine, aminoisobutyric acid, selenocysteine, dehydroalanine, pyrrolysine, α-amino-n-heptanoic acid, t-leucine, pipecolic acid, α,β-diaminopropionic acid, α,γ-diaminobutyric acid, ornithine, allothreonine, homocysteine, isoserine, β-alanine, β-amino-n-butyric acid, β-aminoisobutyric acid, γ-aminobutyric acid, α-aminoisobutyric acid, isovaline, N-ethylglycine, N-propylglycine, N-isopropylglycine, N-methylalanine, N-ethylalanine, N- methyl-β-alanine, N-ethyl-β-alanine, α-hydroxy-γ-aminobutyric acid, D-amino acids, and / or β-amino acids.

[0014] In embodiments, the non-canonical amino acid is or comprises sarcosine (N-methylglycine). In embodiments, the non-canonical amino acid is or comprises hydroxyproline. In embodiments, the non- canonical amino acid is or comprises homoserine, beta-serine, beta / beta-serine, and / or homoglutamine.

[0015] In embodiments, one or more of F1, Q1, X1, and E1is or comprises an L-form amino acid. In embodiments, X1is or comprises L-serine. In embodiments, X1comprises is or L-homoserine. In embodiments, X1 is or comprises L-sarcosine. In embodiments, X1 is or comprises L-hydroxyproline. In embodiments, each of F1, Q1, X1, and E1is or comprises a L-form amino acid.

[0016] In embodiments, one or more of F1, Q1, X1, and E1is or comprises a D-form amino acid. In embodiments, X1 is or comprises D-serine. In embodiments, X1 is or comprises D-homoserine. In embodiments, X1is or comprises D-threonine. In embodiments, Q1is or comprises D-glutamine. In embodiments, each of F1, Q1, X1, and E1 is or comprises a D-form amino acid. In embodiments, each of F1, Q1, X1, and E1 is or comprises a D-form amino acid oriented from C-terminus to N-terminus (EXQF).

[0017] In embodiments, at least one peptide bond and / or at least one amino acid side chain comprises one or more chemical modifications. In embodiments, the one or more chemical modifications is or comprises 3 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 acetylation, amidation, methylation, thiolation, glycosylation, prenylation, PEGylation, biotinylation, aminoethylation, halogenation, lipidation, myristylation, palmitoylation, disulfide bond formation, peptide bond formation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine.

[0018] In embodiments, the one or more chemical modifications is or comprises incorporation of a non- canonical amino acid, non-naturally occurring amino acid, and / or non-canonical peptide bond.

[0019] In embodiments, the X1 residue is or comprises a chemical modification and / or non-canonical serine. In embodiments, the chemical modification and / or non-canonical serine is or comprises N- methylserine (NMe-Ser). In embodiments, the chemical modification and / or non-canonical serine is or comprises Cα-methyl-serine. In embodiments, the chemical modification and / or non-canonical serine is or comprises beta-serine (beta-Ser). In embodiments, the chemical modification and / or non-canonical serine is or comprises a fluorinated serine, optionally difluoromethane serine or trifluoromethane serine. In embodiments, the chemical modification and / or non-canonical serine is or comprises beta-dimethyl-serine (beta / beta-serine). In embodiments, the chemical modification and / or non-canonical serine is or comprises a benzyl-modified serine or a toluene-modified serine (benzyl-serine).

[0020] In embodiments, the Q1glutamine is or comprises N-methylglutamine (NMe-Gln). In embodiments, the Q1glutamine is or comprises homoglutamine (homo-Gln). In embodiments, the Q1glutamine is or comprises beta-glutamine (beta-Gln).

[0021] In embodiments, the one or more modifications comprises one or more chemical modifications that reduces and / or ablates protease degradation and / or peptidase cleavage relative to a peptide lacking the one or more chemical modifications. In embodiments, this reduction and / or ablation of protease degradation and / or peptidase cleavage is in vivo. In embodiments, the one or more chemical modifications is within and / or conjugated to the peptide bond between the F1and Q1residues, the Q1and X1residues, the X1and E1residues, and / or the E1 residue and a R2 residue. In embodiments, the one or more chemical modifications reduces and / or protects against protease and / or peptidase activity and / or peptide bond cleavage between the F1 and Q1 residues, the Q1 and X1 residues, the X1 and E1 residues, and / or the E1 residue and one or more residues at position R2. In embodiments, the one or more chemical modifications reduces and / or protects against dicarboxypeptidase cleavage activity and / or cleavage. In embodiments, the one or more chemical modifications is within and / or conjugated to the peptide bond between the F1 and Q1 residues and / or 4 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 the Q1and X1residues. In embodiments, the one or more chemical modifications comprises a tertiary amine, optionally comprising a methyl group.

[0022] In embodiments, the one or more modifications increases a half-life of the peptide, optionally a serum half-life, and further optionally a serum half-life as measured in humans and / or as measured in dogs and / or other companion animals.

[0023] In embodiments, the one or more modifications comprises one or more amino acids forming a contiguous isopeptide bond with the carboxy-terminus of the E1residue at R2. In embodiments, R2comprises or consists of the amino acid sequence selected from SEQ ID NO: 14 (EQQQTEDELQDK), SEQ ID NO: 15 (EQQQTEDELQD), SEQ ID NO: 16 (EQQQTEDEL), SEQ ID NO: 17 (EQQQTEDE), SEQ ID NO: 18 (EQQQTED), SEQ ID NO: 19 (EQQQTE), SEQ ID NO: 20 (EQQQT), SEQ ID NO: 21 (EQQQ), EQQ, EQ, E, and an amino acid sequence having one or more substitutions, deletions, of insertions thereof.

[0024] In embodiments, the peptide comprises or consists of about or at least about 4 amino acids to about or at least about 50 amino acids. In embodiments, the peptide comprises or consists of about or at least about 4 amino acids, about or at least about 5 amino acids, about or at least about 6 amino acids, about or at least about 7 amino acids, about or at least about 8 amino acids, about or at least about 9 amino acids, about or at least about 10 amino acids, about or at least about 11 amino acids, about or at least about 12 amino acids, about or at least about 13 amino acids, about or at least about 14 amino acids, about or at least about 15 amino acids, about or at least about 16 amino acids, about or at least about 17 amino acids, about or at least about 18 amino acids, about or at least about 19 amino acids, about or at least about 20 amino acids, about or at least about 25 amino acids, about or at least about 30 amino acids, about or at least about 35 amino acids, about or at least about 40 amino acids, about or at least about 45 amino acids, or about or at least about 50 amino acids.

[0025] In embodiments, the peptide comprises or consists of an amino acid sequence selected from SEQ ID NO: 1 (FQSE), SEQ ID NO: 2 (FQSEE), SEQ ID NO: 3 (FQSEEQ), SEQ ID NO: 4 (FQSEEQQ), SEQ ID NO: 5 (FQSEEQQQ), SEQ ID NO: 6 (FQSEEQQQT), SEQ ID NO: 7 (FQSEEQQQTE), SEQ ID NO: 8 (FQSEEQQQTED), SEQ ID NO: 9 (FQSEEQQQTEDE), SEQ ID NO: 10 (FQSEEQQQTEDEL), SEQ ID NO: 11 (FQSEEQQQTEDELQD), SEQ ID NO: 12 (FQSEEQQQTEDELQDK), SEQ ID NO: 13 (ESQF).

[0026] In embodiments, the peptide is a component of a fusion protein. In embodiments, the fusion protein comprises one or more moieties fused to the peptide via a covalent bond to the N-terminus, C- 5 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 terminus, and / or internally, optionally via an isopeptide bond. In embodiments, the one or more moieties increases the half-life of the peptide, relative to a peptide lacking the one or more moieties. In embodiments, the one or more moieties comprise an antibody Fc domain (e.g., IgG, IgG1, IgG2, IgG3, IgG4), albumin (e.g., human serum albumin), transferrin, polyethylene glycol (PEG), elastin, extended recombinant polypeptide (XTEN), elastin-like peptide (ELP), glycine-rich homo-amino-acid polymer (HAP), proline / alanine / serine (PAS) repeats, artificial gelatin-like protein (GLK), and / or C-terminal peptide (CTP) of human chorionic gonadotropin β-subunit.

[0027] In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 1 (FQSE), where the amino-terminus is acetylated, and each residue of SEQ ID NO: 1 comprises a D-form amino acid.

[0028] In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 1 (FQSE), where the amino-terminus is acetylated, and the serine of SEQ ID NO: 1 comprises a D-serine residue.

[0029] In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 1 (FQSE), where the amino-terminus is acetylated, and the glutamine of SEQ ID NO: 1 comprises a D-glutamine residue.

[0030] In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 1 (FQSE), where the amino-terminus is acetylated, and the serine of SEQ ID NO: 1 comprises a beta-serine residue.

[0031] In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 22 (FQTE), wherein the amino-terminus is acetylated, and the threonine of SEQ ID NO: 22 comprises a D-threonine residue.

[0032] In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 13 (ESQF), wherein each of the residues of SEQ ID NO: 13 comprises a D-form amino acid.

[0033] In aspects, described herein in embodiments, are pharmaceutical compositions comprising the peptides described herein and one or more pharmaceutically acceptable excipients and / or one or more delivery vehicles.

[0034] In embodiments, the one or more pharmaceutically acceptable excipients comprises one or more of water, bicarbonate, carbonate, acetate buffer, citrate buffer, phosphate buffer, ethanol, propylene glycol (PEG, PEG 600), glycerin, sodium chloride, sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, dextrose, dextran, DMSO, serum albumin (human serum albumin), phosphate buffered 6 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 saline (PBS), cell media, Dulbecco’s Modified Eagle Medium (DMEM), alpha modified Minimal Essential Medium (alpha MEM), Roswell Park Memorial Institute Media 1640 (RPMI Media 1640), HBSS, Ringer’s solution, PLASMA-LYTE, 1,2-propanediol, isopropanol, glycerol, sorbitol, trehalose, creatine, isoleucine, maltose, sucrose, starch, glucose, lactose, sucrose, gelatin, lipid, arginine, glycine, polysaccharide, cyclodextrin, chitosan, cellulose, alginate, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, and combinations thereof. In embodiments, the one or more pharmaceutically acceptable excipients comprises 5% sodium bicarbonate (NaHCO3).

[0035] In embodiments, the one or more delivery vehicles comprises a liposome, nanoparticle, and / or dendrimer. In embodiments, the one or more delivery vehicles increases the ability of the peptide to cross the blood-brain barrier.

[0036] In embodiments, the pharmaceutical composition is formulated into a solution, suspension, gel, emulsion, drop, tablet, chewable tablet, pill, pellet, capsule, capsule containing liquid, powder, granule, sustained-release formulation, cream, paste, ointment, transdermal delivery patch, implant, aerosol, and / or spray. In embodiments, the pharmaceutical composition is formulated into an oromucosal gel. In embodiments, the pharmaceutical composition is formulated for dogs and / or other companion animals, for example into chewable tablets, granules, cream, paste, ointment, transdermal delivery patch / gel, and / or an implant.

[0037] In embodiments, the pharmaceutical composition is formulated into one or more unit doses. In embodiments, the one or more unit doses comprise a mass of about or at least about 0.01 mg to about or at least about 5,000 mg. In embodiments, the pharmaceutical composition is contained within a syringe, autoinjector, pump, patch, nebulizer, and / or capsule.

[0038] In embodiments, the peptide is selected from Table 1 or Table 20.

[0039] In embodiments, the pharmaceutical composition is suitable for parenteral, oromucosal, intravenous, intranasal, oral, intramuscular, subcutaneous, pulmonary, transdermal, topical, intracranial, intraperitoneal, and / or intrathecal administration.

[0040] Described herein, in embodiments, is a method of treating and / or ameliorating a psychological, behavioral, and / or cognitive disorder in a subject in need thereof comprising administering to the subject one or more of the peptides and / or pharmaceutical compositions thereof, as described herein. 7 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0041] In embodiments, the psychological, behavioral, and / or cognitive disorder comprises one or more of a mood disorder, anxiety, generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, post- traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), postpartum depression (PPD), bipolar and related disorders, schizophrenia, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and stress-related disorders. In embodiments, the stress-related disorders comprise conditions and / or behaviors found in humans and / or non-human animals, comprising separation anxiety, social anxiety, noise anxiety, trembling, hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior.

[0042] In embodiments, the psychological, behavioral, and / or cognitive disorder comprises anxiety. In embodiments, the psychological, behavioral, and / or cognitive disorder comprises depression. In embodiments, the psychological, behavioral, and / or cognitive disorder comprises a stress-related disorder.

[0043] In embodiments, the peptide acts through an interaction with and / or modulation of one or more GABAAreceptors, voltage-gated calcium channels (VGCC), NMDA receptors, thrombospondin proteins (subtypes 1-4), Neurexin-1a protein, scaffolding protein LRP1, dopamine receptors (D1-5), serotonin receptors, glutamate receptors, and acetylcholine receptors. In embodiments, the interaction and / or modulation is via receptor-mediated binding.

[0044] In embodiments, the peptide acts through an interaction with and / or modulation of one or more GABAAreceptors. In embodiments, the GABAAreceptors comprise one or more isoforms selected from α1β3γ2S, α2β3γ2S, α3β3γ2S, α4β3γ2S, α5β3γ2S, α6β3γ2S, α1β2γ2S, α4β3δ, α6β3δ, α1β2, α1β3, α1β2δ, α4β2δ, α3β3θ, and α3β3ε.

[0045] In embodiments, the interaction with and / or modulation of the one or more GABAAreceptors comprises binding at a site that is distinct from a binding site of one or more GABAAreceptor ligands selected from isoguvacine, salicylidene salicylhydrazide, bretazenil, SL651498, MK0343, THDOC, TB21007, gaboxadol, FGIN-1-27, and allopregnanolone.

[0046] In embodiments, the interaction with and / or modulation of the one or more GABAA receptors comprises binding at a benzodiazepine binding site. In embodiments, the binding at the benzodiazepine binding site increases the affinity of one or more GABAAreceptors to gamma-aminobutyric acid (GABA). 8 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0047] In embodiments, the interaction with and / or modulation of the one or more GABAAreceptors comprises binding at an α-β binding site. In embodiments, the interaction with and / or modulation of the one or more GABAA receptors comprises binding at an α-γ binding site. In embodiments, the interaction with and / or modulation of the one or more GABAAreceptors comprises binding at both an α-β binding site and an α-γ binding site.

[0048] In embodiments, the interaction with and / or modulation of the one or more GABAA receptors comprises allosteric regulation.

[0049] In embodiments, the peptide acts through an interaction with and / or modulation of one or more voltage-dependent calcium channels. In embodiments, the one or more voltage-dependent calcium channels comprise a L-type, N-type, P / Q type, and / or R-type. In embodiments, the interaction with and / or modulation of the one or more voltage-dependent calcium channels comprises binding to an α2δ calcium channel subunit, optionally one or more of the α2δ calcium channel subunit isoforms (α2δ1-4).

[0050] In embodiments, the peptide functions as an α2δ-2 modulator (e.g., allosteric modulator). In embodiments, the peptide does not interact with and / or modulate a function of α2δ-1.

[0051] In embodiments, the binding, or competing with binding to, is at a binding site shared with gabapentin. In embodiments, the binding, or competing with binding to, is substantially localized to brain tissue. In embodiments, the binding, or competing with binding to, does not comprise one or more gabapentin binding sites in the α2δ-1 calcium channel isoform. In embodiments, the binding, or competing with binding to, is not substantially localized to cardiac tissue.

[0052] In embodiments, the peptide decreases presynaptic α2δ-2-VGCC representation. In embodiments, the peptide reduces GABAAreceptor level. In embodiments, the peptide enhances AMPA receptor postsynaptic level. In embodiments, the peptide induces long-term potentiation (LTP). In embodiments, the peptide supports synaptogenesis and axon regeneration.

[0053] In embodiments, the peptide does not bind, or does not substantially overlap with a binding site thereof, of pregnenolone sulfate (PREGS). In embodiments, the peptide does not bind, or does not substantially overlap with a binding site thereof, of one or more GABAA receptor binding sites shared with diazepam, muscimol, bicuculline, gabazine, and / or CGS-9895. In embodiments, the peptide does not bind, or does not substantially overlap with a binding site thereof, of one or more binding sites for one or more 9 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 ligands selected from neurotransmitter receptor ligands; dopamine receptors ligands (haloperidol, sulpiride, spiperone, 7-OH-DPAT); serotonin receptors ligands (ketanserin); acetylcholine receptor ligands (nicotine); and glutamate receptor ligands (glutamate, glycine, Ro-256981, LY-354740, MK-801, spermine, arkain).

[0054] In embodiments, the peptide acts through an interaction with and / or modulation of one or more receptors with an affinity of less than about 1 nM, less than about 5 nM, less than about 10 nM, less than about 50 nM, less than about 0.1 µM, less than about 0.5 µM, less than about 1.0 µM, less than about 1.5 µM, less than about 2.0 µM, less than about 2.5 µM, less than about 5.0 µM, less than about 10 µM, less than about 15 µM, less than about 20 µM, less than about 25 µM, less than about 50 µM, or less than about 100 µM.

[0055] In embodiments, the peptide exhibits a half-life of about or at least about 0.5 hours, about or at least about 1 hour, about or at least about 2 hours, about or at least about 3 hours, about or at least about 4 hours, about or at least about 5 hours, about or at least about 6 hours, about or at least about 7 hours, about or at least about 8 hours, about or at least about 9 hours, about or at least about 10 hours, about or at least about 12 hours, about or at least about 14 hours, about or at least about 16 hours, about or at least about 18 hours, about or at least about 20 hours, about or at least about 25 hours, about or at least about 30 hours, about or at least about 35 hours, about or at least about 40 hours, about or at least about 45 hours, about or at least about 50 hours, about or at least about 60 hours, about or at least about 70 hours, about or at least about 80 hours, about or at least about 90 hours, about or at least about 100 hours, about or at least about 120 hours, about or at least about 140 hours, about or at least about 160 hours, about or at least about 180 hours, about or at least about 200 hours, about or at least about 220 hours, about or at least about 240 hours, about or at least about 260 hours, about or at least about 280 hours, or about or at least about 300 hours.

[0056] In embodiments, the half-life is a serum half-life. In embodiments, the half-life is a half-life as measured in humans. In embodiments, the half-life is a half-life as measured in dogs. In embodiments, the half-life is a half-life as measured in cats.

[0057] In embodiments, the administration results in a change in the intensity of and / or occurrence of anxiolytic-like behavior, Anxiety Index (AI), depressive behavior, deficits associated with schizophrenia, intensity of one or more sleep disorders or changes in sleep, appetite fluctuation, body weight fluctuation, fatigue, feelings of low mood or sadness, hopelessness, helplessness, low self-esteem, tearfulness, guilt, irritability, intolerance, restlessness, lack of motivation, difficulty in decision-making, cognitive dysfunction, 10 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 difficulty concentrating, persistent aches and pains, exit frustration, social panic, redirected frustration, reactive communication, immediate frustration, noise sensitivity, separation anxiety, social anxiety, noise anxiety, trembling, hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior. In embodiments, the change is a reduction, amelioration, or ablation.

[0058] In embodiments, the methods further comprise measuring a change in one or more of anxiolytic- like behavior, Anxiety Index (AI), depressive behavior, deficits associated with schizophrenia, intensity of one or more sleep disorders or changes in sleep, appetite fluctuation, body weight fluctuation, fatigue, feelings of low mood or sadness, hopelessness, helplessness, low self-esteem, tearfulness, guilt, irritability, intolerance, restlessness, lack of motivation, difficulty in decision-making, cognitive dysfunction, difficulty concentrating, persistent aches and pains, exit frustration, social panic, redirected frustration, reactive communication, immediate frustration, noise sensitivity, separation anxiety, social anxiety, noise anxiety, trembling, hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior.

[0059] In embodiments, the measuring comprises using a Hamilton Anxiety Scale (HAM-A), a Beck Anxiety Inventory (BAI), a Beck Depression Inventory (BDI-II), an Anxiety Symptoms Questionnaire (ASQ), a Hamilton Rating Scale for Depression (HAM-D), a Montgomery Asberg Depression Rating Scale (MADRS), and a Clinical Global Impression-Severity (CGI-S), and / or using one of more diagnostic tests as outlined in the Diagnostic and Statistical Manual of Mental Disorders 4thEdition (DSM-IV), 5thEdition (DSM-V), and / or DSM-5TR (2022), one or more neuropsychological tests comprising saccadic eye movements, saccadic reaction time, saccadic peak velocity, and saccadic inaccuracy, smooth pursuit eye movements, adaptive tracking, body sway, pupil size, visual analogue scale (VAS) to assess mood, alertness, and / or calmness, cognitive assessment VVLT (Learning and Immediate Recall, Delayed Recall, and Delayed Recognition), and / or qEEG (quantitative electroencephalogram).

[0060] In embodiments, the change occurs within about or at least about 1 day to about 2 days, within about or at least about 2 days to about 4 days, within about or at least about 4 days to about 6 days, within about or at least about 6 days to about 8 days, within about or at least about 8 days to about 10 days, within about or at least about 10 day to about 20 days, within about or at least about 20 day to about 40 days, or within about or at least about 40 day to about 60 days from an initial administration. 11 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0061] In embodiments, the method does not substantially result in one or more adverse events in comparison to a subject that was not administered the peptide. In embodiments, the one or more adverse events is or comprises drowsiness, sedation, trouble sleeping (insomnia, restlessness), appetite fluctuation (suppressed appetite, increased appetite), binge eating, nausea, diarrhea, constipation, loss of muscle tone, memory issues (memory loss, false memories), psychosis, confusion, peptide intolerance, and / or peptide dependence.

[0062] In embodiments, the administering is performed by parenteral, oromucosal, intravenous, intranasal, oral, intramuscular, subcutaneous, oral, pulmonary, transdermal, topical, intracranial, intraperitoneal, and / or intrathecal routes. In embodiments, the administering is intravenous. In embodiments, the administering is intranasal. In embodiments, the administering is oral.

[0063] In embodiments, the administration comprises providing one or more unit doses of the peptide and / or pharmaceutical compositions. In embodiments, the one or more unit doses comprise a total mass of the peptide of about or at least about 0.01 mg to about or at least about 5,000 mg.

[0064] In embodiments, the one or more unit doses comprise a total mass of the peptide of about or at least about 0.01 mg, about or at least about 0.1 mg, about or at least about 0.5 mg, about or at least about 1.0 mg, about or at least about 5.0 mg, about or at least about 10 mg, about or at least about 15 mg, about or at least about 25 mg, about or at least about 50 mg, about or at least about 100 mg, about or at least about 150 mg, about or at least about 200 mg, about or at least about 300 mg, about or at least about 400 mg, about or at least about 500 mg, about or at least about 1,000 mg, about or at least about 1,500 mg, about or at least about 2,000 mg, about or at least about 2,500 mg, about or at least about 3,000 mg, about or at least about 3,500 mg, about or at least about 4,000 mg, about or at least about 4,500 mg, or about or at least about 5,000 mg.

[0065] In embodiments, the administration comprises providing a range of peptide of about 0.001 mg / kg to about 200 mg / kg body weight, about 0.01 mg / kg to about 100 mg / kg body weight, about 0.01 mg / kg to about 50 mg / kg body weight, about 0.01 mg / kg to about 40 mg / kg body weight, about 0.01 mg / kg to about 30 mg / kg body weight, about 0.01 mg / kg to about 20 mg / kg body weight, about 0.01 mg / kg to about 5 mg / kg body weight, about 0.01 mg / kg to about 10 mg / kg body weight, about 0.1 mg / kg to about 10 mg / kg body weight, about 0.1 mg / kg to about 20 mg / kg body weight, about 0.1 mg / kg to about 30 mg / kg body weight, about 0.1 mg / kg to about 40 mg / kg body weight, about 0.1 mg / kg to about 50 mg / kg body weight. 12 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0066] In embodiments, the administering comprises a dosage frequency of about or at least about thrice daily, about or at least about twice daily, about or at least about once daily, about or at least about every 2 days, about or at least about every 3 days, about or at least about every 4 days, about or at least about every 5 days, about or at least about every 6 days, about or at least about weekly, about or at least about biweekly, about or at least about once every three weeks, or about or at least about monthly.

[0067] In embodiments, the methods further comprise administering one or more additional therapeutic agents. In embodiments, the one or more additional therapeutic agents comprises a therapeutic agent for an anxiety disorder, a depression disorder, a stress-related disorder, a bipolar disorder, and / or a mood disorder.

[0068] In embodiments, the one or more additional therapeutic agents comprises one or more of benzodiazepines selected from alprazolam (XANAX), clonazepam (KLONOPIN), diazepam (VALIUM), lorazepam (ATIVAN), oxazepam (SERAX), and chlordiazepoxide (librium); beta blockers selected from propranolol (INDERAL) and atenolol (TENORMIN); tricyclic antidepressants selected from imipramine (TOFRANIL), desipramine (NORPRAMIN, PERTOFRANE), nortriptyline (AVENTYL or PAMELOR), amitriptyline (ELAVIL), doxepin (SINEQUAN or ADAPIN), clomipramine (ANAFRANIL); monoamine oxidase inhibitors (MAOIs) selected from phenelzine (NARDIL), tranylcypromine (PARNATE); selective serotonin reuptake inhibitors (SSRIs) selected from fluoxetine (PROZAC), fluvoxamine (LUVOX), sertraline (ZOLOFT), paroxetine (PAXIL), escitalopram oxalate (LEXAPRO), citalopram (CELEXA); serotonin-norepinephrine reuptake inhibitors (SNRIs) selected from venlafaxine (EFFEXOR), venlafaxine extended release (EFFEXOR XR) and duloxetine (CYMBALTA); mild tranquilizers such as buspirone (BUSPAR); and anticonvulsants selected from valproate (DEPAKOTE), pregabalin (LYRICA), and gabapentin (NEURONTIN), CYMBALTA oral, LEXAPRO oral, EFFEXOR XR oral, ZOLOFT oral, CELEXA oral, TRAZODONE oral, PROZAC oral, WELLBUTRIN XL oral, CITALOPRAM oral, PRISTIQ oral, AMITRIPTYLINE oral, SAVELLA oral, VIIBRYD oral, PAXIL CR oral, WELLBUTRIN oral, PAXIL oral, SERTRALINE oral, REMERON oral, NORTRIPTYLINE oral, VENLAFAXINE oral, FLUOXETINE oral, BUPROPION HCL oral, MIRTAZAPINE oral, RITALIN oral, PAROXETINE oral, WELLBUTRIN SR oral, DOXEPIN oral, METHYLPHENIDATE oral, SYMBYAX oral, ESCITALOPRAM OXALATE oral, PAMELOR oral, IMIPRAMINE oral, BRINTELLIX oral, DULOXETINE oral, NARDIL oral, FETZIMA oral, EMSAM TRANSDERMAL, PARNATE oral, PEXEVA oral, BRISDELLE oral, CLOMIPRAMINE oral, ANAFRANIL oral, TOFRANIL oral, FLUVOXAMINE oral, ZYBAN oral, DESIPRAMINE oral, SARAFEM oral, PROZAC WEEKLY oral, APLENZIN oral, METHYLIN oral, NEFAZODONE oral, QUILLIVANT XR oral, TOFRANIL-PM oral, NORPRAMIN oral, REMERON SOLTAB oral, BUPROPION HBR 13 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 oral, OLEPTRO ER oral, DESVENLAFAXINE SUCCINATE oral, BUPROBAN oral, IMIPRAMINE PAMOATE oral, VILAZODONE oral, MILNACIPRAN oral, PAROXETINE MESYLATE oral, SURMONTIL oral, MAPROTILINE oral, PROTRIPTYLINE oral, PHENELZINE oral, MARPLAN oral, OLANZAPINE- FLUOXETINE oral, TRANYLCYPROMINE oral, SELEGILINE TRANSDERMAL, AMOXAPINE oral, FORFIVO XL oral, ISOCARBOXAZID oral, DESVENLAFAXINE oral, KHEDEZLA oral, LEVOMILNACIPRAN oral, VORTIOXETINE oral, DESVENLAFAXINE FUMARATE oral, bestatine, comostate amylase, leupeptin, aprotinin, bacitracin, amastatine, boroleucine, puromycin, a bile salt, and a fusidic acid (disodium ethylene- diaminetetraacetate).

[0069] In embodiments, the one or more additional therapeutic agents comprises dexmedetomidine (SILEO).

[0070] In embodiments, the subject is human. In embodiments, the subject is a non-human animal

[0071] In aspects, described herein is a method of treating and / or ameliorating a mood disorder in a subject in need thereof comprising administering to the subject a peptide comprising an amino acid sequence of SEQ ID NO: 1 (FQSE), optionally wherein the amino-terminus is acetylated, and wherein the serine of SEQ ID NO: 1 comprises a D-serine residue. In embodiments, the mood disorder is a depression disorder or an anxiety disorder. DESCRIPTION OF THE DRAWINGS

[0072] Fig.1 depicts a diagrammatic representation of an ex vivo peptide stability testing scheme in whole blood and plasma.

[0073] Fig.2 depicts a diagrammatic representation of an ex vivo peptide stability testing scheme in plasma derived from K2EDTA-treated or heparin-treating whole blood.

[0074] Fig.3 depicts a graphical representation of the ex vivo peptide (Ac-FQSE, e.g., LCGA-17) stability testing results in K2EDTA-treated or heparin-treating whole blood after 1 hr. incubation at 4°C.

[0075] Fig.4 depicts a graphical representation of the ex vivo peptide (Ac-FQSE, e.g., LCGA-17) stability testing results in K2EDTA-treated or heparin-treating plasma at time 0, 0.25 hr. incubation, and 2 hr. incubation at 4°C. 14 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0076] Fig.5 depicts a graphical representation of the ex vivo peptide (Ac-FQSE, e.g., LCGA-17) stability testing results in K2EDTA-treated or heparin-treating plasma at time 0, 0.25 hr. incubation, and 2 hr. incubation at 37°C.

[0077] Fig.6 depicts a graphical representation of the ex vivo peptide (Ac-FQSE, e.g., LCGA-17) stability testing results in K2EDTA-treated or heparin-treating in LC / MS samples prepared incubated in the autosampler at 15°C.

[0078] Fig.7 depicts a graphical representation of the ex vivo radiochromatographic analysis of tritium- labeled peptide [3H]Ac-FQSE biodegradation in rat plasma.1 – SE, 2 – Ac-FQ, 3 - Ac-FQSE, 4 – Ac- FQS.

[0079] Fig.8 depicts a graphical representation of the ex vivo calculated pharmacokinetics (PK) of Ac- FQSE peptide in rat plasma.

[0080] Fig.9 depicts a diagrammatic representation of the experimental model using for calculating pharmacokinetic (PK) parameter of the Ac-FQSE peptide.

[0081] Figs.10A-10B depict a graphical representation of a two-compartment pharmacokinetic (PK) model of the Ac-FQSE peptide, with direct coordinates (Fig.10A) and semi-logarithmic coordinates (Fig. 10B).

[0082] Fig. 11 depicts a graphical representation of a representative chromatographic analysis of mouse heart tissue after intranasal administration. Fractions 1 and 2 relate to Ac-FQ and Ac-FQSE, respectively.

[0083] Fig.12 depicts a graphical representation of the change in the ratio of Ac-FQSE concentrations in organs and blood following intraperitoneal administration of peptide Ac-FQSE to Balb / c mice. Values of Сt(organ) / Сt(blood) ratio in relative units the specified time interval were set to 1.

[0084] Fig.13 depicts a graphical representation of the change in the ratio of Ac-FQ concentrations in organs and blood following intraperitoneal administration of peptide Ac-FQSE to Balb / c mice. Values of Сt(organ) / Сt(blood) ratio in relative units the specified time interval were set to 1.

[0085] Fig.14 depicts a graphical representation of the in vivo effects of Ac-FQSE and ESQF on novel tank (NT) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 13 = Ac-FQSE (acetylated, all D-form amino acids, e.g., LCGA-17m13 in Tables 1 and 20), LCGA 17 / 14 = ESQF (non- acetylated, all D-form amino acids, in reversed order compared to FQSE, e.g., LCGA-17m14 in Tables 1 and 15 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 20). Top left shows time spent near the surface; top right shows time spent near the bottom; bottom left shows latent period (LP) to reach the surface zone; bottom right shows total distance covered. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0086] Fig.15 depicts a graphical representation of the in vivo effects of Ac-FqSE and Ac-FQsE on novel tank (NT) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 15 = Ac- FqSE (acetylated, D-glutamine, e.g., LCGA-17m15 in Tables 1 and 20), LCGA 17 / 16 = Ac-FQsE (acetylated, D-serine, e.g., LCGA-17m16 in Tables 1 and 20). Top left shows time spent near the surface; top right shows time spent near the bottom; bottom left shows latent period (LP) to reach the surface zone; bottom right shows total distance covered. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0087] Fig.16 depicts a graphical representation of the in vivo effects of Ac-FQβsE and Ac-FQtE on novel tank (NT) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 34 = Ac- FQβsE (acetylated, beta-serine, e.g., LCGA-17m34 in Tables 1 and 20), LCGA 17 / 39 = Ac-FQtE (acetylated, D-threonine, e.g., LCGA-17m39 in Tables 1 and 20). Top left shows time spent near the surface; top right shows time spent near the bottom; bottom left shows latent period (LP) to reach the surface zone; bottom right shows total distance covered. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0088] Fig.17 depicts a graphical representation of the in vivo effects of Ac-FQSE and ESQF on dark- light box (DLB) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 13 = Ac- FQSE (acetylated, all D-form amino acids, e.g., LCGA-17m13 in Tables 1 and 20), LCGA 17 / 14 = ESQF (non-acetylated, all D-form amino acids, in reversed order compared to FQSE, e.g., LCGA-17m14 in Tables 1 and 20). Top shows time spent near in the light compartment; middle shows latent period (LP) to reach the light compartment; bottom shows number of transitions to the light compartment. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0089] Fig.18 depicts a graphical representation of the in vivo effects of Ac-FqSE and Ac-FQsE on dark-light box (DLB) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 15 = Ac-FqSE (acetylated, D-glutamine, e.g., LCGA-17m15 in Tables 1 and 20), LCGA 17 / 16 = Ac-FQsE 16 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 (acetylated, D-serine, e.g., LCGA-17m16 in Tables 1 and 20). Top shows time spent near in the light compartment; middle shows latent period (LP) to reach the light compartment; bottom shows number of transitions to the light compartment. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0090] Fig.19 depicts a graphical representation of the in vivo effects of Ac-FQβsE and Ac-FQtE on dark-light box (DLB) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 34 = Ac-FQβsE (acetylated, beta-serine, e.g., LCGA-17m34 in Tables 1 and 20), LCGA 17 / 39 = Ac-FQtE (acetylated, D-threonine, e.g., LCGA-17m39 in Tables 1 and 20). Top shows time spent near in the light compartment; middle shows latent period (LP) to reach the light compartment; bottom shows number of transitions to the light compartment. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0091] Fig.20 depicts a graphical representation of the in vivo effects of Ac-FQSE and ESQF on social preference (DSP) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 13 = Ac-FQSE (acetylated, all D-form amino acids, e.g., LCGA-17m13 in Tables 1 and 20), LCGA 17 / 14 = ESQF (non-acetylated, all D-form amino acids, in reversed order compared to FQSE, e.g., LCGA-17m14 in Tables 1 and 20). Left shows time spent out of shoaling zone; right shows the number of transitions out of the shoaling zone. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0092] Fig.21 depicts a graphical representation of the in vivo effects of Ac-FqSE and Ac-FQsE on social preference (DSP) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 15 = Ac-FqSE (acetylated, D-glutamine, e.g., LCGA-17m15 in Tables 1 and 20), LCGA 17 / 16 = Ac-FQsE (acetylated, D-serine, e.g., LCGA-17m16 in Tables 1 and 20). Left shows time spent out of shoaling zone; right shows the number of transitions out of the shoaling zone. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0093] Fig.22 depicts a graphical representation of the in vivo effects of Ac-FQβsE and Ac-FQtE on social preference (DSP) test behavior in Danio rerio (zebrafish). Control 1 = vehicle (0.9% NaCl), LCGA 17 / 34 = Ac-FQβsE (acetylated, beta-serine, e.g., LCGA-17m34 in Tables 1 and 20), LCGA 17 / 39 = Ac-FQtE (acetylated, D-threonine, e.g., LCGA-17m39 in Tables 1 and 20). Left shows time spent out of shoaling zone; 17 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 right shows the number of transitions out of the shoaling zone. Data shown are median ± interquartile range, whiskers represent min to max range, dots represent individual values. *- p <0.05; **- p <0.01.

[0094] Figs.23A-23G depict graphical representations of the ex vivo effects of Ac-FQSE (e.g., LCGA- 17) and Ac-FQsE on hippocampal pyramidal neuron sections of Mus musculus (mice) using patch-clamp electrophysiology. Fig.23A shows control sections incubated in artificial cerebrospinal fluid (ACF) without peptide, where induction shows an increase in EPSC amplitudes at potentiated synapses. Figs.23B, 23C, and 23D show the results of the sections incubated with Ac-FQSE with 1 μM, 10 μM, or 100 μM, respectively, showing long-term potentiation (LTP) induction and a long-term increase in EPSC amplitudes. Fig.23E shows a comparison of the mean relative levels of LTP in control sections and sections treated with Ac- FQSE, where the relative level of LTP was calculated using: (LTPpotentiated̶ LTPcontrol)*100%. Fig.23F-23G show boxplots representing the medians and distributions (lower (25%) and upper (75%) quartile) of mean LTP values obtained in the control slices and in the presence of Ac-FQSE with time intervals: 7-12 min after potentiation (Fig.23F) and 27-32 min after potentiation (Fig.23G).

[0095] Figs.24A-24G depict graphical representations of the ex vivo effects of Ac-FQsE (e.g., D-serine, LCGA-17) on hippocampal pyramidal neuron sections of Mus musculus (mice) using patch-clamp electrophysiology. Fig.24A shows control sections incubated in artificial cerebrospinal fluid (ACF) without peptide, where induction shows an increase in EPSC amplitudes at potentiated synapses. Figs.24B, 24C, and 24D show the results of the sections incubated with Ac-FQsE with 1 μM, 10 μM, or 100 μM, respectively, showing long-term potentiation (LTP) induction and a long-term increase in EPSC amplitudes. Fig.24E shows a comparison of the mean relative levels of LTP in control sections and sections treated with Ac-FQsE, where the relative level of LTP was calculated using: (LTPpotentiated̶ LTPcontrol)*100%. Fig.24F-24G show boxplots representing the medians and distributions (lower (25%) and upper (75%) quartile) of mean LTP values obtained in the control slices and in the presence of Ac-FQsE with time intervals: 7-12 min after potentiation (Fig.24F) and 27-32 min after potentiation (Fig.24G).

[0096] Figs.25A-25B depict graphical representations of the in vivo effects of Ac-FQsE (e.g., D-serine, LCGA-17) on open field test (OFT) behaviors in rats. Fig.25A shows the total distance traveled during the 5-minute OFT in cm. Data are presented as the mean ± SEM. Fig.25B shows the number of rears during the 5-minute OFT. Data are presented as the mean ± SEM. * p<0.05, statistical evaluation using a Student’s T-test. 18 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0097] Figs.26A-26C depict graphical representations of the in vivo effects of Ac-FQsE (e.g., D-serine, LCGA-17) on elevated plus maze (EPM) test behaviors in rats. Fig.26A shows the time spent on the open arms of the EPM. Data are presented as the mean ± SEM, *p < 0.05, statistical evaluation by Student’s T- test. Fig.26B shows the Anxiety Index (AI, %) calculated as follows: 100*(1 − [(time spent on open arms / total time on the maze) / 2 + (number of entries to the open arms / total exploration on the maze) / 2]). Results are presented as the mean ± SEM, *p < 0.05, statistical evaluation by Student’s T-test.

[0098] Fig.27 depicts a graphical representation of the in vivo effects of Ac-FQsE (e.g., D-serine, LCGA-17) on Porsolt forced swim test (FST) behaviors in rats. Fig.27 shows the duration of immobility in the FST. Results are presented as the mean ± SEM, *p < 0.05, statistical evaluation by Student’s T-test.

[0099] Fig.28 depicts a graphical representation of a competitive binding assay in brain tissue between Ac-FQsE (e.g., D-serine, LCGA-17) and gabapentin, demonstrating that Ac-FQsE and gabapentin each displace [3H]-Ac-FQsE binding to cell surface membranes isolated from brain tissue, suggesting a shared binding site.

[0100] Fig.29 depicts a graphical representation of a competitive binding assay in cardiac tissue between Ac-FQsE (e.g., D-serine, LCGA-17) and gabapentin, demonstrating that Ac-FQsE and gabapentin have no effect on [3H]-Ac-FQsE displacement in cell surface membranes isolated from cardiac tissue, suggesting no shared binding site.

[0101] Fig.30 depicts a graphical representation of a competitive binding assay in cardiac tissue between Ac-FQsE (e.g., D-serine, LCGA-17) and gabapentin, demonstrating that only gabapentin and not Ac-FQsE displaces [3H]-gabapentin in cell surface membranes isolated from cardiac tissue, corroborating that Ac-FQsE does not share the gabapentin side effect of off-target being in cardiomyocytes. DETAILED DESCRIPTION Peptides

[0102] The present disclosure provides, in part, peptides comprising the general formula I: R1-[F1Q1X1E1]y-R2 (I).

[0103] In embodiments, F1 includes a phenylalanine, Q1 includes a glutamine, X1 includes one of a serine, threonine, or a non-canonical amino acid, and E1includes a glutamate, and at least one of R1, F1, Q1, 19 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 X1, E1, and / or R2comprises one or more modifications. In embodiments, the one or more modifications is a chemical modification and / or the additional of one or more amino acids.

[0104] In embodiments, peptides herein are generated using a variety of conventional recombinant and / or biosynthetic techniques (e.g., cellular expression in cell lines suitable for incorporating non-canonical amino acids, D-amino acids, post-translational modifications, or hydrolyzing isolated food proteins and / or recombinant proteins, etc.). In embodiments, peptides herein are generated and / or further modified using a variety of chemical and / or biochemical techniques (e.g., acetylation, deamidation, conjugation of chemical species, lipidation, etc.). In embodiments, “peptides” herein are also referred to as “synthetic peptides,” “recombinant peptides,” and / or “chemically-modified peptides.”

[0105] In embodiments, the peptide has a primary structure of R1-F1Q1X1E1-R2, oriented from amino- terminus (N-terminus) to carboxy-terminus (C-terminus). In embodiments, the peptide has a primary structure of R1-F1Q1X1E1-R2, listed from C-terminus to N-terminus, e.g., oriented in the opposite direction, corresponding to a peptide of: R2-E1X1Q1F1-R1, where R2corresponds to an amino-terminal end, and R1corresponds to a carboxy-terminal end (e.g., see LCGA-17m14 as listed in Table 1).

[0106] In embodiments, the peptide comprises and / or consists of any of the peptides described in Table 1. Table 1: Ilustrative peptides. SEQ ID NO Peptide Illustrative Structure20 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Ac-FQSEEQQQTEDE SEQ ID NO: 5 (LCGA-17m5)21 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-500322 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-500323 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-500324 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-500325 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-500326 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0107] In embodiments, R1 is a non-modified amino-terminus. For example, in embodiments, R1 is the amino-terminus of the F1phenylalanine residue (e.g., a naturally occurring peptide end). 28 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0108] Alternatively, in embodiments, R1is an amino-terminus with one or more modifications which includes one or more chemical modifications. In embodiments, the one or more chemical modifications is or comprises acetylation, methylation, thiolation (e.g., maleimide addition), glycosylation, prenylation, PEGylation, biotinylation, aminoethylation, halogenation (e.g., iodoacetamides, difluoromethane, trifluoromethane, etc.), lipidation, myristylation, palmitoylation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine.

[0109] In embodiments, R1is a chemically-modified F1phenylalanine N-terminus. For example, in embodiments, R1 is an acetylated amino-terminus of F1 (e.g., LCGA-17 as shown in Table 1).

[0110] In embodiments, the R1 chemical modification is a hydrophobic chemical modification. In embodiments, the chemical modification to R1is lipidation, where one or more fatty acids, isoprene units, inositol groups, and cholesterol molecules is conjugated to the amino-terminus of the peptide. For example, in embodiments, R1is a myristoylated amino-terminus of F1(e.g., LCGA-17m19 as shown in Table 1), also referred to as N-myristylation. In embodiments, R1is a palmitoylated amino-terminus of F1(e.g., LCGA- 17m19 as shown in Table 1), also referred to as N-palmitoylation. In embodiments, R1 is an isoprene unit, e.g., farnesylation, geranylgeranylation, etc. The lipidation, in embodiments, can be via the amine present in the amino-terminal end of the peptide, e.g., through fatty acid acylation, prenylation, GPI anchoring, cholesterol anchoring, phosphatidylethanolamine anchoring, and the like. In embodiments, lipidation of the N-terminus of the peptide increases the membrane solubility and / or cellular uptake.

[0111] In embodiments, R2is a non-modified carboxy-terminus. For example, in embodiments, R2is the carboxy-terminus of the E1 glutamate residue (e.g., a naturally occurring peptide end). In embodiments, R2 comprises one or more amino acids linked from the carboxy-terminus of the E1glutamate residue, where the carboxy-terminal residue has a non-modified or modified C-terminal end.

[0112] In embodiments, R2 is a carboxy-terminus with one or more modifications which includes one or more chemical modifications. In embodiments, the one or more chemical modifications is or comprises one or more of amidation, acetylation, methylation, thiolation (e.g., maleimide addition), glycosylation, prenylation, PEGylation, biotinylation, aminoethylation, halogenation (e.g., iodoacetamides, difluoromethane, trifluoromethane, etc.), lipidation, myristylation, palmitoylation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine. 29 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0113] In embodiments, R2is a chemically-modified E1glutamate carboxy-terminus. For example, in embodiments, R2 is an amidated amino-terminus of E1 (e.g., LCGA-17m17 as shown in Table 1).

[0114] In embodiments, the R2 chemical modification is a hydrophobic chemical modification. In embodiments, the chemical modification to R2is lipidation, where one or more fatty acids, isoprene units, inositol groups, and cholesterol molecules is conjugated to the carboxy-terminus of the peptide. For example, in embodiments, R2 is a myristoylated carboxy-terminus of E1. In embodiments, the carboxy-terminus myristylation is via a D-Lys residues which forms a contiguous isopeptide bond with E1(e.g., LCGA-17m21 as shown in Table 1). In embodiments, R2 is a palmitoylated carboxy-terminus of E1. In embodiments, the carboxy-terminus palmitoylation is via a D-Lys residues which forms a contiguous isopeptide bond with E1 (e.g., LCGA-17m22 as shown in Table 1). In such embodiments, the ɛ-amino group of the lysine is useful for conjugation of the fatty acid group to the carboxy-terminus of the peptide. In embodiments, R2is an isoprene unit, e.g., farnesylation, geranylgeranylation, etc. The lipidation, in embodiments, can be via the carboxylic acid present in the amino-terminal end of the peptide or via an amine or amide present in one or more C- terminal residues, e.g., through fatty acid acylation, prenylation, GPI anchoring, cholesterol anchoring, phosphatidylethanolamine anchoring, and the like. In embodiments, lipidation of the C-terminus of the peptide increases the membrane solubility and / or cellular uptake.

[0115] In embodiments, X1of the peptide is serine (e.g., SEQ ID NOs: 1-13 as shown in Table 1). In embodiments, X1 of the peptide is threonine (e.g., SEQ ID NOs: 22 as shown in Table 1).

[0116] In embodiments, the peptide includes one or more non-canonical amino acids. In embodiments, “non-canonical amino acids,” also referred to as “non-naturally-occurring amino acids,” “non-proteinogenic amino acids,” or “unnatural amino acids (UAAs),” refers to a class of organic molecules containing an amine, carboxylic acid, and a functional group resembling an “-R group,” e.g., as compared to amino acid side chains. In embodiments, the non-canonical amino acid is selected from sarcosine (N-methylglycine), hydroxyproline, homoserine, β-serine, homoglutamine, homoallylglycine, homopropargylglycine, azidohomoalanine, azidonorleucine, azidophenylalanine, acetylphenylalanine, aminoisobutyric acid, selenocysteine, dehydroalanine, pyrrolysine, α-amino-n-heptanoic acid, t-leucine, pipecolic acid, α,β- diaminopropionic acid, α,γ-diaminobutyric acid, ornithine, allothreonine, homocysteine, isoserine, β-alanine, β-amino-n-butyric acid, β-aminoisobutyric acid, γ-aminobutyric acid, α-aminoisobutyric acid, isovaline, N- 30 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 ethylglycine, N-propylglycine, N-isopropylglycine, N-methylalanine, N-ethylalanine, N-methyl-β-alanine, N- ethyl-β-alanine, α-hydroxy-γ-aminobutyric acid, D-amino acids, and β-amino acids.

[0117] In embodiments, the non-canonical amino acid is selected from sarcosine (N-methylglycine), hydroxyproline, and homoserine. In embodiments, the non-canonical amino acid is incorporated at the X1position. In embodiments, the non-canonical amino acid is conjugated to a serine or threonine at the X1 position. In embodiments, one or more non-canonical amino acids is located at, or incorporated therein, at the R1and / or R2position.

[0118] In embodiments, one or more of F1, Q1, X1, and E1 comprises an L-form amino acid. Generally, L-form amino acids, in embodiments, are often referred to as “naturally-occurring amino acids,” or “canonical amino acids,” which, under typical conditions in the cell, are synthesized and incorporated into most polypeptides. In embodiments, the X1 residue is L-serine (e.g., LCGA-17 as shown in Table 1). In embodiments, one or more non-canonical amino acids incorporated into the peptide is an L-form non- canonical amino acid. For example, in embodiments, the X1residue is L-sarcosine (e.g., LCGA-17m35 as shown in Table 1). L-sarcosine, in embodiments, also referred to as N-methylglycine or monomethylglycine, is an amino acid derivative which is an intermediate and byproduct in glycine synthesis and degradation and can be formed via Strecker amino acid synthesis. In embodiments, the X1residue is L-homoserine (e.g., LCGA-17m29 as shown in Table 1). In embodiments, the X1 residue is L-hydroxyproline (e.g., LCGA-17m36 as shown in Table 1). Sarcosine, homoserine, and hydroxyproline (e.g., L-form or D-form) are not considered one of the 20 naturally-occurring amino acids, e.g., canonical amino acids, typically used in protein biosynthesis.

[0119] In embodiments, each of F1, Q1, X1, and E1comprise or consist of L-form amino acids.

[0120] In embodiments, one or more of F1, Q1, X1, and E1is a D-form amino acid. D-form amino acids, in embodiments, are often referred to as “non-naturally-occurring amino acids” or “non-canonical amino acids,” which possess a different stereochemistry and, under typical conditions in the cell, are not incorporated into polypeptides. In embodiments, the X1 residue is D-serine (e.g., LCGA-17m16 as shown in Table 1). In embodiments, the X1 residue is D-homoserine (e.g., LCGA-17m36 as shown in Table 1). In embodiments, the X1residue is D-threonine (e.g., LCGA-17m39 as shown in Table 1). In embodiments, the Q1 residue is D-glutamine (e.g., LCGA-17m15 as shown in Table 1). 31 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0121] In embodiments, each of F1, Q1, X1, and E1comprise or consist of D-form amino acids. In embodiments, each of F1, Q1, X1, and E1 is a D-form amino acid, oriented from C-terminus to N-terminus, e.g., where the peptide is a retro-inverso peptide (EXQF).

[0122] In embodiments, at least one peptide bond and / or at least one amino acid side chain of the peptide includes a chemical modification. The peptide bond, in embodiments, includes each of the peptide bonds between F1, Q1, X1, and E1, as well as the peptide bond between F1 and R1, E1 and R2, and any peptide bonds between two or more residues in the R2group. Likewise, the amino acid side chain, in embodiments, includes the side chain of any one or more of F1, Q1, X1, and E1, as well as any additional amino acid residues belonging to the R1 and / or R2 group.

[0123] The chemical modification of the peptide bond and / or amino acid side chain includes, in embodiments, acetylation, amidation, methylation, thiolation (e.g., maleimide addition), glycosylation, prenylation, PEGylation, biotinylation, aminoethylation, halogenation (e.g., iodoacetamide, difluoromethane, trifluoromethane, etc.) lipidation, myristylation, palmitoylation, disulfide bond formation, peptide bond formation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine.

[0124] In embodiments, the chemical modification includes incorporation of a non-canonical amino acid, non-naturally occurring amino acid, and / or non-canonical peptide bond. For example, in embodiments, the canonical peptide bond backbone is substituted and / or replaced with an isosteric or isoelectronic analog. In embodiments, the reduced amide (CH2-NH) is isosterically introduced into the peptide. In embodiments, the peptide is made in the form of an azapeptide, where the α-Carbon (Cα) of the peptide backbone is replaced with nitrogen (e.g., without substantially changing the structure-function of the amino acids residues). In embodiments, the peptide is peptidomimetic, having its side chains appended to the nitrogen atom of the peptide backbone, rather than to the Cα. In such embodiments, the peptide, is or resembles a peptoid and / or a poly-N-substituted glycine.

[0125] In embodiments, the X1residue includes a chemical modification and / or non-canonical serine. In embodiments, the chemical modification and / or non-canonical serine comprises N-methylserine (NMe- Ser) (e.g., LCGA-17m26 as shown in Table 1), where the N-methylation is located on the amine contributing to the isopeptide bond in the peptide backbone (e.g., the α-amino group). In embodiments, the chemical modification and / or non-canonical serine comprises Cα-methyl-serine (e.g., LCGA-17m27 as shown in Table 1), where the Cα-methylation is located on the “alpha carbon” contributing to the isopeptide bond in the 32 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 peptide backbone. In embodiments, the chemical modification and / or non-canonical serine comprises beta- serine (beta-Ser) (e.g., LCGA-17m28 as shown in Table 1), where an additional C-C bond is introduced into the peptide backbone.

[0126] In embodiments, the chemical modification modification(s) are to the peptide backbone, or N-C- C (nitrogen-carbon-carbon, or α-amino group, α-carbon, and α-carboxyl group), either within the X1 residue, or within the bonds adjacent to the X1 residue. In embodiments, modification to the peptide backbone reduces and / or ablates hydrolysis, degradation, and / or cleavage at those locations, e.g., due to proteases. In embodiments, this reduction and / or decrease is relative to a peptide lacking the one or more chemical modifications.

[0127] In embodiments, the chemical modification and / or non-canonical serine includes homoserine (homo-Ser), for example, L-homoserine (e.g., LCGA-17m29 as shown in Table 1) or D-homoserine (e.g., LCGA-17m30 as shown in Table 1). In embodiments, modification to the stereochemistry of the X1residue reduces and / or ablates hydrolysis, degradation, and / or cleavage at this location, e.g., due to proteases. In embodiments, this reduction and / or decrease is relative to a peptide lacking the one or more chemical modifications.

[0128] In embodiments, the chemical modification and / or non-canonical serine includes a fluorinated serine, for example, difluoromethane serine (e.g., LCGA-17m32 as shown in Table 1) or trifluoromethane serine (e.g., LCGA-17m33 as shown in Table 1). In embodiments, the chemical modification includes one or more electronegative / electron withdrawing atoms and / or functional groups, such as halides (e.g., fluoride, chloride, iodine, and / or bromine), hydroxyl groups, alkoxy groups, carbonyl groups, sulfonyl groups, cyano groups, nitro groups, haloalkyl groups, ammonium groups, etc. In embodiments, an electronegative / electron withdrawing chemical modification to the peptide reduces and / or ablates hydrolysis, degradation, and / or cleavage, e.g., due to proteases.

[0129] In embodiments, the chemical modification includes the addition of one or more alkyl groups (i.e., alkylation). In embodiments, the alkylation is on a side chain and / or introduced into the peptide backbone. In embodiments, the chemical modification and / or non-canonical serine includes beta-dimethyl- serine (beta / beta-serine) (e.g., LCGA-17m34 as shown in Table 1), where methyl groups can be introduced into the serine side chain. In embodiments, the chemical modification and / or non-canonical serine includes 33 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 a benzyl-modified serine or a toluene-modified serine (e.g., referred to as benzyl-serine) (e.g., LCGA-17m37 as shown in Table 1).

[0130] In embodiments, the chemical modification and / or non-canonical serine includes the addition of one or more non-canonical amino acids (e.g., conjugated to the serine). In embodiments, the addition includes the conjugation of an amino acid into the side chain of the X1 serine. For example, in embodiments the chemical modification and / or non-canonical serine includes hydroxyproline modification (Ser- hydroxyproline), where a neutral heterocyclic amino acid (e.g., hydroxyproline) can be conjugated onto the X1 serine side chain.

[0131] In embodiments, the Q1 glutamine is a non-canonical glutamine. For example, in embodiments, the non-canonical glutamine is N-methylglutamine (NMe-Gln) (e.g., LCGA-17m23 as shown in Table 1). In embodiments, the non-canonical glutamine is homoglutamine (homo-Gln) (e.g., LCGA-17m24 as shown in Table 1). In embodiments, the non-canonical glutamine is β-glutamine (beta-Gln) (e.g., LCGA-17m25 as shown in Table 1). In embodiments, modification of the Q1glutamine reduces and / or ablates hydrolysis, degradation, and / or cleavage, e.g., due to proteases.

[0132] In embodiments, the chemical modification is within the peptide bond between an R1amino acid and the F1residue, the F1and Q1residues, the Q1and X1residues, the X1and E1residues, and / or the E1residue and a R2 residue.

[0133] In embodiments, the peptide is modified by cyclization. For example, in embodiments, the chemical modification includes bond formation between side chains or carbon-nitrogen backbones, e.g., making the amino acid cyclic and / or introducing a linkage between the X1 residue (e.g., serine) and the Q1 glutamine residue. In embodiments, bond formation includes a C-nitroso (nitrosoalkene formation), ester (replacing the amine of glutamine), ether (replacing the amide of glutamine), a linker molecule, etc. In embodiments, making the amino acid cyclic and / or introducing a linkage between side chains reduces and / or ablates hydrolysis, degradation, and / or cleavage between of any one of the peptide bonds of the peptide.

[0134] A major limitation in the development of peptide drugs is the stability of the isopeptide bond against protease degradation and / or isopeptidase activity. These enzymes can severely delimit therapeutic peptide half-life and efficacy. However, modifying peptides (either through mutation or chemical modification) can introduce trade-offs in binding efficiency, especially for smaller (low molecular weight) peptides. In embodiments, the chemical modification reduces and / or protects against degradation, including protease 34 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 and / or isopeptide bond cleavage between an R1amino acid and the F1residue, the F1and Q1residues, the Q1 and X1 residues, the X1 and E1 residues, and / or the E1 residue and a R2 residue. In embodiments, the chemical modification reduces and / or protects against protease degradation and / or isopeptidase activity found in whole blood, plasma, simulated gastric fluid, and / or the gastrointestinal tract, without negatively impacting binding or therapeutic efficacy of the peptide to one or more target receptors. In embodiments, the chemical modification reduces and / or protects against a variety of proteolytic enzymes, including hydrolases, peptidases, proteinases, carboxylases, aminopeptidases, and dipeptidases in vivo. In embodiments, the chemical modification reduces and / or protects against plasma dicarboxypeptidase cleavage, e.g., in blood / plasma. In embodiments, the chemical modification reduces and / or protects against neuropeptidases, including peptidases that are active in the brain that degrade neuropeptides, peptide neuromodulators, or peptide hormones found in the brain, for example as described in Hui KS. “Neuropeptidases,” Handbook of Neurochemistry and Molecular Neurobiology. Jan 1, 2007: pp.625–51, the entire contents of which are incorporated by reference. In embodiments, the chemical modification reduces and / or protects against nasal and oropharyngeal peptidases.

[0135] In embodiments, the chemical modification reduces and / or protects against non-enzymatic degradation of the peptide, e.g., due to pH, temperature, reactive metal ions, reactive oxygen species, free radicals, etc. In embodiments, the enzymatic and / or non-enzymatic degradation is in vivo, where the peptide exhibits reduced susceptibility to degradative mechanisms present in blood, plasma, nasal cavities, mucous, saliva, brain, simulated gastric fluid, the gastrointestinal tract, etc.

[0136] In embodiments, the chemical modification is within the peptide bond between the F1 and Q1 residues and / or the Q1and X1residues, and reduces and / or protects against protease degradation and / or peptidase activity within these bonds. For example, in embodiments, the peptide bond between the F1and Q1 residues and / or the Q1 and X1 residues includes a tertiary amine functional group (e.g., LCGA-17m23). In embodiments, the peptide bond includes other functional groups such as a methyl groups, ethyl groups, etc. In embodiments, the peptide bond between any two residues of the peptide has a modification (e.g., by any functional group described herein) that confers some degree of resistance to protease degradation and / or isopeptidase cleavage.

[0137] In embodiments, the peptide includes one or more chemical modifications which increase the half-life of the peptide. In embodiments, the half-life is the serum half-life (e.g., as calculated in blood / plasma), 35 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 optionally as measured in humans. In embodiments, the half-life is measured in canines. In embodiments, the half-life is gastrointestinal half-life. In embodiments, the reduced and / or ablated activity of proteases, peptidase, and / or other degradative enzymes against the one or more peptide bonds of the peptide increases the half-life of the peptide, which increases the in vivo efficacy of the peptide. The increased in vivo efficacy, in embodiments, is relative to a non-chemically modified and / or non-synthetic peptide, e.g., a naturally- occurring analogue, for example peptides derived from digestion of a larger protein that lack one or more modifications described herein.

[0138] In embodiments, R2 includes one or more amino acids forming a contiguous isopeptide bond with the carboxy-terminal of the E1 residue. In embodiments, the one or more amino acids includes any one of the 20 naturally-occurring amino acids. For example, in embodiments, the one or more amino acids of R2includes alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In embodiments, the one or more amino acids includes one or more non-canonical amino acids, for example as described herein.

[0139] In embodiments, R2comprises or consists of an amino acid sequence selected from:

[0140] SEQ ID NO: 14 (EQQQTEDELQDK, e.g., LCGA-17m2 as shown in Table 1),

[0141] SEQ ID NO: 15 (EQQQTEDELQD, e.g., LCGA-17m3 as shown in Table 1),

[0142] SEQ ID NO: 16 (EQQQTEDEL, e.g., LCGA-17m4 as shown in Table 1),

[0143] SEQ ID NO: 17 (EQQQTEDE, e.g., LCGA-17m5 as shown in Table 1),

[0144] SEQ ID NO: 18 (EQQQTED, e.g., LCGA-17m5 as shown in Table 1),

[0145] SEQ ID NO: 19 (EQQQTE, e.g., LCGA-17m6 as shown in Table 1),

[0146] SEQ ID NO: 20 (EQQQT, e.g., LCGA-17m7 as shown in Table 1),

[0147] SEQ ID NO: 21 (EQQQ, e.g., LCGA-17m8 as shown in Table 1),

[0148] EQQ (e.g., LCGA-17m9 as shown in Table 1),

[0149] EQ (e.g., LCGA-17m10 as shown in Table 1), and

[0150] E (e.g., LCGA-17m11 as shown in Table 1). 36 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0151] In embodiments, R2includes any one of SEQ ID NOs: 14-21, EQQ, EQ, or E with one or more substitutions, deletions, or insertions thereof. In embodiments, the residues are substituted for others sharing similar physicochemical properties, for example, glutamic (E) acid and / or aspartic acid (D) can be substituted for one another (both negatively charged residues); glutamine (Q) and / or threonine (T) can be substituted for one another, or substituted with asparagine and / or serine (each polar, neutral amino acids); leucine (L) can be substituted for any one of the hydrophobic amino acids, such as alanine (A), valine (V), isoleucine (I), methionine (M), phenylalanine (F), tyrosine (Y), or tryptophan (W); and lysine (K) can be substituted for other amino acids with positively charged side chains, such as arginine (R) or histidine (H). Additionally, any one of the residues of SEQ ID NOs: 14-21, EQQ, EQ, or E could be substituted with cysteine (C), e.g., to introduce a thiol for disulfide bond formation, or could be substituted with glycine (G) or proline (P), e.g., to modulate sterics or peptide shape, among other purposes.

[0152] In embodiments, R2includes one or more repeats of SEQ ID NOs: 14-21, EQQ, EQ, or E, or substitutions, deletions, or insertions thereof. For example, in embodiments, the peptide has repeating motifs of one or more of E, EQ, EQQ, EQQQ (SEQ ID NO: 21), EQQQT (SEQ ID NO: 20), EQQQTE (SEQ ID NO: 19), EQQQTED (SEQ ID NO: 18), EQQQTEDE (SEQ ID NO: 17), EQQQTEDEL (SEQ ID NO: 16), EQQQTEDELQD (SEQ ID NO: 15), and EQQQTEDELQDK (SEQ ID NO: 14).

[0153] In embodiments, the peptide comprises or consists of about or at least about 4 amino acids to about or at least about 50 amino acids. In embodiments, the peptide comprises or consists of about or at least about 4 amino acids, about or at least about 5 amino acids, about or at least about 6 amino acids, about or at least about 7 amino acids, about or at least about 8 amino acids, about or at least about 9 amino acids, about or at least about 10 amino acids, about or at least about 11 amino acids, about or at least about 12 amino acids, about or at least about 13 amino acids, about or at least about 14 amino acids, about or at least about 15 amino acids, about or at least about 16 amino acids, about or at least about 17 amino acids, about or at least about 18 amino acids, about or at least about 19 amino acids, about or at least about 20 amino acids, about or at least about 25 amino acids, about or at least about 30 amino acids, about or at least about 35 amino acids, about or at least about 40 amino acids, about or at least about 45 amino acids, or about or at least about 50 amino acids.

[0154] The peptide, in embodiments, exhibits and / or adopts a variety of secondary structural features. For example, the peptide exhibits and / or adopts random coil behavior, e.g., as a linear, substantially unfolded 37 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 peptide, especially at lower molecular weights. In embodiments, the peptide is engineered to adopt a secondary structural element, such as having α-helical or beta-sheet content, or to exhibit a particular fold or motif, such as β-turns, β-α-β motifs, Greek key motif, helix-turn-helix, etc.

[0155] The peptide, in embodiments, includes multi-mer repeats of the “FQXE” motif. For example, in embodiments, the peptide contains more than 1 repeat of the F1Q1X1E1 motif, for example: R1-F1Q1X1E1-R2- F2Q2X2E2-R3-FnQnXnEn-Rn, where n is any whole number integer of repeats, and where each intervening R group (e.g., R2, R3, Rn) includes any number of amino acids, such as linker sequences or repeats of glycine, serine, and / or combinations of glycine and serine, and / or any one of E, EQ, EQQ, EQQQ (SEQ ID NO: 21), EQQQT (SEQ ID NO: 20), EQQQTE (SEQ ID NO: 19), EQQQTED (SEQ ID NO: 18), EQQQTEDE (SEQ ID NO: 17), EQQQTEDEL (SEQ ID NO: 16), EQQQTEDELQD (SEQ ID NO: 15), and / or EQQQTEDELQDK (SEQ ID NO: 14). In embodiments, for example in reference to formula I, y is a whole number integer between 1 and 10. In embodiments, y is 1 (e.g., LCGA-17 as shown in Table 1). In embodiments, y is 2, 3, 4, 5, 6, 7, 8, 9, or at least 10. In embodiments, multi-mer repeats of the “FQXE” motif improves the binding kinetics, activity, and / or overall efficacy of the peptide relative to a peptide having a single motif.

[0156] In embodiments, the peptide comprises or consists of one or more of SEQ ID NOs: 1-13, including amino acid sequences having one or more substitutions, deletions, or insertions thereof (e.g., outside of the FQXE motif).

[0157] In embodiments, the peptide comprises or consists of SEQ ID NO: 1, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 2, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 3, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 4, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 5, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 6, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 7, or an amino acid sequence having one or more substitutions, 38 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 8, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 9, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 10, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 11, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 12, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 13, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif. In embodiments, the peptide comprises or consists of SEQ ID NO: 22, or an amino acid sequence having one or more substitutions, deletions, or insertions thereof outside of the FQXE motif.

[0158] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1) with an acetylated N-terminus. In embodiments, the peptide comprises, from N-terminus to C- terminus, FQSE residues (SEQ ID NO: 1) with an acetylated N-terminus and at least one residue being a D- form amino acids, e.g., D-serine and / or D-glutamine. In embodiments, the peptide comprises, from N- terminus to C-terminus, FQSE residues (SEQ ID NO: 1) with an acetylated N-terminus and one or more sequences selected from SEQ ID NO: 14-21 forming a contiguous peptide sequence via the C-terminal end.

[0159] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), without an N-terminal or C-terminal modification, where each residue is in D-form. In embodiments, the peptide comprises, from N-terminus to C-terminus, ESQF residues (SEQ ID NO: 13), without an N- terminal or C-terminal modification, where each residue is in D-form.

[0160] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and an amidated C-terminus.

[0161] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with a myristic acid conjugated to the N-terminus and without modification of the C-terminus. In 39 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with a palmitic acid conjugated to the N-terminus and without modification of the C-terminus.

[0162] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a D-lysine myristic acid conjugated to the C-terminus. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a D-lysine palmitic acid conjugated to the C-terminus.

[0163] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a N-methylated glutamine residue. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a homo-glutamine residue. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a beta-glutamine residue.

[0164] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a N-methylated serine residue. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a Cα-methylated serine residue. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a beta-serine residue. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a L-homo-serine residue. In embodiments, the peptide comprises, from N-terminus to C- terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a D-homo-serine residue.

[0165] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a difluoro-serine residue. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a tri-serine residue.

[0166] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and a beta / beta-serine residue. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQXE residues, with an acetylated N-terminus and where X = sarcosine. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQXE residues, with an acetylated N-terminus and where X = hydroxyproline or serine-hydroxyproline. 40 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0167] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and where the serine is modified to be benzyl-serine. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and where the serine is modified to be toluene-serine. In embodiments, the peptide comprises, from N-terminus to C-terminus, FQSE residues (SEQ ID NO: 1), with an acetylated N-terminus and where the serine is modified to be toluene-methoxinine.

[0168] In embodiments, the peptide comprises, from N-terminus to C-terminus, FQTE residues (SEQ ID NO: 22), where the N-terminus is acetylated, and the threonine is D-threonine.

[0169] In embodiments, the peptide is a component of a fusion protein. The fusion protein, in embodiments, includes one or more moieties fused to the peptide via a covalent bond to the N-terminus, C- terminus, and / or internally. In embodiments, the covalent bond is an isopeptide bond. For example, in embodiments, the fusion protein has one or more amino acid sequences linked, via a peptide bond, at the R1position and / or R2position (e.g., N-terminally and / or C-terminally). In embodiments, the fusion has one or more moieties, such as a PEG molecule, linker molecule, or a lipid, conjugated via a covalent linkage to one or more side chains located internally (e.g., between the peptide N-terminus and C-terminus).

[0170] In embodiments, the one or more moieties increases the half-life of the peptide, e.g., the serum half-life, gastrointestinal half-life, or half-life as measured in a particular organ system or tissue of the body. In embodiments, the increase of the one or more half-lives is relative to a peptide lacking fusion to the one or more moieties, and / or in comparison to a version of the peptide lacking one or more chemical modifications, as described herein.

[0171] In embodiments, the one or more half-life extension moieties includes an antibody Fc domain (e.g., IgG, IgG1, IgG2, IgG3, IgG4), albumin (e.g., human serum albumin), transferrin, polyethylene glycol (PEG), elastin, extended recombinant polypeptide (XTEN) (e.g., XTENylation, also referred to as “rPEG”), elastin-like peptide (ELP) (e.g., “peptide-ELP” repeats for example from PHASEBIO), glycine-rich homo- amino-acid polymer (HAP), proline / alanine / serine (PAS) repeats (e.g., PASYLATION, a biological alternative to PEGylation based on the genetic fusion, or chemical coupling, with polypeptides made of the natural L- form amino acids Pro, Ala and / or Ser to give random coil structures with larger hydrodynamic volume), artificial gelatin-like protein (GLK), and / or C-terminal peptide (CTP) of human chorionic gonadotropin β- subunit. 41 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0172] In embodiments, the peptide includes one or more moieties as tags, e.g., for purification, stability, and / or shelf-life purposes, to prevent aggregation, for manufacturing considerations, etc., for example in instances where the peptides will be biosynthesized (e.g., produced in a host cell). Examples include, in embodiments, peptides and proteins or protein domains, or even whole proteins (e.g., fluorescent proteins such as GFP, YFP, etc.). The tag, in embodiments, includes a peptide moiety, such as a flag tag (e.g., DYKDDDDK, SEQ ID NO: 23). Adding a peptide, polypeptide, protein, or protein domain tag to a molecule of interest has been extensively described in the art. Examples include, but are not limited to, in embodiments, peptides derived from synuclein (e.g., Park et al., Protein Eng. Des. Sel.2004; 17:251-260), SET (solubility enhancing tag, Zhang et al., Protein Expr Purif, 2004; 36:207-216), thioredoxin (TRX), Glutathione-S- transferase (GST), Maltose-binding protein (MBP), N-Utilization substance (NusA), small ubiquitin-like modifier (SUMO), ubiquitin (Ub), disulfide bond C (DsbC), Seventeen kilodalton protein (Skp), Phage T7 protein kinase fragment (T7PK), Protein G Bl domain, Protein A IgG ZZ repeat domain, and bacterial immunoglobulin binding domains (Hutt et al., J Biol Chem.; 287(7):4462-9, 2012). The nature of the tag can depend on the application, as can be determined by the skilled artisan. For instance, for transgenic expression of the molecules described herein, it might be envisaged to fuse the molecules to a larger domain to prevent premature degradation by the cellular machinery. In embodiments, the tag includes a solubilization tag (e.g., less than 30 amino acids, or less than 20 amino acids, or even less than 10 amino acids) to avoid substantially altering the properties of the molecules during resuspension and / or storage. In embodiments, the tag is flanked (e.g., at the N-terminal end or C-terminal end) by an intein motif, or a stretch of amino acids that spontaneously undergo N-to-S acyl transfer to allow to removal of the tag at specified points in the manufacturing pipeline.

[0173] In embodiments, an isoelectric point (pI) of the peptide as described herein is less than about 6. In embodiments, the pI of the peptide is between about 3.5 and about 4.5. In embodiments, the pI of the peptide is between about 3.3 and about 4.2. In embodiments, the pI of the peptide is about 4.0.

[0174] Persons skilled in the art, upon receiving the benefit of this disclosure in its entirety, will understand the various techniques and methods that can be employed to modify the peptides, as described herein. Compositions and Formulations of Peptides 42 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0175] The present disclosure provides, in part, compositions of peptides. In embodiments, the composition is a pharmaceutical composition, e.g., suitable for use in animals and / or humans. In embodiments, the present disclosure relates to a pharmaceutical composition comprising the peptide of any of the embodiments disclosed herein, and a pharmaceutically acceptable carrier / excipient.

[0176] In embodiments, the pharmaceutical composition is formulated for administration via a variety of routes of administration. In embodiments, the pharmaceutically acceptable excipients are generally sterile and free of microbial contamination when administered to a subject.

[0177] In embodiments, the composition is formulated with one or more pharmaceutically acceptable excipients, e.g., suitable for parenteral administration, including for example, one or more of water, bicarbonate, carbonate, acetate buffer, citrate buffer, phosphate buffer, ethanol, propylene glycol, glycerin, sodium chloride, sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, dextrose, dextran, DMSO, cell media, serum albumin (e.g., human serum albumin), and / or combinations thereof. Water is a useful excipient when any agent disclosed herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. In embodiments, composition is formulated with bicarbonate (e.g., 5% sodium bicarbonate, NaHCO3) and / or carbonate. In embodiments, the composition is formulated with one or more buffering agents, including for example acetate, citrate, or phosphate buffers.

[0178] In embodiments, the composition is formulated with an excipient suitable for culturing cells, including for example, phosphate buffered saline (PBS), Dulbecco’s Modified Eagle Medium (DMEM), alpha modified Minimal Essential Medium (alpha MEM), Roswell Park Memorial Institute Media 1640 (RPMI Media 1640), HBSS, Ringer’s solution, PLASMA-LYTE (Baxter), which is a commercially available, pH-balanced (pH 7.4) formulation commonly used with cell therapies, and the like, and / or any combination thereof.

[0179] In embodiments, the one or more pharmaceutically acceptable excipients is a cryoprotectant for protection during freeze-thaw cycles, such as DMSO, and alternatives to DMSO (e.g., for use in children), including 1,2-propanediol, glycerol, sorbitol, PEG 600, trehalose, creatine, isoleucine, maltose, sucrose, and / or any combination thereof.

[0180] In embodiments, the compositions, including pharmaceutically acceptable compositions, described herein are in the form of and / or comprise a pharmaceutically acceptable salt, buffer, isotonicity 43 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 agent, and the like. Such salts, buffers, isotonicity agents, and the like, include those listed in, for example, Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety.

[0181] Pharmaceutical excipients, in embodiments, are liquids, such as water, oils, and polyols, including those of petroleum, animal, vegetable, or synthetic origin.

[0182] The pharmaceutical excipients can be, for example, solution components useful for solubilizing and / or stabilizing proteins, including for example, free amino acids, bacteriostatic water, gelatin, urea, glycerol, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, lipid, arginine, glycine, PEG, polysaccharide, cyclodextrin, chitosan, cellulose, alginate, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, dried skim milk, glycerol, propylene, glycol, isopropanol, and the like. Any composition disclosed herein, if desired, can also be formulated with wetting agents, emulsifying agents, and / or pH buffering agents. Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed.1995), incorporated herein by reference.

[0183] In embodiments, the peptide is formulated with a delivery vehicle. Delivery vehicles, in embodiments, include for example a liposome, nanoparticle, or dendrimer, among other delivery vehicles for delivering peptides. In embodiments, the peptide is formulated with a delivery vehicle for delivery to and / or crossing the blood-brain barrier.

[0184] In embodiments, the compositions are prepared in any manner well known in the pharmaceutical arts, and can be formulated to be administered via a variety of routes (e.g., subcutaneous, intravenous, parenteral, oral, etc.). In embodiments, administration can be topical or oromucosal (including gels, creams, and / or ointments for ophthalmic delivery and delivery to mucous membranes including intranasal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral, or parenteral. In embodiments, methods include ocular delivery, topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. In embodiments, parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or 44 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 infusion; or intracranial, e.g., intrathecal or intraventricular administration. In embodiments, parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. In embodiments, administration can be oral, e.g., where the composition is formulated into a tablet or capsule. In embodiments, the pharmaceutical composition is formulated into an oromucosal gel, e.g., for oromucosal application.

[0185] In embodiments, the pharmaceutical compositions contain, as the active ingredient, neuromodulatory peptides described herein in combination with one or more pharmaceutically acceptable carriers / excipients. In embodiments, the terms “pharmaceutically acceptable” (or “pharmacologically acceptable”) refer to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction, when administered to an animal or a human, as appropriate. The methods and compositions disclosed herein can be applied to a wide range of species, e.g., humans, non-human primates (e.g., monkeys), horses or other livestock, aquatic animals, dogs, cats, ferrets or other mammals kept as pets, rats, mice, or other laboratory animals. In embodiments, the term “pharmaceutically acceptable carrier,” includes any and all solvents, dispersion media, coatings, anti-infectives, isotonic and absorption delaying agents, buffers, excipients, binders, lubricants, gels, surfactants and the like, that may be used as media for a pharmaceutically acceptable substance.

[0186] In embodiments, the pharmaceutical composition is formulated for non-human animals, for example dogs and / or other companion animals. In embodiments, such a pharmaceutical composition can be formulated into a chewable tablet, granule, cream, paste, ointment, transdermal delivery patch, gel, and / or an implant.

[0187] In embodiments, the compositions can be applied to a surface of a device (e.g., a catheter) or contained within a syringe, autoinjector, pump, patch, nebulizer, capsule, implant, or other drug delivery device.

[0188] In embodiments, the pharmaceutical composition is contained as one or more unit doses, where each unit dose is about or at least about 0.01 mg to about or at least about 5,000 mg. In embodiments, the compositions can be administered alone, or in a mixture, in the presence of a pharmaceutically acceptable excipient or carrier (e.g., physiological saline). The excipient or carrier is selected based on the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington's Pharmaceutical Sciences (E. W. Martin), a well- 45 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 known reference text in this field, and in the USP / NF (United States Pharmacopeia and the National Formulary).

[0189] The present disclosure includes, in part, the disclosed neuromodulatory peptides in various formulations of pharmaceutical compositions. For example, in embodiments, the formulations of pharmaceutical compositions can take the form of solutions, suspensions, gels, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, emulsions, aerosols, sprays, and / or any other form suitable for use. In embodiments, the pharmaceutical composition is formulated into an oromucosal gel. In embodiments, the pharmaceutical composition is formulated for dogs, cats, and / or other companion animals, for example into chewable tablets, granules, cream, paste, ointment, transdermal or transmucosal delivery patch / gel, and / or an implant.

[0190] Pharmaceutical compositions comprising the neuromodulatory peptides described herein can conveniently be presented in unit dosage forms and can be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the pharmaceutical compositions are prepared by uniformly and intimately bringing therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art).

[0191] In embodiments, any neuromodulatory peptides disclosed herein are formulated in accordance with routine procedures as a pharmaceutical composition adapted for a mode of administration disclosed herein.

[0192] In embodiments, any herein-disclosed neuromodulatory peptides or composition comprising the same is formulated in accordance with routine procedures as a pharmaceutical composition adapted for a mode of administration disclosed herein. Methods of Treating and / or Ameliorating Psychological, Behavioral, and / or Cognitive Disorders

[0193] Described herein, in part, are peptides that function as neuromodulatory peptides. In embodiments, described herein are methods of treating and / or ameliorating a psychological, behavioral, and / or cognitive disorder in a subject in need thereof. In embodiments, the methods include administering to 46 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 the subject a peptide (e.g., also referred to herein as a “synthetic neuromodulatory peptide”) and / or a pharmaceutical composition, as described herein. In embodiments, the peptide is a neuromodulatory peptide by virtue of its effect on and / or mechanism of action via one or more cell surface receptors and / or signaling components located within the nervous system.

[0194] In aspects, described herein is a method of using a peptide-based neuromodulatory therapeutic composition for a range of psychiatric conditions within the spectrum of depressive and anxiety disorders. In embodiments, the neuromodulatory peptide(s) described herein are engineered to achieve high specificity of binding and efficacy within the context of target receptors expressed in the nervous system (e.g., CNS). In embodiments, the neuromodulatory peptide(s) described herein demonstrate favorable in vivo safety profile, pharmacokinetics, and / or pharmacodynamics conducive to methods of treatment and / or amelioration of psychiatric conditions in humans and non-human animals.

[0195] In embodiments, the neuromodulatory peptide functions to treat and / or ameliorate one or more of a mood disorder, anxiety, generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, post- traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), postpartum depression (PPD), bipolar and related disorders, schizophrenia, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and stress-related disorders. In embodiments, the stress-related disorders includes conditions and / or behaviors found in humans and / or non-human animals, including for example separation anxiety, social anxiety, noise anxiety, trembling, hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior.

[0196] In embodiments, the neuromodulatory peptide functions to treat and / or ameliorate one or more symptoms or signs of a psychological, behavioral, and / or cognitive disorder in non-human animals (e.g., dogs) that are treated and / or ameliorated by SILEO (dexmedetomidine oromucosal gel, Zoetis). In embodiments, the neuromodulatory peptide is co-administered either before, after, or concurrently with SILEO (dexmedetomidine oromucosal gel, Zoetis) or one or more other α2-adrenergic receptor agonists.

[0197] In embodiments, “treat and / or ameliorate” includes addressing one or more symptoms or signs of a psychological, behavioral, and / or cognitive disorder, e.g., by reducing the severity and / or occurrence of the one or more symptoms or signs. 47 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0198] In embodiments, the psychological, behavioral, and / or cognitive disorder is anxiety. In embodiments, the psychological, behavioral, and / or cognitive disorder is depression. In embodiments, the psychological, behavioral, and / or cognitive disorder is a stress-related disorder.

[0199] Without wishing to be bound by theory, mechanistically, in embodiments, the peptide acts through an interaction and / or modulation of one or more GABAA receptors, voltage-gated calcium channels (VGCC), thrombospondin proteins (subtypes 1-4), Neurexin-1a protein, scaffolding protein LRP1, dopamine receptors (D1-5), serotonin receptors, glutamate receptors, and acetylcholine receptors. In embodiments, the modulation is inhibition. In embodiments, the modulation is activation.

[0200] In embodiments, the peptide functions as a positive allosteric modulator of the one or more receptors. In embodiments, the interaction with and / or modulation of the one or more GABAAreceptors comprises allosteric regulation. GABA-positive allosteric modulators, in embodiments, are medications, such as benzodiazepine-receptor agonists, which are useful in the management and treatment of seizures, sedation, anxiolytic, alcohol withdrawal, sleeplessness, insomnia, appetite fluctuation, muscle spasms, etc. In embodiments, the peptide functions to treat and / or ameliorate one or more conditions, signs, and / or symptoms that GABA-positive allosteric modulator medications (such as benzodiazepine-receptor agonists) can treat and / or ameliorate.

[0201] In embodiments, the interaction and / or modulation is via binding. In embodiments, the peptide functions as an allosteric modulator of one or more receptors, binding to one or more receptors and altering the interactions between the active site(s) and ligand(s) within the receptor(s). In embodiments, binding of the peptide initiates one or more conformation changes within the receptor(s). In embodiments, the conformation change is congruent to that which is initiated by the receptor’s ligand(s). In embodiments, binding of the peptide initiates and / or potentiates one or more intracellular signaling events within a cell. In embodiments, the cell can include one or more of a neuron, glial cell, thalamic relay cell, hippocampal pyramidal cell, cerebellar granule cell, as well as one or more cell types located within the thalamus, hypothalamus, hippocampus, prefrontal cortex, etc.

[0202] In embodiments, the peptide acts through an interaction and / or modulation of one or more GABAAreceptors. GABAAreceptors, in embodiments, refer to a class of ionotropic receptors, encompassing several isoforms, and exhibiting synaptic and / or extrasynaptic functions. In embodiments, the peptide interacts with and / or activates GABAA receptors found in one or more anatomical locations within the subject, 48 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 including for example the reticular thalamic nucleus, thalamic relay cells, hippocampal pyramidal cells, cerebellar granule cells, the thalamus, hypothalamus, hippocampus, prefrontal cortex, as well as widespread neuronal and glial locations. In embodiments, the interaction and / or modulation includes binding to one or more portions of the receptor and / or potentiating signaling via the receptor.

[0203] The endogenous ligand of GABAA, gamma-aminobutyric acid (GABA), is the major inhibitory neurotransmitter of the central nervous system. GABAA receptors are the predominant type of GABA receptors in the brain. The prototypical GABAAreceptor is composed of 5 subunits. To date, at least 19 different genes of the 16 identified subunits have been described, grouped into α, β, γ, δ, ε, or σ subunits, of which α, β, and γ are among the most studied, for example as described in Olsen and Sieghart, “GABAA Receptors: Subtypes Provide Diversity of Function and Pharmacology,” Neuropharmacology, Vol.56, No.1, 2009: pp.141-8, the contents of which are hereby incorporated by reference in their entirety.

[0204] In embodiments, the one or more GABAAreceptors includes one or more isoforms selected from α1β3γ2S, α2β3γ2S, α3β3γ2S, α4β3γ2S, α5β3γ2S, α6β3γ2S, α1β2γ2S, α4β3δ, α6β3δ, α1β2, α1β3, α1β2δ, α4β2δ, α3β3θ, and α3β3ε.

[0205] There are several druggable sites in the GABAAreceptor. For example, GABA (among several other drugs) bind the GABAAreceptor at the interface between the α and β subunits. The GABAAreceptor is also the target of benzodiazepines (BDZ), a class of tranquilizer drugs, bind to a so-called benzodiazepine binding site located at the interface between the α and γ subunits of α / γ subunit-containing GABAAreceptors, for example as described in Barnard, “Subtypes of gamma-aminobutyric acid A receptors: classification on the basis of subunit structure and receptor function,” Pharmacol. Rev. Vol.50, No.2, 1998: pp.291–313, the contents of which are hereby incorporated by reference in their entirety. Upon benzodiazepine binding, the GABAAreceptor undergoes allosteric conformational changes, increasing the affinity of the GABAAreceptor to GABA.

[0206] In embodiments, the peptide binds the one or more GABAAreceptors at a benzodiazepine binding site. In embodiments, GABAA receptor binding by the peptide results in increasing the affinity of GABA to the GABAA receptor. In embodiments, the peptide binds the one or more GABAA receptors at an α- β binding site. In embodiments, wherein the peptide binds the one or more GABAAreceptors at an α-γ binding site. In embodiments, the peptide binds both the α-β binding site and α-γ (BDZ) binding site. 49 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0207] In embodiments, one or more of the F1, Q1, X1, E1amino acids forms one or more molecular contacts with the BDZ binding site, α-β binding site, and / or α-γ binding site. In embodiments, one or more of R1 and / or R2 forms one or more molecular contacts with the BDZ binding site, α-β binding site, and / or α-γ binding site. In embodiments, the N-terminus of the peptide interacts with the BDZ binding site, α-β binding site, and / or α-γ binding site, or be positioned in close proximity to one or more of these sites. Alternatively, in embodiments, the C-terminus of the peptide interacts with the BDZ binding site, α-β binding site, and / or α-γ binding site, or be positioned in close proximity to one or more of these sites.

[0208] In embodiments, the peptide has an improved (e.g., increased) activity relative to the peptide Ac-FQSE (e.g., LCGA-17, SEQ ID NO: 1, as shown in Table 1). In embodiments, the peptide has an improved (e.g., increased) affinity, interaction, and / or modulation effect relative to the peptide Ac-FQSE (e.g., LCGA- 17, SEQ ID NO: 1, as shown in Table 1).

[0209] In embodiments, the peptide functions as a GABAApositive allosteric modulator. In embodiments, the peptide functions as a GABAApositive allosteric modulator peptide with affinity to the BDZ binding site of GABAA between the α and γ subunits (e.g., α-γ binding site). In embodiments, the peptide exhibits anxiolytic and / or antidepressant activity comparable to diazepam and / or fluvoxamine.

[0210] In embodiments, the interaction with and / or modulation of the one or more GABAAreceptors comprises binding at a site that is distinct from a binding site of one or more GABAA receptor ligands selected from isoguvacine, salicylidene salicylhydrazide, bretazenil, SL651498, MK0343, THDOC, TB21007, gaboxadol, FGIN-1-27, and allopregnanolone. In embodiments, the interaction with and / or modulation of the one or more GABAA receptors comprises binding at a benzodiazepine binding site. In embodiments, the binding at the benzodiazepine binding site increases the affinity of one or more GABAAreceptors to gamma- aminobutyric acid (GABA).

[0211] In embodiments, the peptide acts through an interaction with and / or modulation of one or more voltage-dependent calcium channels. In embodiments, the one or more voltage-dependent calcium channels comprise a L-type, N-type, P / Q type, and / or R-type. In embodiments, the interaction with and / or modulation of the one or more voltage-dependent calcium channels comprises binding to an α2δ calcium channel subunit. In embodiments, the peptides binds the α2δ calcium channel subunit of each of the four isoforms, e.g., α2δ1, α2δ2, α2δ3, α2δ4. In embodiments, the peptide inhibits Ca-currents (calcium-currents) through one or more VGCCs and / or VGCC isoforms. In embodiments, the peptide functions as a negative allosteric 50 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 modulator through α2δ binding. In embodiments, the peptide binds the same receptor(s) and / or binding sites as gabapentin (e.g., α2δ calcium channel subunit of voltage-dependent calcium channels: L-type, N-type, P / Q type, and / or R-type).

[0212] Of all four known α2δ calcium channel isoforms, gabapentinoids are known to bind only to α2δ- 1 and α2δ-2, for example, as described in Chen, et al. “Structural basis for CaVα2δ:gabapentin binding. Nat Struct Mol Biol. (2023) 30(6): pp.735-739. Both α2δ-1 and α2δ-2 are highly expressed in the brain, including the cortex, and are described to mediate the central effects of gabapentinoids, for example, as described in Dolphin, A. C. (2018). Voltage-gated calcium channel α 2δ subunits: an assessment of proposed novel roles. F1000Research, 7).

[0213] Use of gabapentinoids is associated with a significantly increased risk of adverse cardiovascular effects, including atrial fibrillation, acute heart failure, cardiomyopathy, myocardial infarction, and intraoperative hypotension that is thought to be triggered by direct action on α2δ in cardiomyocytes and vascular smooth muscle, for example, as described in Pendyala, et al., “Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats,” Cells, (2023) 12(23), 2705; and Largeau, et al., “Gabapentinoid-induced peripheral edema and acute heart failure: a translational study combining pharmacovigilance data and in vitro animal experiments,” Biomedicine & Pharmacotherapy, (2022).149, 112807. α2δ-1 is reported to be a dominant isoform expressed in cardiac tissues in humans, and multiple in vivo knock-out studies indicate its exclusive role in producing adverse cardiac events by gabapentinoids, for example, as described in Dolphin, A. C. (2018). “Voltage-gated calcium channel α 2δ subunits: an assessment of proposed novel roles,” F1000Research, 7; and Page, et al., “The importance of cache domains in α2δ proteins and the basis for their gabapentinoid selectivity,” Channels, (2023).17(1), 2167563. By contrast, α2δ-2 is not represented in cardiac or vascular tissues and is not reported to be involved in cardiac function regulation, but is expressed primarily in central nervous tissue (e.g., the brain), for example, as described in Davies, et al., “Functional biology of the a2 d subunits of voltage-gated calcium channels,” TRENDS in Pharmacological Sciences, (2007) 28(5), 221). Even though α2δ-2 mRNA has also been identified in other tissues, such as in human lung tissue, α2δ-2 protein is not detectable in the lung (Davies, 2007), therefore α2δ-2 is believed to produce primarily neuronal functions.

[0214] α2δ ligands typically do not function by influencing calcium currents directly, rather the mechanism of action involves altering the protein-protein interactions of α2δ with its interacting proteins and 51 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 altering the densities of the proteins on the cell surface, for example, as described in Hendrich, et al., “Pharmacological disruption of calcium channel trafficking by the α2δ ligand gabapentin,” Proceedings of the National Academy of Sciences, (2008) 105(9), 3628-3633; and Dolphin, “Voltage-gated calcium channel α 2δ subunits: an assessment of proposed novel roles,” F1000Research, (2018) 7. Gabapentinoids impair the trafficking of the α1 pore-forming VGCC subunit to the plasma membrane by influencing its association with α2δ (both α2δ-1 and α2δ-2), thereby decreasing channel density and thus reducing the magnitude of Ca2+ currents, for example, as explained in Reyes Fernandez, et al., “Effects of Gabapentin and Pregabalin on Calcium Homeostasis: Implications for Physical Rehabilitation of Musculoskeletal Tissues,” Current Osteoporosis Reports, (2022) 20(6), 365-378.

[0215] Biochemical data indicates that gabapentinoid action is largely mediated by N-methyl-d- aspartate receptors (NMDARs). For example, α2δ-1 directly interacts with NMDARs, increasing their presence on the membranes, and driving synaptic NMDAR activity that is reversed by gabapentinoids disrupting the association between α2δ-1 and NMDARs, e.g., as explained in Taylor, C. P., & Harris, E. W. (2020). Analgesia with gabapentin and pregabalin may involve NMDARs, neurexins, and thrombospondins, for example as described in the Journal of Pharmacology and Experimental Therapeutics, 374(1), 161-174; Wu, et al., “The α2δ-1-NMDA receptor complex and its potential as a therapeutic target for ischemic stroke,” Frontiers in Neurology, (2023) 14, 1148697; and Chen, et al., “The α2δ-1-NMDA receptor complex is critically involved in neuropathic pain development and gabapentin therapeutic actions,” Cell reports, (2018) 22(9), pp.2307-2321. This mechanism underlies the ability of gabapentinoids to reduce long-term potentiation (LTP) and cause long-term depression (LTD). Gabapentin is reported to decrease NMDAR-mediated frequency of excitatory postsynaptic currents (EPSCs), for example, as explained in Jin, et al., “α2δ‐1 protein drives opioid‐induced conditioned reward and synaptic NMDA receptor hyperactivity in the nucleus accumbens,” Journal of neurochemistry, (2023).164(2), 143-157, and to abolish LTP through disruption of α2δ-1-NMDAR interaction, for example, as explained in Zhou, et al., “The α2δ-1–NMDA receptor coupling is essential for corticostriatal long-term potentiation and is involved in learning and memory,” Journal of Biological Chemistry, (2018) 293(50), 19354-19364.

[0216] α2δ-2 is reported to play a role of an important transsynaptic organizer. Abundance of presynaptic α2δ-2 strongly increases clustering of postsynaptic GABAA receptors and downscales the density of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), for example, as explained in Schöpf, et al., “Presynaptic α2δ subunits are key organizers of glutamatergic synapses,” 52 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Proceedings of the National Academy of Sciences, (2021). 118(14), e1920827118; Geisler, et al., “Presynaptic α2δ-2 calcium channel subunits regulate postsynaptic GABAA receptor abundance and axonal wiring,” Journal of Neuroscience, (2019) 39(14), 2581-2605; and Ablinger, et al., “Neuronal α2δ proteins and brain disorders,” Pflügers Archiv-European Journal of Physiology, (2020) 472(7), 845-863. Biochemical data suggests that the mechanism underlying this process is VGCC-dependent, where association of α2δ-2 with VGCC on a presynaptic membrane regulates active zone architecture and morphogenesis resulting in the accumulation of synaptic vesicles influencing the alignment of the postsynaptic membrane structure and content, including postsynaptic AMPAR and GABAA receptor presence.

[0217] Without wishing to be bound by theory, in embodiments, peptides and their chemically-modified equivalents herein function as an α2δ-2 modulator (e.g., allosteric modulator), decreasing presynaptic α2δ- 2-VGCC representation on the cell surface, leading to reduced GABAA receptor levels and enhanced AMPAR postsynaptic levels on the cell surface. Without wishing to be bound by theory, in embodiments, peptides and their chemically-modified equivalents herein induce long-term potentiation (LTP) with α2δ-2 antagonism and increased postsynaptic AMPAR level on the cell surface. Without wishing to be bound by theory, in embodiments, peptides and their chemically-modified equivalents herein support synaptogenesis and axon regeneration via α2δ-2 antagonism.

[0218] These mechanisms are supported by the biochemical data of the field which demonstrates that α2δ-2 inhibits synaptogenesis and axon regeneration, for example, as described in Tedeschi, et al., “The calcium channel subunit Alpha2delta2 suppresses axon regeneration in the adult CNS,” Neuron, (2016) 92(2), 419-434, and its pharmacological blockade results in increased neuroplasticity, for example, as described in Tedeschi, et al., “Harnessing cortical plasticity via gabapentinoid administration promotes recovery after stroke,” Brain, (2022) 145(7), 2378-2393.

[0219] In embodiments, peptides and their chemically-modified equivalents herein bind to, or compete with binding at, one or more gabapentin binding sites in the α2δ-2 calcium channel isoform, e.g., in brain tissue. In embodiments, chemically-modified peptides herein do not exhibit substantial binding to, or do not exhibit substantial competition of binding at, one or more gabapentin binding sites in the α2δ-1 calcium channel isoform, e.g., in cardiac tissue.

[0220] In embodiments, the peptide does not bind, or does not substantially overlap with a binding site thereof, of pregnenolone sulfate (PREGS). In embodiments, the peptide does not bind, or does not 53 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 substantially overlap with a binding site thereof, of one or more GABAAreceptor binding sites shared with diazepam, muscimol, bicuculline, gabazine, and / or CGS-9895. In embodiments, the peptide does not bind, or does not substantially overlap with a binding site thereof, of one or more binding sites for one or more ligands selected from neurotransmitter receptor ligands; dopamine receptors ligands (haloperidol, sulpiride, spiperone, 7-OH-DPAT); serotonin receptors ligands (ketanserin); acetylcholine receptor ligands (nicotine); and glutamate receptor ligands (glutamate, glycine, Ro-256981, LY-354740, MK-801, spermine, arkain).

[0221] In embodiments, the peptide binds one or more receptors and / or binding sites with an affinity (e.g., IC50) of less than about 1 nM, less than about 5 nM, less than about 10 nM, less than about 50 nM, less than about 0.1 µM, less than about 0.5 µM, less than about 1.0 µM, less than about 1.5 µM, less than about 2.0 µM, less than about 2.5 µM, less than about 5.0 µM, less than about 10 µM, less than about 15 µM, less than about 20 µM, less than about 25 µM, less than about 50 µM, or less than about 100 µM. In embodiments, the peptide with one or more chemical modifications (e.g., at R1, R2, carbon-nitrogen backbone, and / or amino acid side chain), and / or with one or more D-form amino acids or non-canonical amino acids, exhibits a different affinity (e.g., IC50) in comparison to FQSE (SEQ ID NO: 1). In embodiments, the difference in binding affinity is off-set by a marked increase in half-life (e.g., serum half-life), resulting in an overall more efficacious peptide within the context of treatment.

[0222] In embodiments, binding affinity is an IC50 measurement. The affinity of the peptide, in embodiments, can be tested and / or measured using a variety of in vitro and / or ex vivo methods. For example, in embodiments, binding affinity can be measured using patch-clamp electrophysiology, e.g., as described in Example 6. In embodiments, binding affinity can be measured using a radioligand assay, e.g., as described in Example 4. In further examples, in embodiments, other assays can be used to measure the binding of the peptides such as isothermal titration calorimetry (ITC), enzyme-linked immunoassay (ELISA), as well as various spectroscopic, fluorometric, and luminescence-based assays. In embodiments, a competitive binding assay can be used to determine binding kinetics and / or binding sites of the peptide relative to one or more known ligands, substrates, or therapeutics. Persons skilled in the art, with the benefit of this disclosure in its entirety, will be aware of the various techniques that can be employed to measure binding affinity of the peptides.

[0223] In embodiments, the peptide exhibits a half-life (e.g., a circulating half-life, or serum half-life) of about or at least about 1 hour, about or at least about 2 hours, about or at least about 3 hours, about or at 54 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 least about 4 hours, about or at least about 5 hours, about or at least about 6 hours, about or at least about 7 hours, about or at least about 8 hours, about or at least about 9 hours, about or at least about 10 hours, about or at least about 12 hours, about or at least about 14 hours, about or at least about 16 hours, about or at least about 18 hours, about or at least about 20 hours, about or at least about 25 hours, about or at least about 30 hours, about or at least about 35 hours, about or at least about 40 hours, about or at least about 45 hours, about or at least about 50 hours, about or at least about 60 hours, about or at least about 70 hours, about or at least about 80 hours, about or at least about 90 hours, about or at least about 100 hours, about or at least about 120 hours, about or at least about 140 hours, about or at least about 160 hours, about or at least about 180 hours, about or at least about 200 hours, about or at least about 220 hours, about or at least about 240 hours, about or at least about 260 hours, about or at least about 280 hours, or about or at least about 300 hours. In embodiments, the half-life is serum half-life, e.g., as measured in whole blood or plasma.

[0224] In embodiments, the half-life (T1 / 2) of the peptide, relative to SEQ ID NO: 1 (e.g., FQSE and / or Ac-FQSE, T1 / 2of ~4 min), is increased by about or at least about 1-fold (e.g., T1 / 2of ~8 min), about or at least about 2-fold, about or at least about 3-fold, about or at least about 4-fold, about or at least about 5-fold, about or at least about 10-fold, about or at least about 15-fold, about or at least about 20-fold, about or at least about 25-fold, about or at least about 50-fold, about or at least about 75-fold, about or at least about 100- fold, about or at least about 150-fold, about or at least about 200-fold, about or at least about 250-fold, about or at least about 500-fold, about or at least about 1,000-fold, about or at least about 1,500-fold, about or at least about 2,000-fold, about or at least about 2,500-fold, or about or at least about 3,000-fold (e.g., T1 / 2of ~12,000 min) or more. For example, in embodiments, the half-life (T1 / 2) of Ac-FQsE is about or at least about 1975 min (~33 hrs.), which is approximately an increase of about or at least about 493-fold.

[0225] In embodiments, the half-life is a half-life as measured in humans. In embodiments, the half-life is a half-life as measured in dogs. In embodiments, the half-life for any animal can be extrapolated, e.g., using data from one or more animal models such as the data described in Table 20 and Example 3. Persons skilled in the art, upon receiving the benefit of this disclosure in its entirety, will understand how to calculate and / or extrapolate the half-life (e.g., serum half-life) using allometric scaling for any particular model or animal (e.g., rats, mice, zebrafish, dogs, humans, etc.) using the disclosure presented herein.

[0226] The peptides herein, in embodiments, represent feasible peptide therapeutics due to, in part, a greatly increased half-life, e.g., in comparison to the half-life for a non-modified peptide having the amino 55 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 acid sequence of SEQ ID NO: 1 (FQSE), and / or in comparison to the half-life of Ac-FQSE (e.g., LCGA-17, SEQ ID NO: 1, as in Table 1). In embodiments, the half-life is increased to the magnitude of hours to days, where regular scheduled dosing sustains circulating concentrations within the blood / plasma, brain, cerebrospinal fluid, and / or tissues of the body that are considered therapeutic. In embodiments, this half-life improvement enables a level of bioavailability that results in appreciable therapeutic effects within the context of the one or more disorders, as described herein.

[0227] In embodiments, the administration results in a change in the intensity of and / or occurrence of anxiolytic-like behavior, Anxiety Index (AI), depressive behavior, deficits associated with schizophrenia, intensity of one or more sleep disorders and changes in sleep, appetite fluctuation, body weight fluctuation, fatigue, feelings of low mood or sadness, hopeless and helpless, low self-esteem, tearfulness, guilt, irritability, intolerance, restlessness, lack of motivation, difficulty in decision-making, cognitive dysfunction and difficulty concentrating, and / or persistence aches and pains. In embodiments, for example in instances where the administration is to a non-human animal, the administration results in a change in the intensity of and / or occurrence of exit frustration, social panic, redirected frustration, reactive communication, immediate frustration, noise sensitivity, separation anxiety, social anxiety, noise anxiety, trembling, hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior. In embodiments, the change is a reduction, amelioration, or ablation.

[0228] In embodiments, the change is evaluated and / or measured by one of more of a Hamilton Anxiety Scale (HAM-A), a Beck Anxiety Inventory (BAI), a Beck Depression Inventory (BDI-II), an Anxiety Symptoms Questionnaire (ASQ), a Hamilton Rating Scale for Depression (HAM-D), a Montgomery Asberg Depression Rating Scale (MADRS), and a Clinical Global Impression-Severity (CGI-S). In embodiments, the change is evaluated and / or measured by one of more diagnostic tests as outlined in the Diagnostic and Statistical Manual of Mental Disorders 4thEdition (DSM-IV), 5thEdition (DSM-V), and / or DSM-5TR (2022). In embodiments, the change is evaluated and / or measured by one or more diagnostic tests suitable for non- human animals, for example in gauging anxiety, stress, and / or behavioral issues in dogs and other companion animals (e.g., cats, horses, household pets, etc.). Such diagnostic tests, in embodiments, include diagnostic frameworks used in veterinary settings, for example evaluating one or more of exit frustration, social panic, elimination, redirected frustration, reactive communication, immediate frustration, noise sensitivity, separation anxiety, social anxiety, noise anxiety, trembling, hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior. 56 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0229] In embodiments, the change is evaluated and / or measured by one or more neuropsychological tests. In embodiments, the one or more neuropsychological tests include evaluating, in non-limiting examples, saccadic eye movements, saccadic reaction time (e.g., measured in seconds), saccadic peak velocity (e.g., measured in degrees / second), saccadic inaccuracy (e.g., measured in percent), smooth pursuit eye movements (e.g., measured in percentage of time the eyes of the subject are in smooth pursuit of the target), adaptive tracking (e.g., measured in average performance as a percentage), body sway (e.g., measured in antero-posterior sway distance), pupil size, visual analogue scale (VAS) to assess mood, alertness, and calmness (e.g., measured in duration), cognitive assessment VVLT (Learning and Immediate Recall, Delayed Recall, and Delayed Recognition), and / or qEEG (quantitative electroencephalogram).

[0230] In embodiments, the method pertains to administration to one or more non-human animals, where the change is evaluated and / or measured by one or more of an open-field test (OFT), elevated plus maze (EPM), forced swim test (FST), dark-light box (DLB) test, novel tank (NT) test, and / or social preference (SP) test. The test is selected, in embodiments, based on the nature of the animal, for example open-field test (OFT), elevated plus maze (EPM), forced swim test (FST) may be more appropriate for rodents, such as mice and rats, whereas the dark-light box (DLB) test and novel tank (NT) test may be more appropriate for aquatic animals, such as zebrafish.

[0231] In embodiments, the change elicited by the peptide is about or at least about 5%, about or at least about 10%, about or at least about 15%, about or at least about 20%, about or at least about 25%, about or at least about 30%, about or at least about 40%, about or at least about 50%, about or at least about 60%, about or at least about 70%, about or at least about 80%, about or at least about 90%, or about or at least about 100% reduction of one or more symptoms, e.g., a return towards a normal, healthy state. For example, in embodiments, the change is population-based, where a population of subjects administered the peptide exhibits about a 25% reduction in anxiolytic-like behavior compared to a population that did not receive the peptide. In embodiments, the change is in intensity and / or magnitude, for example where body weight or sleep duration is changed by about 20% within the subject cohort over a defined period of time of being administered the peptide. In embodiments, the change is measured and / or reported in comparison to a healthy patient cohort, e.g., not exhibiting the one or more conditions intended to address with the peptide. In embodiments, the change is between the pre-treatment and post-treatment states of an individual subject, for example, where one or more symptoms change by about 5% to about 99% from before administration to after administration of the peptide. 57 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0232] In embodiments, the administration results in a change that occurs within about or at least about 1 day to about 2 months of administration of the peptide. In embodiments, the change occurs within about or at least about 1 day to about 2 days, within about or at least about 2 days to about 4 days, within about or at least about 4 days to about 6 days, within about or at least about 6 days to about 8 days, within about or at least about 8 days to about 10 days, within about or at least about 10 days to about 20 days, within about or at least about 20 days to about 40 days, or within about or at least about 40 days to about 60 days from an initial administration.

[0233] Methods herein, in embodiments, result in psychological, behavioral, and / or cognitive changes that are contingent on adherence to dosing, where the change may result within 2 months if, e.g., daily dosing is followed. In embodiments, the change is dose-dependent, where the effect of the peptide is dependent on the amount taken, and the frequency of dosing.

[0234] In embodiments, the method does not substantially result in one or more adverse events in comparison to a subject that was not administered the peptide. In embodiments, the one or more adverse events include drowsiness, sedation, trouble sleeping (insomnia, restlessness), appetite fluctuation (suppressed appetite, increased appetite), binge eating, nausea, diarrhea, constipation, loss of muscle tone, memory issues (memory loss, false memories), psychosis, confusion, peptide intolerance, and / or peptide dependence. Dosing and Administration

[0235] In embodiments, methods herein include administering the peptide and / or compositions thereof to a subject in need thereof. In embodiments, the pharmaceutical composition is administered.

[0236] In embodiments, the administration is performed by one or more of intranasal, oral, parenteral, oromucosal, intravenous, intramuscular, subcutaneous, pulmonary, transdermal, topical, intracranial, intraperitoneal, and intrathecal routes. In embodiments, the administration is intranasal (e.g., via a nebulizer). In embodiments, the administration is oral (e.g., via tablets or capsules). In embodiments, the administration is intravenous (e.g., via an injection or IV catheter).

[0237] In embodiments, the intranasal and / or oral delivery is a noninvasive route of administration for the therapeutic peptides and compositions described herein, and provides a convenient alternative to intravenous or subcutaneous injections, especially for chronic dosing. 58 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0238] In embodiments, the administration comprises providing one or more unit doses of the peptide and / or pharmaceutical composition. In embodiments, the one or more unit doses comprise a total mass of the peptide of about or at least about 0.01 mg to about or at least about 5,000 mg. In embodiments, the administration includes providing a range of peptide of about 10-4mg / kg to about 200 mg / kg body weight, about 0.001 mg / kg to about 100 mg / kg body weight, about 0.01 mg / kg to about 50 mg / kg body weight, about 0.01 mg / kg to about 40 mg / kg body weight, about 0.01 mg / kg to about 30 mg / kg body weight, about 0.01 mg / kg to about 20 mg / kg body weight, about 0.01 mg / kg to about 5 mg / kg body weight, about 0.01 mg / kg to about 10 mg / kg body weight, about 0.1 mg / kg to about 10 mg / kg body weight, about 0.1 mg / kg to about 20 mg / kg body weight, about 0.1 mg / kg to about 30 mg / kg body weight, about 0.1 mg / kg to about 40 mg / kg body weight, about 0.1 mg / kg to about 50 mg / kg body weight.

[0239] In embodiments, the one or more unit doses comprise a total mass of the peptide of about or at least about 0.01 mg, about or at least about 0.1 mg, about or at least about 0.5 mg, about or at least about 1.0 mg, about or at least about 5.0 mg, about or at least about 10 mg, about or at least about 15 mg, about or at least about 25 mg, about or at least about 50 mg, about or at least about 100 mg, about or at least about 150 mg, about or at least about 200 mg, about or at least about 300 mg, about or at least about 400 mg, about or at least about 500 mg, about or at least about 1,000 mg, about or at least about 1,500 mg, about or at least about 2,000 mg, about or at least about 2,500 mg, about or at least about 3,000 mg, about or at least about 3,500 mg, about or at least about 4,000 mg, about or at least about 4,500 mg, or about or at least about 5,000 mg.

[0240] In embodiments, the administration comprises a dosage frequency of about or at least about thrice daily, about or at least about twice daily, about or at least about once daily, about or at least about every 2 days, about or at least about every 3 days, about or at least about every 4 days, about or at least about every 5 days, about or at least about every 6 days, about or at least about weekly, about or at least about biweekly, about or at least about once every three weeks, or about or at least about monthly.

[0241] Methods herein, in embodiments, represent chronic treatment strategies for addressing disorders which may require long-term dosing, e.g., for years, or even the life of the subject. The dosing regimen of methods herein, in embodiments, includes administering the peptide indefinitely to address the etiology and / or symptoms of any disorder described herein, e.g., as directed by a health care professional. Additional Therapeutic Agents 59 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0242] In embodiments, methods herein include administering one or more additional therapeutic agents. For example, in embodiments, the peptide is a component of a treatment regimen, intended to be taken as one therapeutic in a suite of therapeutics. In embodiments, the peptide is intended to produce a synergistic effect with one or more additional therapeutics to treat a neurological, behavioral, and / or cognitive disorder.

[0243] In embodiments, the one or more additional therapeutic agents comprises a therapeutic agent for an anxiety disorder, a depression disorder, a stress-related disorder, a bipolar disorder, and / or a mood disorder.

[0244] In embodiments, the one or more additional therapeutic agents comprises one or more of benzodiazepines selected from alprazolam (XANAX), clonazepam (KLONOPIN), diazepam (VALIUM), lorazepam (ATIVAN), oxazepam (SERAX), and chlordiazepoxide (librium); beta blockers selected from propranolol (INDERAL) and atenolol (TENORMIN); tricyclic antidepressants selected from imipramine (TOFRANIL), desipramine (NORPRAMIN, PERTOFRANE), nortriptyline (AVENTYL or PAMELOR), amitriptyline (ELAVIL), doxepin (SINEQUAN or ADAPIN), clomipramine (ANAFRANIL); monoamine oxidase inhibitors (MAOIs) selected from phenelzine (NARDIL), tranylcypromine (PARNATE); selective serotonin reuptake inhibitors (SSRIs) selected from fluoxetine (PROZAC), fluvoxamine (LUVOX), sertraline (ZOLOFT), paroxetine (PAXIL), escitalopram oxalate (LEXAPRO), citalopram (CELEXA); serotonin-norepinephrine reuptake inhibitors (SNRIs) selected from venlafaxine (EFFEXOR), venlafaxine extended release (EFFEXOR XR) and duloxetine (CYMBALTA); mild tranquilizers such as buspirone (BUSPAR); and anticonvulsants selected from valproate (DEPAKOTE), pregabalin (LYRICA), and gabapentin (NEURONTIN), CYMBALTA oral, LEXAPRO oral, EFFEXOR XR oral, ZOLOFT oral, CELEXA oral, TRAZODONE oral, PROZAC oral, WELLBUTRIN XL oral, CITALOPRAM oral, PRISTIQ oral, AMITRIPTYLINE oral, SAVELLA oral, VIIBRYD oral, PAXIL CR oral, WELLBUTRIN oral, PAXIL oral, SERTRALINE oral, REMERON oral, NORTRIPTYLINE oral, VENLAFAXINE oral, FLUOXETINE oral, BUPROPION HCL oral, MIRTAZAPINE oral, RITALIN oral, PAROXETINE oral, WELLBUTRIN SR oral, DOXEPIN oral, METHYLPHENIDATE oral, SYMBYAX oral, ESCITALOPRAM OXALATE oral, PAMELOR oral, IMIPRAMINE oral, BRINTELLIX oral, DULOXETINE oral, NARDIL oral, FETZIMA oral, EMSAM TRANSDERMAL, PARNATE oral, PEXEVA oral, BRISDELLE oral, CLOMIPRAMINE oral, ANAFRANIL oral, TOFRANIL oral, FLUVOXAMINE oral, ZYBAN oral, DESIPRAMINE oral, SARAFEM oral, PROZAC WEEKLY oral, APLENZIN oral, METHYLIN oral, NEFAZODONE oral, QUILLIVANT XR oral, TOFRANIL-PM oral, NORPRAMIN oral, REMERON SOLTAB oral, BUPROPION HBR 60 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 oral, OLEPTRO ER oral, DESVENLAFAXINE SUCCINATE oral, BUPROBAN oral, IMIPRAMINE PAMOATE oral, VILAZODONE oral, MILNACIPRAN oral, PAROXETINE MESYLATE oral, SURMONTIL oral, MAPROTILINE oral, PROTRIPTYLINE oral, PHENELZINE oral, MARPLAN oral, OLANZAPINE- FLUOXETINE oral, TRANYLCYPROMINE oral, SELEGILINE TRANSDERMAL, AMOXAPINE oral, FORFIVO XL oral, ISOCARBOXAZID oral, DESVENLAFAXINE oral, KHEDEZLA oral, LEVOMILNACIPRAN oral, VORTIOXETINE oral, DESVENLAFAXINE FUMARATE oral.

[0245] In embodiments, the one or more additional therapeutic agents comprises SILEO (dexmedetomidine oromucosal gel, Zoetis).

[0246] In embodiments, peptide is formulated for intranasal administration and methods concerning its administration can include co-administering at least one inhibitor of nasal mucosa proteases. Non-limiting examples of the nasal mucosa protease inhibitors include bestatine, comostate amylase, leupeptin, aprotinin, bacitracin, amastatine, boroleucine, puromycin, a bile salt, and a fusidic acid (e.g., disodium ethylene- diaminetetraacetate). Subjects and Animals

[0247] In embodiments, the subject of methods herein is a human. In embodiments, the subject of methods herein is a non-human animal.

[0248] In embodiments, the subject and / or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In embodiments, the subject and / or animal is a non-mammal, for example aquatic animals such as a zebrafish. In embodiments, e.g., in cases where the methods of use are in vitro, the subject can comprise cells and / or tissues, including for example fluorescently tagged cells (with e.g., GFP). In embodiments, the subject and / or animal is a transgenic animal comprising a fluorescent cell.

[0249] In embodiments, the human is a pediatric human. In embodiments, the human is an adult human. In embodiments, the human is a geriatric human. In embodiments, the human is referred to as a patient and / or is a person having a psychological, behavioral, neurological, and / or cognitive disorder.

[0250] In embodiments, the human has an age in a range of from about 0 months to about 6 months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 61 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old or older.

[0251] In embodiments, the subject is a non-human animal and therefore the peptide and compositions thereof pertain to veterinary use. In embodiments, the non-human animal is a companion animal and / or household pet. In embodiments, the companion animal and / or household pet includes domesticated or domestic-bred animals whose physical, emotional, behavioral, and social needs can be met as companions within the home, or in close daily relationship with humans. In embodiments, the companion animal and / or household pet includes dogs, cats, horses, pigs, cows, sheep, goats, rabbits, ferrets, guinea pigs and other small mammals, mice, rats, hamsters and other rodents, birds, small reptiles, and fish. In embodiments, the non-human animal is a livestock animal. Kits

[0252] In aspects, described herein are kits comprising the peptide, or compositions thereof, which can find use in performing methods described herein.

[0253] In embodiments, the compositions of the present disclosure are assembled into a kit. In embodiments, the kit includes the peptide formulated into one or more compositions.

[0254] In embodiments, the kit can include one or more containers housing components for performing the methods described herein, and optionally instructions for use. In embodiments, the kit can further include components useful for performing the methods herein. Each component of the kits, where applicable, can be provided in liquid form (e.g., in solution), in a semi-solid form (e.g., in a gel, cream, or salve), or in solid form, (e.g., a dry powder). In embodiments, one or more of the components are reconstitutable or otherwise processible (e.g., to an active form), for example, by the addition of a suitable solvent or other species (for example, water, bicarbonate, saline, dextran, or PBS), which may or may not be provided with the kit. 62 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0255] In embodiments, the kits can optionally include instructions and / or promotion for use of the components provided. As used herein, "instructions" can define a component of instruction and / or promotion, and typically involve written instructions on or associated with packaging of the disclosure. Instructions also can include any oral or electronic instructions provided in any manner such that a user will clearly recognize that the instructions are to be associated with the kit, for example, audiovisual (e.g., videotape, DVD, etc.), Internet, and / or web-based communications, etc. The written instructions can be in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which can also reflect approval by the agency of manufacture, use, or sale for animal administration. As used herein, "promoted" includes all methods of doing business including methods of education, hospital and other clinical instruction, scientific inquiry, drug discovery or development, academic research, pharmaceutical industry activity including pharmaceutical sales, and any advertising or other promotional activity including written, oral and electronic communication of any form, associated with the disclosure. Additionally, the kits can include other components depending on the specific application, as described herein.

[0256] In embodiments, the kits can contain any one or more of the components described herein in one or more containers. The components can be prepared sterilely, packaged (e.g., in a syringe, nebulizer, or blister pouch), and shipped refrigerated. Alternatively, components can be housed in a vial or other container for storage. A second container can have other components prepared sterilely. Alternatively, the kits can include the active agents premixed and shipped in a vial, tube, or other container.

[0257] In embodiments, the kits can have a variety of forms, such as a blister pouch, a shrink wrapped pouch, a vacuum sealable pouch, a sealable thermoformed tray, or a similar pouch or tray form, with the accessories loosely packed within the pouch, one or more tubes, containers, a box or a bag. The kits can be sterilized after the accessories are added, thereby allowing the individual accessories in the container to be otherwise unwrapped. The kits can be sterilized using any appropriate sterilization techniques, such as radiation sterilization, heat sterilization, or other sterilization methods known in the art. The kits can also include other components, depending on the specific application, for example, containers, cell media, salts, buffers, reagents, syringes, needles, a fabric, such as gauze, for applying or removing a disinfecting agent, disposable gloves, a support for the agents prior to administration, etc.

[0258] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present disclosure to its fullest extent. The following specific embodiments are, 63 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever. EXAMPLES Example 1: Neuromodulatory Peptide Stability Evaluation

[0259] The acetylated tetrapeptide, Ac-FQSE (e.g., LCGA-17 as described in Table 1), was evaluated for its stability in freshly collected, K2EDTA or heparin-treated rat blood and rat plasma. The peptide stock solution preparation was performed with the peptide as listed in Table 2. Table 2: Illustrative test compound. Compound Analytical MW Formula Weight Purity Storage Condition

[0260] Methods

[0261] Male Sprague Dawley rats were used for blood collection peptide stability studies. Rats were 8 weeks of age, having body weights of 250-300 g, and had been acclimated to experimental enclosures for more than 3 days prior to blood collection.

[0262] A total of 10 mL of whole blood was collected by terminal exsanguination and aliquoted into tubes containing K2EDTA or heparin anti-coagulant. Immediately following collection, the K2EDTA or heparin- treated blood was spiked with Ac-FQSE to a final concentration of 5 μM. The blood was mixed by gentle swirling and inversion, and immediately incubated on ice (approx.4°C). All subsequent manipulation of the blood and plasma samples were carried out at approx.4°C. Each of the K2EDTA or heparin-treated blood samples containing 5 μM Ac-FQSE were divided into 2 equal aliquots, where one aliquot was incubated as the whole blood stability sample, and the second aliquot was used for plasma stability, e.g., as illustrated in Fig.1. Plasma preparation was performed by centrifuging the K2EDTA or heparin-treated blood samples at 4,000 x g at 4°C for 5 min and removing the supernatant, e.g., as illustrated in Fig.2.

[0263] A 10 mM stock solution of Ac-FQSE (5.52 x 106ng / mL) was generated by dissolving the peptide in 1% sodium bicarbonate buffer, and diluted with a 1:1 (v / v) methanol: water solution to prepare a working solution at 0.5 mM. The working solution was used for calibration standards (e.g., at 100, 1,000, 10,000, 64 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 50,000 ng / mL), where 5 µL of each of the calibration solutions were added to 50 μL of non-peptide spiked K2EDTA-treated and heparin-treated rat whole blood or plasma to achieve calibration standards of 10, 100, 1,000, and 5,000 ng / mL concentrations in a total volume of 55 μL. Ac-FQSE was also dissolved in DMSO to achieve a 1 mg / mL stock solution, which was further diluted in methanol to 50 ng / mL as a protein precipitation standard for LC / MS / MS analysis and accurate peptide concentration determination.

[0264] 50 μL of K2EDTA-treated or heparin-treated whole blood and plasma samples containing 5 μM of Ac-FQSE were centrifuged, and then 200 μL of methanol containing IS (protein precipitation agent) was immediately added. The blood samples were vortexed for 30 seconds and then centrifuged at 4°C, 15,000 rpm, for 5 min. After centrifugation, the supernatant was collected and diluted 1:2 (v / v) with ultrapure water. The supernatant was injected into the LC / MS / MS system for LCGA-17 quantitative analysis.

[0265] Each of the K2EDTA-treated or heparin-treated whole blood and plasma samples were incubated for one or three time points: 0 min (analyzed immediately after peptide spike), 0.25 hr., or 2 hr. and at one or three incubation temperatures: 4°C, 15°C, or 37°C.

[0266] LC / MS / MS Analysis of Peptide Stability: the LC / MS / MS system consisted of two SHIMADZU LC-30AD pumps, a DGU-20A5 degasser, a Rack changer II and a SHIMADZU 8060 LC / MS / MS mass spectrometer. Chromatographic separation was performed on a RAPTOR Biphenyl 2.7 μm, 50 × 2.1 mm (RESTEK, cat #: 9309A52) column at room temperature. Mobile Phase A: 5% acetonitrile containing 0.1% formic acid; Mobile Phase B: 95% acetonitrile containing 0.1% formic acid. The flow rate was 0.6 mL / min, and the injection volume was 10 μL.

[0267] Positive mode electrospray ionization (ESI) was performed on a TURBO V ion source to obtain a protonated form of Ac-FQSE. A multiple reaction monitoring (MRM) method was selected for the quantitative analysis. The instrument parameters were set as: nebulizing gas flow: 3 L / min; heating gas flow: 10 L / min; interface temperature: 300°C; DL Temperature: 250°C; heat block temperature: 400°C; driving gas flow: 10 L / min.

[0268] The ratio between the peak area of LCGA-17 and the peak area of IS determined by LC / MS / MS was used to quantitate the amounts of LCGA-17. The area ratio (%) reflective of LCGA-17 stability was calculated as follows: ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ =^^ ^^ ^^ ^^( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^⁄ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^) ^^ ^^^^0;DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0270] Where txis the incubation time point, and t0is the sample at time = 0 min (no incubation). If the area ratio (%) was within 20% of the area ratio at t0, then the analyte was considered stable. If the area ratio (%) was less than 80%, it was considered unstable.

[0271] Results

[0272] The stability results of the peptide, Ac-FQSE (e.g., LCGA-17), in whole blood at 4°C after 1 hr. incubation are summarized in Fig.3. The Ac-FQSE peptide was nearly entirely degraded in heparin-treated whole blood after 1 hr, with approx.1% of the peptide recovered after the incubation. Ac-FQSE stability in K2EDTA-treated and heparin-treated plasma at 4°C and 37°C is shown in Fig.4 and Fig.5, respectively. Likewise, approximately half of the Ac-FQSE peptide was degraded within 15 min (0.25 hr.) at 4°C in the heparin-treated plasma (with approx.80% degraded within 15 min at 37°C), and nearly 90% of the peptide was degraded within 2 hr, regardless of temperature. Ac-FQSE stability in LC / MS samples prepared from K2EDTA-treated and heparin-treated plasma and incubated in the autosampler at 15°C is shown in Fig.6.

[0273] The data demonstrated, inter alia, that while Ac-FQSE (e.g., LCGA-17) had modestly improved half-life in comparison to the non-acetylated peptides, Ac-FQSE was considered stable in K2EDTA-treated whole blood and plasma; however, the peptide lacked stability in heparin-treated whole blood and plasma. These results suggested that the peptide is susceptible to degradation by proteases present in blood and plasma. Example 2: Pharmacokinetic (PK) and Biodistribution Evaluation of Ac-FQSE.

[0274] A tritium-labeled peptide Ac-FQSE ([3H]Ac-FQSE) was used to evaluate the in vivo PK profile and biodistribution of the peptide. The tritium-labeled peptide was produced by high temperature solid phase catalytic isotope exchange (HSCIE), resulting in homogenously labeled peptides with the tritium isotopes. The reaction produced [2H]Ac-FQSE labeled homogenously with deuterium, with a mean deuterium inclusion value 0.313, and produced tritium-labeled peptide [3H]Ac-FQSE with molar radioactivity 22 Ki / mmol. The molar radioactivity of fragments derived from peptide [3H]Ac-FQSE formed due to proteolytic hydrolysis of peptide Ac-FQSE in rat plasma was calculated based on the fractional data of deuterium inclusion into amino acid fragments of peptide [2H]Ac-FQSE.

[0275] The radiolabeled peptides were dissolved and administered to a total of 72 C57Bl / 6 mice and 12 Winstar rats, either intravenously (i / v), intranasally (i / n), or intraperitoneally (i / p) at a dose of 300 μg / kg, as 66 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 summarized in Table 3. The peptide was administered via a one-time (bolus injection) intranasally, intraperitoneally, or intravenously. Table 3: Distribution of in vivo administration of [3H]Ac-FQSE. Group Model Dose Administration Dose volume Dose Concentration

[0276] The C57Bl / 6 mice received 25 μKi [3H]Ac-FQSE at a dose of 300 μg / kg (about 6 μg total), and the rats received 500 μKi [3H]Ac-FQSE in dose 300 μg / kg (about 100 μg total). [3H]Ac-FQSE was dissolved in saline solution (0.9% NaCl) and could be stably stored for at least 3 hr. at 4°C ± 2°C. The total volume for intranasal administration was 8 μL and 20 μL for mice and rats, respectively. The total volume used for intraperitoneal administration to mice and intravenous administration to rats was 200 μL and 300 μL, respectively.

[0277] Prior to administration the 72 male C57Bl / 6 mice weighed 20 g ± 2 g and were 8 weeks old; the 12 male Winstar rats were 200 g ± 20 g and 12 weeks old.

[0278] For the Winstar rat experiments, intravenous administration of peptide [3H]Ac-FQSE and blood sampling were implemented through jugular veins. Following intranasal administration, blood was also withdrawn through the jugular vein. Rats were anesthetized with chloral hydrate (300 mg / kg) within 5-10 min, the fur was removed from the ventral side in the area adjacent to the thoracic limbs and neck, and two longitudinal incisions (right and left) approx.3 cm long were made, and the jugular veins were prepared. Intravenous FLEXICATH G24 catheters were inserted into the left jugular vein, and 80 μL of heparin was administered through the vein. FLEXICATH G22 catheters were inserted into the right jugular vein for blood sampling. The solution of the radiolabeled peptide (500 μKi) in a dose of 300 μg / kg in a volume 300 μL was administered to the left jugular vein for 10-15 s, and 0.2 mL of venous blood was withdrawn from the right 67 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 jugular vein at 2 min, 4 min, 6 min, 10 min, 15 min, 20 min, and 30 min after the injection. Following intranasal administration, the blood was sampled in the same manner. Blood was collected into weighted plastic tubes and flash frozen in liquid nitrogen.

[0279] For the C57Bl / 6 mice experiments, intranasal or intraperitoneal administration of [3H]Ac-FQSE labeled peptide (25 μKi) at a dose 300 μg / kg was administered in a volume 8 μL or 200 μL, respectively. Mice were euthanized by decapitation, and organ biopsies were rinsed in the saline solution and stored in weighted plastic tubes and flash frozen in liquid nitrogen.

[0280] HPLC was used for detection and analysis of any products of proteolytic hydrolysis of peptide [3H]Ac-FQSE in heparin plasma of rats ex vivo. A UV-detector and flow radioactivity detector were connected in series for the analysis. Chromatography was performed using column KROMASIL С18, 150 х 4 mm, with a sorbent particle diameter of 4 μm in a methanol gradient in the presence of a mixture of trifluoroacetic acid (TFA) and heptafluorobutyric acid (HFBA) in a ratio of 1:4 (v / v). To identify the potential peptide fragments that are formed from various pathways of peptide biotransformation in rats, a series of 2-3 amino acid peptide fragments were synthesized from the N-terminus and C-terminus of the Ac-FQSE peptide chain (e.g., Ac- FQ, SE, Ac-FQS, and QSE). Using tritium-labeled peptide [3H]Ac-FQSE, the peptide stability was determined in heparin plasma ex vivo with an initial peptide concentration 125 μM.

[0281] 1 mL of heparin-treated plasma from rats was transferred to a 1.5 mL microtube and incubated at 37°С. An alcohol solution of tritium-labeled peptide [3H]Ac-FQSE in the amount of 750 μKi was evaporated in reduced pressure to dryness and dissolved in 340 μL of saline solution. The obtained solution of tritium- labeled peptide was administered to plasma and mixed while shaking. At defined time intervals (from 1-45 min), 100 μL of the analyzed plasma was withdrawn and transferred to a stopping solution of 900 μL of 90% aqueous acetonitrile containing 1% trifluoroacetic acid. Plasma protein precipitate was separated by centrifugation. The resulting supernatants were evaporated to dryness, dissolved in 300 μL of 0.1% heptafluorobutyric acid and were re-centrifuged. This processing did not affect the peptide structure and stability. The obtained solutions were used for radiochromatographic analysis.

[0282] Results

[0283] A representative radiochromatographic analysis is provided in Fig.7.50 μL of the tritium-labeled peptide extract was obtained after a 16-minute incubation and mixed with 20 μL of a solution containing 10 μg of peptides Ac-FQSE, Ac-FQS, Ac-FQ and SE as standards for the UV-detector. Chromatogram analysis 68 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 was run on KROMASIL С184 х 150 mm in methanol concentration gradient 18-38% in the presence of 0.1% heptafluorobutyric acid (HFBA) and 0.1% trifluoroacetic acid (TFA) mixture in ratio 1:4; flow rate: 0.80 mL / min; flow radioactivity detector.1 – SE, 2 – Ac-FQ, 3 - Ac-FQSE, 4 – Ac- FQS. Based on the peak area values for each fragment, and the values of their molar radioactivity, the change in plasma concentration of fragments Ac-FQSE, Ac-FQ, and SE over the 45 minute time course was calculated, with the results summarized in Table 4. Table 4: Molar concentrations of peptide Ac-FQSE and its fragments formed as a result of proteolytic hydrolysis in heparin plasma of rats ex vivo, according to the radiochromatographic analysis. Peptide concentration (μM)

[0284] To calculate the molar radioactivity of tritium-labeled peptide fragments formed as a result of biodegradation, the data on the isotope label distribution in deuterium-labeled peptide was used. The qualitative data on molar concentration of peptide fragments was calculated from their molar radioactivity and peak areas of their fractions on the radiochromatogram. The concentration of each metabolite of the Ac- FQSE peptide was used to calculate the pharmacokinetics of Ac-FQSE in rat plasma, as shown in Fig.8. The ex vivo stability of the peptide demonstrated that Ac-FQ was the major intermediate that formed with concomitant loss of Ac-FQSE, suggesting dipeptide proteolytic cleavage between Q and S, as well as C- 69 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 terminal degradation. Nearly a total loss of the Ac-FQSE peptide was observed within 1 hr in rat blood / plasma. As a result of the analysis, it was observed that hydrolysis of peptide Ac-FQSE in plasma occurs from С-terminus of the peptide, and the main contribution to its hydrolysis is made by plasma dicarboxypeptidases cleaving the dipeptide fragment SE. It was observed that the half-life of Ac-FQSE in plasma was approx.13 minutes (T1 / 2 = 13.4 min). The dipeptide Ac-FQ was the most stable product of the hydrolysis.

[0285] Frozen and weighted tissue samples collected from animals for PK analysis, were subjected to freeze-drying for 48 hrs. prior to HPLC analysis. Freeze-dried tissue samples were then heated at 65°С for 30 min, after which they were dispersed and extracted with 90% aqueous acetonitrile containing 1% TFA. A solution containing 10 μg of standard peptides Ac-FQSE, Ac-FQS, Ac-FQ, and SE was spiked into aqueous acetonitrile solution before the HPLC analysis, used for identification of fractions in chromatography. The quantitative analysis of peptides was made using HPLC on column KROMASIL C18, 8 x 150 mm in methanol gradient (0-40%), in the presence of 0.02% HFBA heptafluorobutyric acid (HFBA) and 0.08% trifluoroacetic acid (TFA) mixture in ratio 1:4 (v / v). Fractions containing the peptides Ac-FQSE, Ac-FQS, Ac-FQ, and SE, were collected and used for determination of radioactivity using liquid scintillation counting.

[0286] Pharmacokinetic (PK) parameters were calculated with a model-independent approach. Pharmacokinetic curves (“peptide concentration – time”) for calculation of pharmacokinetic parameters were plotted on averaged blood concentrations of peptides Ac-FQSE and Ac-FQ obtained for each cohort of 6 animals. The experimental data were approximated exponentially, and equation parameters were calculated using a least square method. Using the obtained exponential equation parameters, the main pharmacokinetic parameters were calculated (e.g., as summarized in Tables 5 and 6). Table 5: Pharmacokinetics of peptides Ac-FQSE and Ac-FQ in ex vivo rat blood over 2 min to 45 min after intravenous administration of peptide Ac-FQSE at dose level 300 μg / kg. DMP / g = disintegrations per minute per gram.DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 4 2220 250 454 22500 1860 5870 6 1820 205 372 20800 1720 5430Table 6: Pharmacokinetics of peptides Ac-FQSE and Ac-FQ in ex vivo rat blood over 2 min to 45 min after intranasal administration of peptide Ac-FQSE at dose level 300 μg / kg. DMP / g = disintegrations per minute per gram. Time Ac-FQSE Ac-FQ

[0287] To calculate the pharmacokinetic (PK) parameters, an experimental two-component PK model approach, e.g., as shown in Fig.9 was used. The results for an open two-compartment model with peptide elimination from the central compartment modeled using the minimal pharmacokinetic model for the experimental data is shown in Figs.10A-10B. The decaying monoexponential dependence is used for 71 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 mathematic description of one-compartment PK model, and decaying bi-exponential dependence – for description of the simplest two-compartment pharmacokinetic model. The equations of decaying mono- and bi-exponential dependences are presented as follows:

[0288] ^^^^= ^^ ∙ exp (− ^^ ∙ ^^) (I)

[0289] ^^^^= ^^ ∙ exp(− ^^ ∙ ^^) + ^^ ∙ exp (− ^^ ∙ ^^) (II)

[0290] Where Ct is the blood concentration of the pharmacological substance at time t and A, B, α, and β are hybrid constants (macroconstant) of integral equations (I) and (II). In the event of the bi-exponential dependence (two-compartment model), the first exponential function (macroconstants A and α) reflects process of the substance distribution between the central and peripheral compartments, and the second exponential function (macroconstants B and β) relate to the process of the substance elimination from the central compartment. To fit parameters of equations (I) and (II) (macroconstants) in experimental data most accurately, non-linear regression and the least square method was applied. The accuracy of the models that were used for description of available experimental data were assessed using determination coefficient (r2) and corrected determination coefficient (adjusted r2). The calculated values for the accuracy parameters for both models are provided in Table 7. The presented results show that the experimental data are described unsatisfactorily by the monoexponential dependence (equation (1)) but described very well – by the bi- exponential dependence (equation (2)). Consequently, it was appropriate to analyze the experimental data (e.g., as summarized in Table 7) within the context of the two-compartment pharmacokinetic model. Table 7: Comparison of accuracy of one-compartment and two-compartment pharmacokinetic model. Parameter / criterion One-compartment model Two-compartment model )DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0291] Using non-linear regression, the values of macroconstants were determined in the equation (II), as described in Table 8. Table 8: The values of macroconstants for bi-exponential dependences in the model describing a two- compartment pharmacokinetic model of peptide Ac-FQSE. Macroconstant Mean Error of the mean (SE) Student’s t-test p value

[0292] Based on the values of the macroconstants, the values of microconstants k10, k12 and k21 (e.g., as illustrated in the model scheme in Fig.9), the half-life times of distribution phase (t1 / 2α), and the elimination phase (t1 / 2β), several systemic pharmacokinetic (PK) parameters were calculated, e.g., as summarized in Table 9. Table 9: Pharmacokinetic (PK) parameters for intravenous administration of peptide Ac-FQSE in rats.DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 C0Blood concentration of the pharmacological substance at initial time (t = 0 min) “Half-life” of distribution phase of the pharmacological substance between the

[0293] Based on the data for Ac-FQ contents in blood following intravenous Ac-FQSE administration to rats, the estimated values of pharmacokinetic parameters for Ac-FQ can be accurately calculated. It is not appropriate to calculate values of pharmacokinetic parameters (ClT, Vdss, Vdβ), in equations where parameter “dose” is used for calculations (e.g., ‘D’ in Fig.9) as: i) Ac-FQSE can be transformed, along with Ac-FQ, to other metabolites, and ii) Ac-FQSE can be eliminated via kidneys, etc. prior to its transformation to Ac-FQ. The experimental data was approximated by the equation:

[0294] ^^^^= ^^ ∙ exp(− ^^ ∙ ^^)+ ^^ ∙ exp(− ^^ ∙ ^^)− ( ^^ + ^^) ∙ exp (− ^^ ∙ ^^)

[0295] Where Ct is the blood concentration of the pharmacological substance at time t; A, B, α and β are hybrid constants (macroconstants) of the integral equation. The values of the PK parameters of Ac-FQ in blood after intravenous administration are provided in Table 10. 74 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Table 10: Pharmacokinetic (PK) parameters of Ac-FQ in blood following intravenous administration of peptide Ac-FQSE to rats at a dose of 80 μg / kg. PK parameter Measuring units Estimated value for Ac-FQEstimated value for Ac-FQSE(re: Table 9)ts

[0296] The data analysis showed that the elimination rate of Ac-FQ in blood (kel and t1 / 2,el) is approximately 20-fold lower than that of the initial peptide. Additionally, the half-life of Ac-FQ after (establishing the pseudostationary condition to which the final monoexponential segment of the pharmacokinetic curve corresponds, (t1 / 2β)) is significantly lower in comparison to the initial peptide; the mean residence time (MRT) of Ac-FQ molecule is significantly lower than the initial peptide – 57.1 min versus 17.5 min. These differences are due to the higher rate of proteolytic degradation of Ac-FQSE in comparison to its metabolite, Ac-FQ. Correspondingly, the elimination rate of Ac-FQ is likely to be related to renal excretion. 75 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0297] The stability of the Ac-FQ metabolite and the Ac-FQSE peptide were also different with respect to the AUC values. Regarding the molecular concentrations, the AUC values of Ac-FQSE and Ac-FQ following intravenous administration of Ac-FQSE are 16405 and 260950 nM•min, respectively. Specifically, the AUC value for the metabolite was significantly higher than AUC value for initial peptide.

[0298] The analysis for C57Bl / 6 mice (e.g., groups 3 and 4 of Table 3) is summarized in Table 11. Table 11: Pharmacokinetics of peptides Ac-FQSE and Ac-FQ in tissues of C57Bl / 6 mice 2-30 min after intraperitoneal administration of peptide Ac-FQSE at a dose of 300 μg / kg. Time (min) Blood Brain Kidneys Liver Heart OmentumTable 12: Pharmacokinetics of peptides Ac-FQSE and Ac-FQ in tissues of C57Bl / 6 mice 2-30 min after intranasal administration of peptide Ac-FQSE at a dose of 300 μg / kg. Time (min) Blood Brain Kidneys Liver Heart Omentum76 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 4 5.6 0.7 3.6 2.5 1.1 5.8 8 96 08 56 32 26 48

[0299] A representative chromatographic analysis of mouse heart tissue (50 μL homogenized sample) following the intranasal administration for the Ac-FQSE peptide (at 300 μg / kg) and its metabolite, Ac-FQ, is shown in Fig.12. Isolated fractions 1 and 2 relate to Ac-FQ and Ac-FQSE, respectively, and were further analyzed via liquid scintillation counting. A 20 μL standard solution containing 10 μg of peptides Ac-FQSE, Ac-FQS, Ac-FQ and SE were used as reference points for the UV-detector; KROMASIL С184 х 150 mm in concentration gradient of methanol 18-38% in the presence of 0.1% HFBA and 0.1% TFA mixture in ratio 1:4 (v / v); delivery rate: 0.80 mL / min; peptide fractions collected by the UV-detector: 1 – Ac-FQ, 2 - Ac-FQSE. The proportion of peptide Ac-FQ is recalculated in accordance with the molecular weights of baseline peptide Ac-FQSE and its fragment Ac-FQ (MW 317 / 551 = 0.575). Table 13: Proportion of peptides Ac-FQSE and Ac-FQ of the administered dose of peptide Ac-FQSE (6 μg) in blood and brain tissues of mice 2-30 min after intraperitoneal administration. Time minBlood, % of the administeredBrain, % of the administeredDB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 20 1.16 5.25 0.0094 0.061 30 0.86 3.54 0.0086 0.055

[00300] To further analyze the relative distribution of Ac-FQSE and Ac-FQ in the tissues of mice, the ratio of peptide concentrations in the tissue and blood were calculated for each time point, e.g., as summarized in Table 14. Table 14: Distribution of the peptide Ac-FQSE and its metabolite Ac-FQ in tissues of mice 2-30 min following intraperitoneal administration of peptide Ac-FQSE at a dose of 300 μg / kg. Ac-FQSE, Time n per of Ac-FQSE(organ) / Ac-FQSE(blood)rel. un.

[0301] To compare the time dynamics of the values in various tissues, the values obtained at end-points of the tested time intervals were set to a value of 1 (e.g., as shown in Figs.12 and 13). A steady-state balance 78 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 is established between the peptide concentration in blood and tested organs / tissue over the time over the range of 12-30 min for Ac-FQSE and 20-30 min for Ac-FQ. The values of distribution coefficients (Kd) of the peptides were calculated between blood and the tested organ / tissue (e.g., as summarized in Table 15) using this linear portion. The greatest peptide concentration was found in the omentum and kidneys, the lowest concentrations were found in the brain. Table 15: The apparent distribution coefficient (Kd) of peptides Ac-FQSE and Ac-FQ between blood and the tested organ / tissue following intraperitoneal and intranasal administration of peptide Ac-FQSE to Balb / c mice. Kd, rel.un. Organ Table 16: Distribuo o pep e c- a s ea o e c- ssues o ce 2- 30 min following intranasal administration of peptide Ac-FQSE at a dose of 300 μg / kg. Time Ac-FQSE,79 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 8 9.6 0.083 0.58 0.33 0.27 0.50 12 81 0173 084 044 046 063

[0302] The distribution of the peptides Ac-FQSE and Ac-FQ between the tissues was similarly analyzed following intranasal administration of peptide Ac-FQSE to mice (e.g., Tables 15 and 16, and Figs.12 and 13). Following intranasal administration, the steady-state balance between the peptide concentration in the blood and the organs / tissues is established much quicker in comparison to intraperitoneal administration: after 2 min for Ac-FQSE and after 4 min for Ac-FQ. The values of distribution coefficients (Kd) of the peptides between blood and the tested organ / tissue were calculated from these linear portions. The greatest peptide concentration was observed in the kidneys, and the lowest concentration was observed in the brain. In comparison to IP administration, intranasal administration resulted in lower concentrations of the peptides in the kidneys, heart, and omentum, resulted in approx. the same concentration in the liver, and resulted in higher concentrations in the brain.

[0303] Next, the extent of Ac-FQSE transformation into Ac-FQ (e.g., the main consistent metabolite) was evaluated. The Ac-FQ and Ac-FQSE ratio was calculated in various tissues according to the methods of tetrapeptide administration, e.g., as summarized in Table 17 and 18. Table 17: The ratio of blood concentrations of Ac-FQ and Ac-FQSE following intravenous and intranasal administration of peptide Ac-FQSE to rats (80 μg dose). 80 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Time (min)[Ac-FQ] / [Ac-FQSE],nM / nMTable 18: The ratio of blood concentrations of Ac-FQ and Ac-FQSE following intravenous and intranasal administration of peptide Ac-FQSE to mice (300 μg / kg dose). *Values exceeding [Ac-FQ] / [Ac-FQSE] values in blood for a certain time point for more than 20%.DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 4 2.5 *3.3 *3.6 1.7 2.6 *4.1 8 27 *37 *54 24 30 *41

[0304] The concentration of the metabolite, Ac-FQ, was higher than the concentration of the peptide, Ac-FQSE, in all tissues via all routes of administration. Over time, the Ac-FQ / Ac-FQSE ratio in the blood of rats and mice continued to increase, reaching maximal values at 20-30 min after administration. This trend was observed with each route of administration. A similar pattern is observed in the organs of mice following IP administration. Following intranasal administration, a more consistent ratio of the Ac-FQSE peptide concentrations was achieved.

[0305] Following intranasal administration, the intensity of Ac-FQSE hydrolysis to Ac-FQ was less intensive than IV and IP administration. The data suggested that mice exhibited less intensive Ac-FQSE hydrolysis to Ac-FQ compared to rats (e.g., a comparison of [Ac-FQ] / [Ac-FQSE] values in blood following intranasal administration).

[0306] A significant increase in [Ac-FQ] / [Ac-FQSE] values within the tested range of time was observed in the kidneys, brain, and heart following intraperitoneal administration, and in the kidneys and liver following intranasal administration. The relative ratios in each organ / tissue can be related to both to the distribution of the peptides in the tissues and increased levels of peptidases responsible for hydrolysis of Ac-FQSE to Ac- FQ in each respective organ / tissue. 82 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0307] In conclusion, the half-life of the peptide Ac-FQSE in rat plasma ex vivo was calculated to be about 13 minutes. The primary main pharmacokinetic (PK) parameters of peptide AC-FQSE following intravenous administration in rats and mice were calculated, showing that the half-life of the peptide was about 17 minutes, with the dipeptide, Ac-FQ, being the major metabolite identified in the tissues of the rats and mice, and was the most stable product of tetrapeptide hydrolysis. The greatest concentrations of peptide Ac-FQSE and its metabolite following IP and intranasal administration were found in renal and omentum tissues where its levels were significantly higher than in blood. The peptide Ac-FQSE was found to penetrate the blood- brain barrier. Intranasal routes of administration resulted in better bioavailability to the brain than IP administration. Example 3: Evaluation of Peptide Modifications on Stability.

[0308] The effect of the peptide modifications on stability was evaluated to test if half-life could be increased without sacrificing activity.

[0309] 1 mM solutions of each test or control compound were dissolved in DMSO. For sample preparation, 398 µL of heparin-treated rat plasma was incubated at 37°C for 15 minutes. After the incubation, 2 µL of 1 mM working solution (test compound or control compound) was spiked into 398 µL of the rat (Sprague Dawley) heparin-treated plasma to reach a final concentration of 5 µM. The final concentration of the organic solvents was 0.5% v / v. Initial time samples (e.g., time = 0) samples were prepared by adding 50 μL of the spiked rat plasma to a new plate and then adding 400 μL of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, or 100 nM tolbutamide). Each assay was performed in duplicate.

[0310] The spiked samples were incubated at 37°C in a water bath shaking at approximately 50 rpm, where 50 μL aliquots were transferred into new plates at 0 min, 15 min, 30 min, 60 min, 90 min, 120 min, and 240 min. Each reaction was stopped by adding 400 μL of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, or 100 nM tolbutamide).

[0311] All samples were vortexed for 10 minutes, followed by centrifugation at 3,220 x g for 30 minutes to precipitate the protein.100 μL of the supernatant was transferred to a new plate. The supernatant was diluted with ultrapure water according to the LC-MS signal response and peak shape.

[0312] Samples were analyzed by LC-MS / MS. Chromatographic conditions were as follows: LC system: SHIMADZU LC-30AD; MS analysis: SCIEX triple quad 4500 or SCIEX triple quad 5500; Column temperature: 83 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 40°C; Injection volume: 5 µL; Column: Waters XSelect HSS T3 C18, 2.5 μm, 2.1 x 50 mm; Mobile phase: 0.1% formic acid in water and 0.1% formic acid in acetonitrile; Elution rate: 0.6 mL / min.

[0313] Mass spec (MS) parameters: ion source: turbo spray; ionization model: ESI; scan type: MRM; collision gas: medium; curtain gas: 30 L / min; temperature: 550°C; Ionspray voltage:-4500 v (negative MRM) or +5500 v (positive MRM).

[0314] Peak area ratios were determined from extracted ion chromatograms. Percent compounds remaining at each time point were calculated by the following equation:

[0315] ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^^^( ^^ ^^ ^^)(%)=^^( ^^ ^^ ^^)(%)^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^(0)∙100and test compounds at time, t, in minutes. The Peak Area Ratio t(0) is the peak area ratio of the control and test compounds at the zero time point. The in vitro half-life (in vitro t1 / 2) was determined from the slope value:

[0317] ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^1 / 2= −(0.693 / ^^)

[0318] Data processing was performed as described in Table 19. Table 19: Data processing rules for LC-MS / MS. Remaining % Processing Rules When the calculated T1 / 2value is within 0 to 144000 min re ort the calculated T1 / 2d ve

[0319] The list of tested peptides (e.g., termed the “LCGA-17” suite, as listed in Table 1) were evaluated for their ex vivo half-life in rat blood, with the results listed in Table 20. Table 20: Half-life calculations for peptides. Compound Replicate Remaining Percentages (%) t1 / 2 (min)84 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 0minm1530 60 90 120 240 inmin min min min min R li t 7 8 2 3 0 0 6 785 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Mean 100 91 89 91 91 86 88 1975.2 Replicate 100 81 69 50 34 27 10 63.3 2 18 8 2 5 7DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Replicate Ac-FQSE (Ca-methyl1100 82 72 69 58 52 30 149.7R li t 7 1 3 8 6 4 387 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Replicate Ac-FQSE (Ser Benzyl1100 91 77 66 51 40 25 116.7R li t

[0320] In conclusion, although most chemical modifications resulted in marked increases in half-life, among the most stable peptides (e.g., ≥80% peptide detected at 240 min) included Ac- FQSEEQQQTEDELQDK; Ac-FQSE (all D-form amino acids); ESQF (all D-form amino acids in reverse); Ac- FqSE (q = D-Gln); Ac-FQsE (s = D-Ser); (palmitic)-FQSE; Ac-FQSEk (Lys D-amino acid)-Fatty acid (myristic); Ac-FQSEk(Lys D-amino acid)-Fatty acid (palmitic); Ac-FQSE (Gln-beta amino acid); Ac-FQSE (Ser-beta / beta ME mod); Ac-FQSE (S = sarcosine); Ac-FQSE (S = Serine-hydroxyproline mod); and Ac-FQSE (S = D-Thr analogue). According to the obtained data, the half-life (T1 / 2) of the original molecule LCGA-17 in rat blood plasma was approx.4.4 minutes, corresponding well with previous replicates. Chemical modification of the molecule resulted in a significant increase in this parameter of up to 50+ hrs., confirming the validity of the structure-guided approach. Six of molecules were selected for further analysis: LCGA-17 / 13 – FQSE (all L- amino acids in original LCGA-17 structure replaced with D-amino acids); LCGA-17 / 14 – ESQF (the original LCGA-17 structure replaced with D-amino acids, in reversed order); LCGA-17 / 15 – Ac-FqSE (tetrapeptide Ac-FqSE, where ‘q’ is D-glutamine as a replacement for L-glutamine in the original structure); LCGA-17 / 16 – Ac-FQsE (tetrapeptide Ac-FQsE, where ‘s’ is D-serine as a replacement for L-serine in the original structure); LCGA-17 / 34 (tetrapeptide Ac-FQβsE, where ‘βs’ is beta-serine as a replacement in the original structure); and LCGA-17 / 39 (tetrapeptide Ac-FQtE, where ‘t’ is D-threonine as a replacement for L-serine in the original structure). Example 4: In vitro Evaluation of Peptide Binding. 88 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0321] Next, the modifications to the peptides were evaluated for their effect on peptide binding in receptors present in the cerebral cortex using ex vivo samples from rats.

[0322] Frontal bran cortex membrane preparations were produced from the frontal cortex of male Wistar rats, for example as described in Hawkinson, et al., “Steroid inhibition of [3H]SR 95531 binding to the GABA(A) recognition site,” European Journal of Pharmacology, Vol. 304, 1–3, 1996: pp. 141–146. doi.org / 10.1016 / 0014-2999(96)00090-8; Ito, et al., “Effects of bicuculline on [3H]SR 95531 binding in discrete regions of rat brains,” Neurochemical Research, Vol. 17, No. 4, 1992: pp. 307–313, doi.org / 10.1007 / BF00974570; and Zolotarev, et al., “New development in the tritium labelling of peptides and proteins using solid catalytic isotopic exchange with spillover-tritium,” Amino Acids, Vol.24, No.3, , 2003: pp. 25–333, doi.org / 10.1007 / s00726-002-0404-7; and Zolotarev, et al., “Anxiolytic activity of the neuroprotective peptide HLDF-6 and its effects on brain neurotransmitter systems in BALB / c and C57BL / 6 mice,” Journal of Psychopharmacology, Vol. 30, No. 9, 2016: pp. 922–935. doi.org / 10.1177 / 026988111666070, each of which is incorporated herein by reference in its entirety. The tissue samples were homogenized in 25 volumes of cold buffer (50 mM Tris-HCl, pH 7.4) in a Teflon-glass homogenizer. The homogenate was centrifuged for 20 min 40,000 x g. The precipitate was then resuspended in 50 mM Tris-HCl buffer (pH 7.4) and centrifuged at 40,000 x g for 20 min. The obtained precipitate was homogenized in 50 mM Tris-HCl buffer (pH 7.4), centrifuged twice at 40,000 x g for 20 min, and the precipitate was resuspended in 15 mL of the same buffer to be used for the radioligand analysis.

[0323] Tritium-labeled Ac-FQSE ([3H]-FQSE) was used as a radioligand in rat brain membrane for a competition assay with unlabeled FQSE. The incubation mixture (final volume 0.5 mL) contained 50 μL [3H]- Ac-FQSE (70 Ci / mmol, final concentration 16 nM), 200 or 250 μL buffer (50 mM Tris-HCl, pH = 7.4) and 200 μL of membrane protein suspension.50 μL of unlabeled Ac-FQSE, FQSE, and Ac-FQsE (acetylated, non- acetylated, or modified with a D-serine, e.g., LCGA-17m16 as listed in Tables 1 and 20) was added for non- specific binding in a concentration range 10-8-10-4М. The reaction mixture was incubated at room temperature (RT) for 60 minutes.

[0324] To compare the binding of the acetylated form of Ac-FQSE and Ac-FQsE (s = D-serine) to specific binding sites in the brain cortex, studies were carried out to select incubation conditions using various combinations of acetylated and non-acetylated forms of labeled and unlabeled FQSE: Acetylated labeled - acetylated unlabeled" as a control; "acetylated labeled – Ac-FQsE (unlabeled)" as an experimental group; 89 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 "non-acetylated labeled - acetylated unlabeled" as a control; "non-acetylated labeled - FQsE (unlabeled)" as an experimental group.

[0325] Liquid Scintillation Spectroscopy: After each incubation period, the samples were filtered through GF / B fiberglass filters previously equilibrated with 0.3% polyethyleneimine for 2 hrs. at approx.20°C. Each sample was washed twice with cold buffer, after which the filters were washed twice with the same volume of buffer. The filters were air-dried and transferred to scintillation vials with 5 mL of a toluene-based scintillation liquid (4 g 2,5-diphenyloxazole (PPO), 0.2 g [1,4-bis-2-(5-phenyloxazolyl)-benzene] (POPOP) per L of toluene). The radioactivity of the samples was determined on a Tri-Carb 2900TR counter (Perkin Elmer) with a counting efficiency of 42-46%. Protein concentration was measured by a standard Lowry method. The calculated KDand Bmaxvalues reflect the degree of affinity of the receptor for the ligand (nM) and the number of ligand binding sites (fmol / mg of protein), respectively. For saturation analysis and Bmax and KD characterization, specific binding for Ac-FQSE binding sites in the cerebral cortex was measured from 1.25 nM to 40 nM, e.g., as summarized in Table 21. Specific binding was calculated as the difference between total and non-specific binding. Table 21: Results of the competitive radioligand binding assay for the Ac-FQSE specific binding sites in rat brain cortex. % specific binding of total binding l l i90 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 10-5M 74 ± 2 74 ± 2

[0326] In conclusion, the radiolabeled peptide revealed an IC50 of ~2 µM. Chemical modification by N- terminal acetylation and / or incorporation of a D-form serine did not significantly alter peptide binding. Gabapentin showed high affinity (IC50~11 µM) for the same binding site, while pregnenolone sulfate (PREGS) was ineffective as a competitor (IC50 > 100 µM). No cross-reactivity with other GABAA receptor binding sites, including for diazepam, muscimol, bicuculline, gabazine, and CGS-9895, was detected. No cross-reactivity was found in ligand binding sites for other major neurotransmitter receptors, including dopamine receptors: haloperidol, sulpiride, spiperone, 7-OH-DPAT; serotonin receptors: ketanserin; acetylcholine receptors: nicotine; and for glutamate receptors: glutamate, glycine, Ro-256981, LY-354740, MK-801, spermine, arkain. The FQSE-binding site was found to be distinct from those for other GABAA receptor ligands including isoguvacine, salicylidene salicylhydrazide, bretazenil, SL651498, MK0343, THDOC, TB21007, gaboxadol, FGIN-1-27, and allopregnanolone. Example 5: In vivo Evaluation of the Behavioral Effects of Chemically-Modified FQSE in Danio rerio.

[0327] A zebrafish (Danio rerio) animal model was used to evaluate the in vivo neuromodulatory effects of the modified peptides. The following 7 peptides were selected for the in vivo evaluation:

[0328] Ac-FQSE (acetylated, all L-form amino acids, e.g., LCGA-17 in Tables 1 and 20), T1 / 2 in rat plasma of approx.4 min. This peptide was used for comparison to the other 7 to evaluate the effects of the various chemical modifications;

[0329] Ac-FQSE (acetylated, all D-form amino acids, e.g., LCGA-17m13 in Tables 1 and 20), T1 / 2 in rat plasma of approx.3022 min;

[0330] ESQF (non-acetylated, all D-form amino acids, in reversed order compared to FQSE, e.g., LCGA-17m14 in Tables 1 and 20), T1 / 2 in rat plasma of approx.820 min;

[0331] Ac-FqSE (acetylated, where ‘q’ is D-glutamine as a replacement for L-glutamine, e.g., LCGA- 17m15 as in Tables 1 and 20), T1 / 2in rat plasma of approx.3132 min; 91 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0332] Ac-FQsE (acetylated, where ‘s’ is D-serine as a replacement for L-serine, e.g., LCGA-17m16 as in Tables 1 and 20), T1 / 2 in rat plasma of approx.1975 min;

[0333] Ac-FQβsE, (acetylated, where ‘βs’ is beta-serine as a replacement of L-serine, e.g., LCGA- 17m34 as in Tables 1 and 20), T1 / 2in rat plasma of approx.13785 min; and

[0334] Ac-FQtE, (acetylated, where ‘t’ is D-threonine as a replacement for L-serine, e.g., LCGA-17m39 as in Tables 1 and 20), T1 / 2 in rat plasma of approx.701 min.

[0335] Methods

[0336] Danio rerio (zebrafish) is a suitable species for assessing neuroactive compounds associated with the GABAA receptor because the structure, subunit composition, and expression of these receptor in the Danio rerio brain have been studied and found to be similar to that in other vertebrates such as rodents and humans. Zebrafish were kept in a flow-through ZebTEC system at a temperature of 28°C, a pH of 6.8-7.5, and an osmolarity of 550-700 osmol / liter, with a light regimen of 12 hr. / 12 hr., and constant aeration. Zebrafish were fed a special diet, selected for suitability with the study, and fed twice daily. During the experiment, animals were fed in the evening on the day prior to the experiment and in the evening on the day of the experiment, after completion.

[0337] The peptides were dissolved in a saline vehicle (0.9% NaCl) within 1-2 hrs. prior to administration and administered intraperitoneally (IP) using a syringe. Anesthesia and immobilization were achieved by placing the zebrafish in cold water (10°C); control zebrafish received IP injections of an equivalent volume of saline (0.9% NaCl). The zebrafish were removed from the cold water and allowed to equilibrate under standard aquarium conditions for 10 min prior to behavioral testing. Three behavioral tests were utilized: the novel tank (NT) test, the dark-light box (DLB) test, and the social preference (SP) test. The zebrafish model experimental setup is summarized in Table 22. Table 22: Experimental series, groups, and treatment regimen; novel tank (NT), dark-light box (DLB) and social preference (SP); vehicle = 0.9% NaCl. Group name Group size Administration, Dose, TestDB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Ac-FQSE (all D-from) 20 IP, 10 mg / kg, LDB ESQF (all D-form) 20 IP, 10 mg / kg, LDB

[0338] Novel tank (NT) test: the NT test was performed, for example as described in Maximino et al, “Role of serotonin in zebrafish (Danio rerio) anxiety: Relationship with serotonin levels and effect of buspirone, WAY 100635, SB 224289, fluoxetine and para-chlorophenylalanine (pCPA) in two behavioral models,” Neuropharmacology, Vol.71, 2013: pp.83-97, the entirety of which is hereby incorporated by reference. NT tests were performed in a 4-liter trapezoid aquarium, with the base and side walls made of opaque, matte black plastic, and the front panel made of transparent plexiglass. Video recording (background shooting) was started 20-30 seconds before the fish were placed in the test aquarium. The experimental animals were placed in the novel tank (NT) apparatus using a net. The recording lasted 5 minutes. The data processing was carried out using ETHOVISION XT animal behavior tracking software package (Noldus). The program calculated the distance covered by the animal, its speed, the number of visits to the three conventional zones of the aquarium: the bottom, center, and middle (lower, middle, and upper thirds of the 93 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 aquarium, respectively), the time spent in these zones, and the latency to visit the middle and the surface of the aquarium.

[0339] Dark-light box (DLB) test: the Dark / Light preference test (also referred to as light-dark test) was performed, for example as described in Maximino et al, “Pharmacological analysis of zebrafish (Danio rerio) scototaxis,” Prog. Neuro-Psychopharmacology Biol. Psychiatry, Vol. 35, 2011: pp. 624–631, the entire contents of which are hereby incorporated by reference. The dark-light box consisted of three main parts: a launch (central) compartment, a light compartment made of white plastic, and a dark compartment made of opaque, black plastic. The light source used in these tests was provided by a lamp (LED lamp PL, 11 W, light flux ≈ 600 Lm, about 500 lx directly above the water surface), which was attached to the upper part of the aquarium. Video recording was turned on simultaneously upon placing the fish in the setup and lasted 5 minutes. The videos were processed using RealTimer software (OpenScience). The time spent and the number of visits to the light and dark compartments of the test setup were recorded, as well as the time of the first enter (latency) of visiting light compartment.

[0340] Social preference (SP) test: the SP test was performed using a plexiglass aquarium (20 x 20 x 28 cm) with a removable partition separating a small compartment (e.g., the shoal) and a larger compartment (e.g., open water) for investigating shoaling behavior, for example as described in Parker et al., “The utility of zebrafish to study the mechanisms by which ethanol affects social behavior and anxiety during early brain development,” Prog. Neuropsychopharmacology Biol. Psychiatry. Vol. 55, 2014: pp. 94-100, the entire contents of which are hereby incorporated by reference. Five adult Danio rerio zebrafish were placed into the small compartment (e.g., simulating a shoal) with diffused lighting in the installation provided by the ambient lighting of the room (approx.200 Lx). Test fish were placed in the larger compartment and the camera was switched on simultaneously upon opening of the sliding doors, and the behavior was recorded for 5 minutes. The video was processed using RealTimer (OpenScience) to evaluate the residence time and the number of visits to the three conventional zones of the aquarium wall that were recorded: near the shoal, in the middle of the aquarium, and near the wall opposite to the shoal (all three zones were equal in size).

[0341] Statistical Analysis: data were assessed for normality using the Kolmogorov-Smirnov test to determine whether to use parametric or non-parametric statistical tests. For pairwise comparison, a Mann- Whitney (M-W) U-test was used. When comparing multiple groups, a Kruskal-Wallis test with post hoc Dunn's test was used. The results are presented as mean ± standard error of the mean (SEM.). 94 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0342] Results

[0343] Series I NT Test: results are shown in Fig.14. ESQF (all D-form amino acids, e.g., LCGA 17 / 14) at a dose of 10 mg / kg significantly increased the time spent near the surface of the test aquarium (Kruskal- Wallis test p = 0.0091 with an uncorrected Dunn’s test for multiple comparisons p = 0.0067) and respectively decreased time spent near bottom at a statistical trend (Kruskal-Wallis test p=0.0597 with uncorrected Dunn’s test for multiple comparisons p=0.0728). Ac-FQSE (all D-form), e.g., LCGA 17 / 13, did not affect latent period (LP) of reaching the surface zone or locomotion of tested fish, whereas Ac-FQSE (all D-form), e.g., LCGA 17 / 13, at a dose 10 mg / kg did not have any significant effects of the Danio rerio behavioral parameters in NT test.

[0344] Series 2 NT Test: results are shown in Fig.15. Ac-FQsE (D-serine, e.g., LCGA 17 / 16) at a dose of 10 mg / kg increased time spent near surface of the test setup (One-way ANOVA F(2,78) = 3.711, p = 0.0289 with an uncorrected Fisher’s LSD test p=0,008), and decreased time near bottom (One-way ANOVA F(2,78) = 2.555 p = 0.0842 with uncorrected Fisher’s LSD test p = 0.0273). Ac-FQsE did not have a significant effect on LP and total locomotion of the experimental fish. Ac-FqSE (D-glutamine, e.g., LCGA 17 / 15) did not significantly alter time spent near surface, time near bottom, LP of reaching the surface and total movement.

[0345] Series 3 NT Test: results are shown in Fig.16. Ac-FQtE (D-threonine, e.g., LCGA 17 / 39) at a dose of 10 mg / kg increased time spent near surface of the test setup (Kruskal-Wallis test p = 0.0235 with an uncorrected Dunn’s test for multiple comparisons p = 0.0077), and decreased time near bottom (Kruskal- Wallis test p = 0.0571 with an uncorrected Dunn’s test for multiple comparisons p = 0.017). Ac-FQtE also reduced latency of reaching the water surface significantly (Kruskal-Wallis test p = 0.0361 with an uncorrected Dunn’s test for multiple comparisons p = 0.0137) and increased total movement at a trend level (One-way ANOVA F(2,44) = 3.711, p = 0.22 with an uncorrected Fisher’s LSD test p = 0.044). Ac-FQβsE (beta-serine, e.g., LCGA 17 / 34) at a dose 10 mg / kg did not have any significant effects of the Danio rerio behavioral parameters in NT test.

[0346] Series I DLB Test: results are shown in Fig.17. ESQF (all D-form amino acids, e.g., LCGA 17 / 14) at a dose of 10 mg / kg significantly increased time spent in light compartment and number of transitions to the light compartment (Kruskal-Wallis test p = 0.0406 with an uncorrected Dunn’s test for multiple comparisons p = 0.0181), reduced LP of reaching the light compartment at a trend level (Kruskal-Wallis test p = 0.0931 with an uncorrected Dunn’s test for multiple comparisons p = 0.0294), and increased number of 95 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 transitions to the light compartment at a trend level (Kruskal-Wallis test p = 0.0505 with uncorrected Dunn’s test for multiple comparisons p = 0.0147). Ac-FQSE (all D-form), e.g., LCGA 17 / 13, at a dose 10 mg / kg significantly increased time spent in light compartment of DLB setup (Kruskal-Wallis test p = 0.0406 with an uncorrected Dunn’s test for multiple comparisons p = 0.0467), but did not have significant impact on LP or number of transitions to the light compartment.

[0347] Series 2 DLB Test: results are shown in Fig. 18. Ac-FQsE (D-serine, e.g., LCGA 17 / 16) administered at a dose of 10 mg / kg significantly increased the time spent in the light compartment and the number of transitions to the light compartment (Kruskal-Wallis test, p = 0.0287, with an uncorrected Dunn's test for multiple comparisons, p = 0.0327). Additionally, Ac-FQsE (D-serine, e.g., LCGA 17 / 16) significantly increased the number of transitions to the light compartment (Kruskal-Wallis test, p = 0.0248, with an uncorrected Dunn's test for multiple comparisons, p = 0.0364). Ac-FQsE (D-serine, e.g., LCGA 17 / 16) did not have a significant effect on the latency period of visiting the light compartment. Ac-FqSE (D-glutamine, e.g., LCGA 17 / 15) administered at a dose of 10 mg / kg did not have any significant effects on the behavioral parameters of Danio rerio in the DLB test.

[0348] Series 3 DLB Test: results are shown in Fig.19. Ac-FQtE (D-threonine, e.g., LCGA 17 / 39) at a dose of 10 mg / kg significantly increased time spent in light compartment (Kruskal-Wallis test p = 0.0284 with an uncorrected Dunn’s test for multiple comparisons p = 0.0077), reduced LP of reaching the light compartment (Kruskal-Wallis test p = 0.0335 with an uncorrected Dunn’s test for multiple comparisons p = 0.0095), and increased the number of transitions to the light compartment (Kruskal-Wallis test p = 0.0244 with an uncorrected Dunn’s test for multiple comparisons p = 0.0097). Ac-FQβsE (beta-serine, e.g., LCGA 17 / 34) at a dose 10 mg / kg did not have any significant effects of the Danio rerio behavioral parameters in the DLB test.

[0349] Series I SP Test: results are shown in Fig.20. ESQF (all D-form amino acids, e.g., LCGA 17 / 14) at a dose of 10 mg / kg did not have any significant effects on time out of shoal (One-way ANOVA F(2,49) = 2.945, p = 0.0619 with an uncorrected Fisher’s LSD test p = 0.7103) or number of transitions (One-way ANOVA F(2,49) = 3.729, p = 0.0752 with an uncorrected Fisher’s LSD test p = 0.2842). Ac-FQSE (all D- form), e.g., LCGA 17 / 13, at a dose 10 mg / kg increased time spent out of shoal zone at a trend level (One- way ANOVA F(2,49) = 2.945, p = 0.0619 with uncorrected Fisher’s LSD test p = 0.0285) and increased the 96 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 number of transitions out of social zone at a trend level in SP test (One-way ANOVA F(2,49) = 2.729, p = 0.0752 with an uncorrected Fisher’s LSD test p = 0.0238).

[0350] Series 2 SP Test: results are shown in Fig.21. Ac-FQsE (D-serine, e.g., LCGA 17 / 16) at a dose of 10 mg / kg increased time spent out of the shoal zone at a trend level (Kruskal-Wallis test p = 0.1062 with an uncorrected Dunn’s test for multiple comparisons p=0.0831) and significantly increased the number of transitions out of social zone (Kruskal-Wallis test p = 0.0064 with an uncorrected Dunn’s test for multiple comparisons p = 0.0259). Ac-FqSE (D-glutamine, e.g., LCGA 17 / 15) significantly increased the number of transitions out of the social zone (Kruskal-Wallis test p = 0.0064 with an uncorrected Dunn’s test for multiple comparisons p = 0.0074), but did not have impact on time spent out of shoaling zone (Kruskal-Wallis test p = 0.1062 with an uncorrected Dunn’s test for multiple comparisons p > 0.9999).

[0351] Series 3 SP Test: results are shown in Fig.22. Ac-FQtE (D-threonine, e.g., LCGA 17 / 39) and Ac-FQβsE (beta-serine, e.g., LCGA 17 / 34), each at a dose of 10 mg / kg, did not significantly alter the time spent out of the shoaling zone (Kruskal-Wallis test summary p = 0.1260), or the number of transitions out of the shoaling zone (Kruskal-Wallis test summary p = 0.1537).

[0352] Increased anxiety in zebrafish is associated with specific behavioral patterns that were measured in the NT, BLB, and SP tests. For example, increased time spent in the dark compartment of the DLB (increased scototaxis - seeking dark shelter as a result of exploratory / hiding motivation balance) is a sign of anxiety-like behaviors in zebrafish, for example as described in Maximino et al., 2011. Increased shoal preference (shoaling reflex is the basic protective response of shoaling fish to a predator) is a sign of anxiety- like behaviors in zebrafish, for example as described in Parker et al., 2014; and Nguyen et al., “Aquatic blues: Modeling depression and antidepressant action in zebrafish,” Prog. Neuro-Psychopharmacology Biol. Psychiatry. Vol.55, 2014: pp.26–39, which is hereby incorporated by reference in its entirety. Increased time spent at the surface of the NT apparatus reflects the balance between exploratory / hiding motivation in fish, which is a marker of anxiety-like behaviors, for example as described in Sackerman et al., “Zebrafish Behavior in Novel Environments: Effects of Acute Exposure to Anxiolytic Compounds and Choice of Danio rerio Line,” Int J Comp Psychol, Vol.23, No.1, 2010: pp.43-61, which is hereby incorporated by reference in its entirety. Thus, Danio rerio (zebrafish) is a valid animal model, sensitive to several kinds of psychoactive drugs, and useful for psychoactive drug discovery and validation. A summary of the effects of each peptide on Danio rerio behavior is listed in Table 23. 97 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 Table 23: Behavioral changes after acute administration of the peptides compared to Ac-FQSE (e.g., LCGA- 17, as listed in Tables 1 and 20); novel tank (NT), dark-light box (DLB) and social preference (SP). Modification NT LDB SP Ac-FQSE ↑ Time surface ↑ Time on light ↑ Tim t f h l

[0353] In conclusion, the tested peptides were modified based on the acetylated tetrapeptide, Ac-FQSE (e.g., LCGA-17 as listed in Tables 1 and 20), and each peptide demonstrated anxiolytic-like behavioral effects in the Danio rerio model by either increasing time and reducing latency to surface in the NT test, increasing time spent in the light and reducing latency to enter the light compartment in the DLB test, and / or increasing time spent out of shoal in the SP test. The peptides, overall, demonstrated similar behavioral profile to the original, unmodified tetrapeptide (FQSE) in the NT, LDB, and SP tests, by increasing behavioral activity near surface, in the light compartment, and reducing activity near shoaling zone, respectively. Modification of peptides to improve half-life can introduce a trade-off, where altering the chemistry to increase the half-life may reduce or negate the effects due to binding, etc. However, the phenotypic effects of the peptides remained despite their chemical modification(s), which resulted in a 100-fold to 1,000-fold or more increase 98 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 in serum half-life (e.g., as summarized in Table 20 and Example 3), without a significant sacrifice in in vivo effect in zebrafish. Example 6: Ex vivo Evaluation of the Central Effects of Chemically-Modified FQSE in Mus musculus.

[0354] Next, the postsynaptic excitatory currents and long-term potentiation (LTP) in pyramidal neurons of the CA1 field of the hippocampus was evaluated for Ac-FQSE (e.g., LCGA-17, as described in Table 1 and 20) and Ac-FQsE (e.g., D-serine, LCGA-17m16, as described in Table 1 and 20).

[0355] Methods

[0356] The experiment was carried out in 26 male and female C57BL / 6 mice aged 28-35 days. Mice were maintained at 20-24°C, relative humidity 35-75%, under a 12-hr. light / dark cycle, and with a standard diet. Animals were euthanized by decapitation and the brains were removed and transferred into ice-cold solution for sections preparation (140 mM potassium gluconate, 15 mM sodium gluconate, 10 mM HEPES, 4 mM NaCl, 0.2 mМ EGTA, рН 7.2). Horizontal sections at 350 μm thick were cut on an EMS 5000 vibrotome (Electron Microscopy Sciences, USA), for example as described in Rozov, et al., “GluA2-lacking AMPA receptors in hippocampal CA1 cell synapses: evidence from gene-targeted mice,” Front Mol Neurosci, Vol. 5, No.22, 2012, the entire contents of which are hereby incorporated by reference. The slices were placed in an incubation chamber filled with artificial cerebrospinal fluid (ACF) heated to 35-37°C containing 125 mM NaCl, 25 mM NaHCO3, 25 mM glucose, 2.5 mM KCl, 1.25 mM NaH2PO4, 2 mM CaCl2, and 1 mM MgCl2. ACF was constantly sparged with carbogen (95% O2+ 5% CO2). After 30 minutes of incubation, one of the sections was transferred to the experimental chamber on the Slicescope microscope platform (Scientifica, UK), where the section was constantly perfused with ACF at room temperature (approx.20°C). Patch pipettes were filled with a solution containing 110 mM Cs-gluconate, 30 mM CsCl, 8 mM NaCl, 10 mM HEPES, 4 mM MgATP, 10 mM Na-phosphocreatine, 0.3 mM NaGTP, pH 7.2.

[0357] Identification of the pyramidal neurons in CA1 field of the hippocampus was carried out by localization in the section and morphological characteristics. Synaptic inputs were stimulated by applying short (100 μs) electrical currents through the glass electrodes. To stimulate Shaffer's collaterals, the electrodes were placed in the stratum radiatum (potentiated input) and the stratum oriens (control input). Long-term potentiation (LTP) was induced by depolarization of the postsynaptic neuron by 0 mV and simultaneous stimulation of inputs to the apical dendrites (stratum radiatum) at a frequency of 0.66 Hz for 3 min. GABAergic synapses were blocked by the application of the blocker SR-95531 throughout the 99 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 experiment. To test the effect of the Ac-FQSE and Ac-FQsE peptides, brain sections were preincubated in ACF containing 1 μM, 10 μM, or 100 μM of the peptide for 30 min before the start of the experiment and throughout the duration of recording. Signals were recorded using a HEKA EPC 10 amplifier (HEKA Elektronik, Germany).

[0358] Results

[0359] The results of the analysis are shown in Figs.22A-22G, where the values are shown as the mean ± standard error of the mean, or as the median ± lower (25%) and upper (75%) quartile. The number, n, corresponds to the number of experiments / cells obtained for certain experimental conditions. The significance of the occurrence of LTP in individual experimental groups was assessed by pairwise comparison of the EPSC amplitudes in the control (synapses on the basal dendrites) and potentiated (synapses on the apical dendrites) using a paired Student's t-test. The statistical significance of the differences was assessed by comparing the samples obtained in the control experiments and in the presence of test drugs, where a Kruskal-Wallis One Way Analysis of Variance on Ranks was used as a test

[0360] The CA1 recordings of hippocampal pyramidal neurons were performed in a whole cell patch- clamp configuration. During the pre-induction and post-induction phases of the experiments, the membrane potential of the cell was -70 mV. LTP in synapses on apical dendrites was induced by a combination of low- frequency presynaptic stimulation of Shaffer collaterals (0.66 Hz) with postsynaptic depolarization up to 0 mV. In control sections incubated in ACF without peptide, the induction resulted in an increase in EPSC amplitudes at potentiated synapses (e.g., as shown in Fig.23A). For comparison between groups, the relative level of LTP was calculated by subtracting the normalized values of the amplitudes of the control input EPSC from the normalized values of the amplitudes of the potentiated input EPSC and expressed as a percentage of the relative increase (e.g., as shown in Figs.23E-23G and Figs.24E-24G).

[0361] The median initial increase (measured 7-12 minutes after potentiation) in EPSC relative to the control input (synapses on basal dendrites) was 81% (n = 8; p < 0.001), the median LTP 27 minutes after induction was 83% (p < 0.001). In sections incubated in Ac-FQSE, the LTP induction protocol described above resulted in a long-term increase in EPSC amplitudes (e.g., as shown in Figs.23B-23D). The median relative values of the early phase of LTP in sections incubated in ACF containing various concentrations of Ac-FQSE were 95% (1 μM; n = 8; p < 0.001), 65% (10 μM; n = 7; p < 0.001) and 149 % (100 µM; n = 7; p < 0.001). Median LTPs at 27 minutes after induction were 100% (1 µM; p < 0.001), 61% (10 µM; p < 0.001) 100 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 and 123% (100 µM; p < 0.001). Comparative analysis between the groups revealed that a statistically significant increase in LTP was observed in the presence of 100 μM Ac-FQSE both in the early phase and 27 minutes after induction (p < 0.001).

[0362] Sections incubated with Ac-FQsE (e.g., LCGA-17m16) exhibited LTP induction that led to a long- term increase in the amplitudes of postsynaptic responses (e.g., as shown in Figs.24B-24D). The median relative values of the early phase of LTP in sections incubated in ACF containing various concentrations of Ac-FQsE were 84% (1 μM; n = 8; p < 0.001), 114% (10 μM; n = 9; p < 0.001) and 104% (100 μM; n = 8; p < 0.001). The median LTP relative to the control input at 27 minutes post-induction were 71% (1 μM; p < 0.001), 94% (10 μM; p < 0.001) and 80% (100 μM; p < 0.001). A comparative between-groups analysis revealed a statistically significant short-term increase in EPSC amplitudes after LTP induction in sections incubated with 10 µM and 100 µM Ac-FQsE relative to control conditions (p < 0.01; e.g., as shown in Figs.24E-24F).

[0363] In conclusion, pyramidal neurons of the CA1 field of the hippocampus retained the ability to generate LTP after the incubation of sections in ACF containing Ac-FQSE or Ac-FQsE peptides. Concentrations of 100 μM caused an increase in LTP both in the early and late phases. Concentrations of 10 μM and 100 μM caused a short-term statistically significant increase in EPSC amplitudes in potentiated synapses relative to the values obtained in control sections. Overall, the data demonstrated, inter alia, that the chemical modification of the amino terminus by acetylation and the substitution of L-serine for D-serine did not substantially hinder the ability of the peptides to bind and / or elicit an effect ex vivo. Example 7: In vivo Evaluation of the Behavioral Effects of Chemically-Modified FQSE in Rats.

[0364] The behavioral effects of the chemically-modified peptides were evaluated in vivo using a rat model. To date, there are no clinically effective drugs with anxiolytic and antidepressant activity with an intranasal route of administration that could be used as effective comparators in the study. Data are compared only to a negative control (vehicle control).

[0365] Methods

[0366] 20 male Sprague-Dawley rats were used in the study with starting bodyweights of 500-650 g, 20 weeks of age, with standard diet and care. The Ac-FQsE (e.g., LCGA17m16 as listed in Tables 1 and 20) peptide was dissolved in 5% sodium bicarbonate solution. Animals were intranasally (i.n.) administered Ac- FQsE at a dose of 0.05 mg / kg or 0.5 mg / kg, or a vehicle control (VEH) of 5% sodium bicarbonate solution 101 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 for comparison of the peptide’s effect on behavior. The injection volume was 0.1 µL / g bodyweight (e.g., approx.50-65 μL). Table 24 summarizes the treatment groups. Table 24: In vivo behavioral evaluation treatment groups. Group Size Treatment Control 10Intranasal vehicle at 0.1 μL / g bodyweight,

[0367] Animals were provided a 14-day adaptation period to the experimental enclosures, after which each of the following behavioral tests were performed: an open field test (OFT), elevated plus maze (EPM) test, and Porsolt forced swim test (FST). One behavioral test was performed per day, and the behavioral tests were performed 30 min post-administration of the peptide or vehicle.

[0368] Open Field Test (OFT): on Day 1, an OFT was performed, measuring the following characteristics: rears (measured as a number, N), grooming (measured as a number, N), Defecation (measured as a number, N) Total Distance traveled (cm), mean velocity (cm / s), time spent in the center (s), number of center entries (N), and freezing (time in seconds). The experimental arena had a diameter of 97 cm and was illuminated by a bright light (500 lx). Recorded parameters including the total distance traveled (cm), time spent moving (at a speed of more than 5 cm / sec), time spent immobile (at a speed of less than 0.2 cm / sec), average and maximum velocity, the number of periods of movement and rest. The same set of parameters, as well as the latency and duration of immobility, was recorded for statistical analysis. Defecation and rears were evaluated visually. The OFT is designed to assess the level of motor and exploratory activity.

[0369] Elevated Plus Maze (EPM) Test: on Days 5-6, an EPM test was performed, measuring grooming (measured as a number, N), number of risk behaviors (N), center rears (measured as a number, N), closed arms rears (measured as a number, N), total distance (cm), mean velocity (cm / s), time spent in the center (s), time spent on the open arms (s), time spent in the closed arms (s), number of exits to the open arms (N), number of visits to the closed arms (N), and anxiety index (AI, %). The EPM test consisted of two closed and two open arms located perpendicularly to each other (each arm having a length of 30 cm). The height of the sides of the closed arms was 15 cm. The entire installation was raised 70 cm above the floor. The open arms 102 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 had a bright uniform illumination of 400 lx, with the closed arm illuminated at approx.30-40 lx. The animal was placed in the center of the maze, with its head facing an open arm. Within five minutes, an animal tracking video-recoding software ETHOVISION (Noldus) program automatically recorded the following behavior parameters: total distance traveled (in cm), time spent moving (at a speed of more than 5 cm / s), immobility time (at a speed of less than 0.2 cm / s), average and maximum speed, the number of episodes of mobility, and freezing (e.g., stopping motion). The same set of parameters, as well as the latent period and duration of stay, were separately recorded for the central sector, the open arm, and the closed arm. The ‘Anxiety Index’ (AI) was an integrative behavioral measure in the EPM and was calculated as follows: 100*(1 − [(time spent on open arms / total time on the maze) / 2 + (number of entries to the open arms / total exploration on the maze) / 2]).

[0370] Modified Porsolt Forced Swimming Test (FST): on Days 9-10, a FST was performed, measuring freezing (s), passive swimming duration (s), and active swimming duration (s). As part of the FST, two tests were carried out within two days. The swimming installation was a transparent cylinder, 30 cm high, 10 cm in diameter, and filled with water (water temperature 21-23°C˚) to a volume height of 25 cm. On the first day, the animal was placed in the cylinder for ten minutes and the behavioral parameters were not recorded as an equilibration period. On the second day, the animals were placed in the apparatus for 10 minutes and recorded using the animal tracking video-recoding software, Real Timer Program (OpenScience). After each test, the animals were warmed and dried in a heated cage until dry. The duration of active swimming (vigorous movements with all paws) and passive swimming (weak strokes with hind legs), as well as immobility were recorded.

[0371] Statistical Analyses: the data were analyzed using a Student’s T-test. The data are represented as the mean ± standard error of mean (SEM).

[0372] Results

[0373] Open Field Test (OFT): a single i.n. administration of Ac-FQsE did not affect the horizontal motor activity of rats, e.g., as shown in the total distance traveled in Fig.25A; however, a statistically significant increase in the number of rears after administration was observed, suggesting that the peptide enhanced the exploratory activity in the rats e.g., as shown in Fig.25B. Other parameters (mean velocity, time in the center, freezing) did not differ between groups, indicating that the peptide had no significant deleterious effects. 103 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0374] Elevated Plus Maze (EPM) Test: a single i.n. administration of Ac-FQsE resulted in a statistically significant increase in the time spent in the open arms, e.g., as shown in Fig.26A, while the number of open arms entries failed to reach statistical significance (e.g., as shown in Fig.26B). The calculated Anxiety Index (AI) was statistically lower in animals treated with the peptide, e.g., as shown in Fig.26C. Overall, the EPM results suggested that Ac-FQsE exhibited anxiolytic-like effects.

[0375] Modified Porsolt Forced Swimming Test (FST): a single i.n. administration of Ac-FQsE resulted in significantly reduced immobility in the FST, e.g., as shown in Fig.27, suggesting an antidepressant-like potential of the peptide.

[0376] In conclusion, the data demonstrated, inter alia, that the Ac-FQsE peptide administered intranasally at a dose of 0.05 mg / kg and 0.5 mg / kg for 30 minutes before testing demonstrated pronounced anxiolytic-like and antidepressant-like effects in male Sprague Dawley rats. In the OFT, Ac-FQsE increased the exploratory activity of the animals without affecting locomotion, suggesting anxiolytic activity without signs of sedation. Rearing in rats is a normal, healthy activity in which the rat rears onto its hinds during exhibition of exploratory / search behavior. Increased rearing behavior in rats is used as a proxy measure for understanding if the rat is more comfortable with its surroundings, e.g., increased rearing would indicate decreased anxiety and uneasiness in the animal. The Ac-FQsE peptide exhibited a statistically significant increase in rearing behavior in the OFT, without signs of sedation. The anxiolytic potential of Ac-FQsE was further exhibited in the EPM. The peptide significantly enhanced the exploration of the open, brightly lit arms of the maze in rats. In the FST, rats administered Ac-FQsE had shorter duration of immobility, which is an effect observed after classical antidepressant treatment in rodents, suggesting antidepressant-like activity of the studied peptide without any negative sedation effects. Administration of Ac-FQsE also resulted in a statistically significant decrease in the AI, which is a field-recognized, quantitative measure of animals’ anxiety. Example 8: Evaluation of the presence of specific Ac-FQsE binding sites ex vivo and the affinity of Ac-FQsE to gabapentin binding sites.

[0377] This Example details the results of experiments used to demonstrate the binding of chemically- modified FQSE in tissue extracts. This Examples uses a chemically-modified tetrapeptide, Ac-FQsE (acetylated tetrapeptide, where ‘s’ is D-serine as a replacement for L-serine, e.g., LCGA-17m16 as in Tables 1 and 20), which as described herein demonstrated a T1 / 2 in rat plasma of approx.1975 min (~33 hrs.). Ac- 104 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 FQsE was used as a representative chemically-modified peptides, with the results generally extrapolatable to other chemically-modified peptides herein, and to estimate whether Ac-FQsE possesses specific binding to central nervous system tissue (e.g., in the brain) or off-target binding in cardiomyocytes, and to perform differentiation from gabapentinoids regarding their cardiac side effect.

[0378] Gabapentinoids are ligands of the α2δ subunit of high-voltage-gated calcium channels (Cav). Cardiomyocytes are used as model tissue for evaluating drugs that bind / modulate the activity of these channels due to their expression of these channels. For example, with respect to rat mesenteric arteries, gabapentinoids were found to significantly decrease the myogenic tone to the same extent as verapamil and nifedipine, as described in Largeau, et al, “Gabapentinoid-induced peripheral edema and acute heart failure: a translational study combining pharmacovigilance data and in vitro animal experiments,” Biomedicine & Pharmacotherapy, (2022), Vol.149, 112807. Gabapentinoid drugs directly bind to α2δ-1 and α2δ-2 isoforms of α2δ subunit, for example, as described in Chen Z, et al., “Structural basis for CaVα2δ: gabapentin binding,” Nat Struct Mol Biol. (2023) Vol.30, No.6, pp.735-739, of which only α2δ-1 is represented in cardiac and vascular myocytes and is responsible for side effects, for example, as described in Dolphin, A. C. (2018). “Voltage-gated calcium channel α2δ subunits: an assessment of proposed novel roles,” F1000Research, 7; and Page, et al., “The importance of cache domains in α2δ proteins and the basis for their gabapentinoid selectivity,” Channels, (2023) 17(1), 2167563.

[0379] Methods

[0380] Radioactive ligands: Tritium-labeled [3H]-gabapentin (64 Ci / mmol) and [3H]-Ac-FQsE (73 Ci / mmol) were synthesized by high-temperature solid-state catalytic isotope exchange (HSCIE). Gabapentin (Product# G154) was commercially-available from SIGMA-ALDRICH.

[0381] Isolation of plasma membranes from frontal cortex and from cardiac tissues: Membrane preparations from the frontal brain cortex of male Wistar rats were produced according to modified methods of Hawkinson, et al., “Steroid inhibition of [3H]SR 95531 binding to the GABA(A) recognition site,” European Journal of Pharmacology, (1996) 304(1–3), 141–146; Ito, et al., “Effects of bicuculline on [3H]SR 95531 binding in discrete regions of rat brains,” Neurochemical Research, (1992) 17(4), 307–313; and Zolotarev, et al., “Anxiolytic activity of the neuroprotective peptide HLDF-6 and its effects on brain neurotransmitter systems in BALB / c and C57BL / 6 mice,” Journal of Psychopharmacology, (2016) 30(9), 922–935). A tissue sample was homogenized in 25 volumes of cold buffer (50 mM Tris-HCl, pH 7.4) in a TEFLON-glass 105 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 homogenizer. The homogenate was centrifuged for 20 min at 40,000 x g. The precipitate was then resuspended in 50 mM Tris-HCl buffer (pH 7.4) and centrifuged at 40,000 x g for 20 min. The obtained precipitate was homogenized in 50 mM Tris-HCl buffer (pH 7.4) and centrifuged twice at 40,000 x g for 20 min. After, the precipitate was resuspended in 15 mL of the same buffer and used for the radioligand analysis.

[0382] For the production of membrane preparations of the cardiac tissues, the hearts of male Wistar rats were frozen in liquid nitrogen immediately after collection and stored at -80°C. Cardiac tissue samples were homogenized in 25 volumes of cold buffer (50 mM Tris-HCl, pH 7.4) in a TEFLON-glass homogenizer. The homogenate was centrifuged for 10 min at 500 x g. The obtained supernatant was centrifuged for 20 min at 40,000 x g. The precipitate was then resuspended in 50 mM Tris-HCl buffer (pH 7.4) and centrifuged at 40,000 x g for 20 min, where this procedure was repeated twice. The precipitate was then resuspended in 7 mL of the same buffer and used for the radioligand analysis.

[0383] Incubation protocols: The incubation mixture (final volume 0.5 mL) contained 50 μL of [3H]- Gabapentin (64 Ci / mmol, final concentration 16 nM) or [3H]-Ac-FQsE (73 Ci / mmol, final concentration 16 nM), 200 or 250 μL of the buffer (50 mM Tris-HCl, pH = 7.4) and 200 μL of membrane protein suspension (brain or cardiac preparations). 50 μL of unlabeled Ac-FQsE or gabapentin was added for non-specific binding. The reaction mixture was incubated at ambient temperature for 60 min for both tissue types. Specific binding was calculated as the difference between total and non-specific binding.

[0384] The half-maximal inhibitory concentration (IC50) value for the binding of labeled ligands was determined by adding 50 μL of the test compounds to the incubation medium at final concentrations of 10-9M to 10-4M. To generate the binding curves of the radioactive ligand’s displacement, each concentration of the test substance was tested in triplicate.

[0385] Liquid scintillation spectrometry: At the end of the incubation, the samples were filtered through GF / B fiberglass filters previously moistened with 0.3% (v / v) polyethyleneimine for 2 hrs. at ambient temperature. The filters were rinsed with buffer, air-dried, and transferred to scintillation vials. Filters were poured with 5 mL of toluene-based scintillation liquid (4 g 2,5-diphenyloxazole (PPO) and 0.2 g [1,4-bis-2-(5- phenyloxazolyl)-benzene] (POPOP) per L of toluene). The radioactivity of the samples was determined on a TRI-CARB 2900TR counter (PERKIN ELMER) with a counting efficiency of 42-46%. Protein concentration was measured by a standard Lowry method. Statistical analysis was performed for the radioligand binding results. 106 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0386] Results

[0387] Gabapentin possesses high affinity to specific Ac-FQsE binding sites in the brain. Membrane preparations of the frontal brain cortex were labeled with [3H]-Ac-FQsE, and then competitive binding was measured with unlabeled Ac-FQsE and gabapentin. As shown in Fig.28, Ac-FQsE and gabapentin displaced [3H]-Ac-FQsE with high efficiency, with a similar IC50 for Ac-FQsE of 2 µM ± 0.1 µM. These data corroborated the presence of specific Ac-FQsE binding sites in the brain and shared affinity with gabapentin to these sites.

[0388] Ac-FQsE lacks specific binding sites in cardiac tissue: To assess the presence of specific binding sites for Ac-FQsE in cardiac tissue, cardiac rat membrane preparations were labeled with labeled [3H]-Ac- FQsE and competitive binding was measured with unlabeled Ac-FQsE and gabapentin. As shown in Fig.29, neither Ac-FQsE nor gabapentin demonstrated competitive binding with [3H]-Ac-FQsE, indicating the absence of specific binding of Ac-FQsE in cardiac tissue.

[0389] Ac-FQsE performs no affinity to specific gabapentin binding sites in cardiac tissue: To test the specificity of Ac-FQsE to gabapentin binding sites in cardiac tissue, cardiac rat membrane preparations were incubated with [3H]-gabapentin and a competitive binding was measured with unlabeled Ac-FQsE and gabapentin. As shown in Fig.30, gabapentin demonstrated an efficient replacement of [3H]-gabapentin from the membranes of cardiac tissue preparations, confirming the presence of specific gabapentin binding sites on cardiomyocytes. Ac-FQsE did not displace [3H]-gabapentin from the membrane preparations, indicating the absence of its affinity to specific gabapentin binding sites on cardiomyocytes.

[0390] The data from the present study indicated that Ac-FQsE shared specific binding sites in the brain with gabapentin, but lacked specific binding in cardiac tissue and did not compete for gabapentin-specific binding sites on cardiac membranes. This suggests a distinction based on α2δ isoform specificity. The data suggested that α2δ-2 exclusively served as the primary molecular target for chemically-modified FQSE peptides, using Ac-FQsE as a representative chemically-modified peptide. The results indicated the absence of direct peripheral action of the peptide through α2δ-1 and the lack of the related cardiac adverse effects typical for gabapentinoids. α2δ isoform specificity provides an explanation of the differences in Ac-FQsE and gabapentinoids mechanisms of action. Gabapentinoids, primarily act through the disruption of α2δ-1- NMDARs association as the effect on α2δ-2 is less prominent, cause LTP depression, while Ac-FQsE induces LTP by affecting α2δ-2 as an exclusive target. 107 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003

[0391] These data demonstrated, inter alia, that chemically-modified FQSE peptides have affinity for binding sites in brain tissue that are shared with gabapentin, but that chemically-modified FQSE peptides do not share the side effect with gabapentin of affinity for cardiac tissue. DEFINITIONS

[0392] The following definitions are used in connection with the disclosure disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this disclosure belongs.

[0393] As used herein, “a,” “an,” or “the” can mean one or more than one.

[0394] Further, the term “about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language “about 50” covers the range of 45 to 55.

[0395] As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word “include,” and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the compositions and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[0396] Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the disclosure, the present disclosure, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.”

[0397] In embodiments, as used herein, the words “preferred” and “preferably” refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology. 108 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 EQUIVALENTS

[0398] While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure as come within known or customary practice within the art to which the disclosure pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

[0399] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. INCORPORATION BY REFERENCE

[0400] All patents and publications referenced herein are hereby incorporated by reference in their entireties.

[0401] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure.

[0402] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections. 109 DB1 / 149168710.1

Claims

Attorney Docket No.: LACT-003PC / 121851-5003 CLAIMS What is claimed is:

1. A peptide comprising a general formula I: R1-[F1Q1X1E1]y-R2(I), wherein F1 is or comprises a phenylalanine, Q1 is or comprises a glutamine, X1 is or comprises a serine, threonine, or a non-canonical amino acid, and E1 is or comprises a glutamate; and wherein at least one of R1, F1, Q1, X1, E1, and / or R2comprises one or more modifications.

2. The peptide of claim 1, wherein the peptide is oriented amino-terminus to carboxy-terminus, or wherein the peptide is oriented carboxy-terminus to amino-terminus.

3. The peptide of claim 1 or 2, wherein y comprises a whole number integer of 1 to 10.

4. The peptide of claim 3, wherein y is 1.

5. The peptide of any one of the preceding claims, wherein R1is or comprises a non-modified amino- terminus.

6. The peptide of any one of claims 1-4, wherein R1 is or comprises an amino-terminus comprising one or more modifications which comprise one or more chemical modifications.

7. The peptide of claim 6, wherein the one or more chemical modifications is or comprises one or more of acetylation, methylation, thiolation, glycosylation, prenylation, PEGylation, biotinylation, aminoethylation, halogenation, lipidation, myristylation, palmitoylation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine.

8. The peptide of claim 6 or 7, wherein R1 is or comprises an acetylated amino-terminus of F1.

9. The peptide of claim 6 or 7, wherein R1is or comprises a myristoylated amino-terminus of F1.

10. The peptide of claim 6 or 7, wherein R1is or comprises a palymitoylated amino-terminus of F1.

11. The peptide of any one of the preceding claims, wherein R2 is or comprises a non-modified carboxy- terminus.

12. The peptide of any one of claims 1-10, wherein R2 is or comprises a carboxy-terminus comprising one or more modifications which comprise one or more chemical modifications. 110 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 13. The peptide of claim 12, wherein the one or more chemical modifications is or comprises one or more of amidation, acetylation, methylation, thiolation, glycosylation, prenylation, PEGylation, biotinylation, aminoethylation, halogenation, lipidation, myristylation, palmitoylation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine.

14. The peptide of claim 12 or 13, wherein R2 is or comprises an amidated carboxy-terminus of E1.

15. The peptide of claim 12 or 13, wherein R2 is or comprises a myristoylated carboxy-terminus.

16. The peptide of claim 13, wherein R2is or comprises a myristoylated D-lysine carboxy-terminus.

17. The peptide of claim 9 or 10, wherein R1 is or comprises a palymitoylated carboxy-terminus of E1.

18. The peptide of claim 17, wherein R2 is or comprises a palymitoylated D-lysine carboxy-terminus.

19. The peptide of any one of the preceding claims, wherein X1is or comprises serine.

20. The peptide of any one of claims 1-18, wherein X1 is or comprises threonine.

21. The peptide of any one of the preceding claims, wherein the modification is comprises one or more non-canonical amino acids comprising sarcosine (N-methylglycine), hydroxyproline, homoserine, β- serine, homoglutamine, homoallylglycine, homopropargylglycine, azidohomoalanine, azidonorleucine, azidophenylalanine, acetylphenylalanine, aminoisobutyric acid, selenocysteine, dehydroalanine, pyrrolysine, α-amino-n-heptanoic acid, t-leucine, pipecolic acid, α,β- diaminopropionic acid, α,γ-diaminobutyric acid, ornithine, allothreonine, homocysteine, isoserine, β- alanine, β-amino-n-butyric acid, β-aminoisobutyric acid, γ-aminobutyric acid, α-aminoisobutyric acid, isovaline, N-ethylglycine, N-propylglycine, N-isopropylglycine, N-methylalanine, N-ethylalanine, N- methyl-β-alanine, N-ethyl-β-alanine, α-hydroxy-γ-aminobutyric acid, D-amino acids, and / or β-amino acids.

22. The peptide of claim 21, wherein the non-canonical amino acid is or comprises sarcosine (N- methylglycine).

23. The peptide of claim 21, wherein the non-canonical amino acid is or comprises hydroxyproline.

24. The peptide of claim 21, wherein the non-canonical amino acid is or comprises homoserine, beta- serine, beta / beta-serine, and / or homoglutamine. 111 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 25. The peptide of any one of the preceding claims, wherein one or more of F1, Q1, X1, and E1is or comprises an L-form amino acid.

26. The peptide of claim 25, wherein X1 is or comprises L-serine.

27. The peptide of claim 25, wherein X1is or comprises L-homoserine.

28. The peptide of claim 25, wherein X1 is or comprises L-sarcosine.

29. The peptide of claim 25, wherein X1 is or comprises L-hydroxyproline or L-serine-hydroxyproline.

30. The peptide of any one of claims 25-29, wherein each of F1, Q1, X1, and E1is or comprises a L-form amino acid.

31. The peptide of any one of claims 1-24, wherein one or more of F1, Q1, X1, and E1 is or comprises a D-form amino acid.

32. The peptide of claim 31, wherein X1 is or comprises D-serine.

33. The peptide of claim 31, wherein X1is or comprises D-homoserine.

34. The peptide of claim 31, wherein X1is or comprises D-threonine.

35. The peptide of claim 31, wherein Q1 is or comprises D-glutamine.

36. The peptide of any one of claims 31-35, wherein each of F1, Q1, X1, and E1is or comprises a D-form amino acid.

37. The peptide of claim 36, wherein each of F1, Q1, X1, and E1 is or comprises a D-form amino acid oriented from C-terminus to N-terminus (EXQF).

38. The peptide of any one of the preceding claims, wherein at least one peptide bond and / or at least one amino acid side chain comprises one or more chemical modifications.

39. The peptide of claim 38, wherein the one or more chemical modifications is or comprises acetylation, amidation, methylation, thiolation, glycosylation, prenylation, PEGylation, biotinylation, aminoethylation, halogenation, lipidation, myristylation, palmitoylation, disulfide bond formation, peptide bond formation, formylation, pyroglutamylation, urea, carbamylation, sulfonamide, alkylamine. 112 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 40. The peptide of claim 38 or 39, wherein the one or more chemical modifications is or comprises incorporation of a non-canonical amino acid, non-naturally occurring amino acid, and / or non- canonical peptide bond.

41. The peptide of any one of claims 38-40, wherein the one or more chemical modifications is or comprises cyclization.

42. The peptide of any one of the preceding claims, wherein the X1 residue is or comprises a chemical modification and / or a non-canonical serine.

43. The peptide of claim 42, wherein the chemical modification and / or non-canonical serine is or comprises N-methylserine (NMe-Ser).

44. The peptide of claim 42, wherein the chemical modification and / or non-canonical serine is or comprises Cα-methyl-serine.

45. The peptide of claim 42, wherein the chemical modification and / or non-canonical serine is or comprises beta-serine (beta-Ser).

46. The peptide of claim 42, wherein the chemical modification and / or non-canonical serine is or comprises a fluorinated serine, optionally difluoromethane serine or trifluoromethane serine.

47. The peptide of claim 42, wherein the chemical modification and / or non-canonical serine is or comprises beta-dimethyl-serine (beta / beta-serine).

48. The peptide of claim 42, wherein the chemical modification and / or non-canonical serine is or comprises a benzyl-modified serine or a toluene-modified serine (benzyl-serine).

49. The peptide of any one of the preceding claims, wherein the Q1 glutamine is or comprises N- methylglutamine (NMe-Gln).

50. The peptide of any one of claims 1-48, wherein the Q1glutamine is or comprises homoglutamine (homo-Gln).

51. The peptide of any one of claims 1-48, wherein the Q1glutamine is or comprises beta-glutamine (beta-Gln). 113 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 52. The peptide of any one of the preceding claims, wherein the one or more modifications comprises one or more chemical modifications that reduces and / or ablates protease degradation and / or peptidase cleavage relative to a peptide lacking the one or more chemical modifications.

53. The peptide of claim 52, wherein the one or more chemical modifications comprises a chemical modification within and / or conjugated to the peptide bond between the F1 and Q1 residues, the Q1 and X1 residues, the X1 and E1 residues, and / or the E1 residue and one or more residues at position R2.

54. The peptide of claim 52 or 53, wherein the one or more chemical modifications reduces and / or protects against protease and / or peptidase activity and / or peptide bond cleavage between the F1 and Q1residues, the Q1and X1residues, the X1and E1residues, and / or the E1residue one or more residues at position R2.

55. The peptide of any one of claims 52-54, wherein the one or more chemical modifications reduces and / or protects against dicarboxypeptidase activity and / or cleavage.

56. The peptide of claim 53, wherein the one or more chemical modifications is within and / or conjugated to the peptide bond between the F1and Q1residues and / or the Q1and X1residues.

57. The peptide of claim 55, wherein the one or more chemical modifications comprises a tertiary amine, optionally comprising a methyl group.

58. The peptide of any one of the preceding claims, wherein the one or more modifications increases a half-life of the peptide, optionally a serum half-life, and further optionally a serum half-life as measured in humans and / or as measured in dogs, and / or as measured in a companion animal.

59. The peptide of any one of the preceding claims, wherein the one or more modifications comprises one or more amino acids forming a contiguous isopeptide bond with the carboxy-terminus of the E1residue at R2.

60. The peptide of claim 59, wherein R2comprises or consists of an amino acid sequence selected from SEQ ID NO: 14 (EQQQTEDELQDK), SEQ ID NO: 15 (EQQQTEDELQD), SEQ ID NO: 16 (EQQQTEDEL), SEQ ID NO: 17 (EQQQTEDE), SEQ ID NO: 18 (EQQQTED), SEQ ID NO: 19 (EQQQTE), SEQ ID NO: 20 (EQQQT), SEQ ID NO: 21 (EQQQ), EQQ, EQ, E, and an amino acid sequence having one or more substitutions, deletions, of insertions thereof. 114 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 61. The peptide of any one of the preceding claims, wherein the peptide comprises or consists of about or at least about 4 amino acids to about or at least about 50 amino acids.

62. The peptide of claim 61, wherein the peptide comprises or consists of about or at least about 4 amino acids, about or at least about 5 amino acids, about or at least about 6 amino acids, about or at least about 7 amino acids, about or at least about 8 amino acids, about or at least about 9 amino acids, about or at least about 10 amino acids, about or at least about 11 amino acids, about or at least about 12 amino acids, about or at least about 13 amino acids, about or at least about 14 amino acids, about or at least about 15 amino acids, about or at least about 16 amino acids, about or at least about 17 amino acids, about or at least about 18 amino acids, about or at least about 19 amino acids, about or at least about 20 amino acids, about or at least about 25 amino acids, about or at least about 30 amino acids, about or at least about 35 amino acids, about or at least about 40 amino acids, about or at least about 45 amino acids, or about or at least about 50 amino acids.

63. The peptide of any one of the preceding claims, wherein the peptide is or comprises an amino acid sequence selected from SEQ ID NO: 1 (FQSE), SEQ ID NO: 2 (FQSEE), SEQ ID NO: 3 (FQSEEQ), SEQ ID NO: 4 (FQSEEQQ), SEQ ID NO: 5 (FQSEEQQQ), SEQ ID NO: 6 (FQSEEQQQT), SEQ ID NO: 7 (FQSEEQQQTE), SEQ ID NO: 8 (FQSEEQQQTED), SEQ ID NO: 9 (FQSEEQQQTEDE), SEQ ID NO: 10 (FQSEEQQQTEDEL), SEQ ID NO: 11 (FQSEEQQQTEDELQD), SEQ ID NO: 12 (FQSEEQQQTEDELQDK), and SEQ ID NO: 13 (ESQF).

64. The peptide of any one of the preceding claims, wherein the peptide is a component of a fusion protein.

65. The peptide of claim 64, wherein the fusion protein comprises one or more moieties fused to the peptide via a covalent bond to the N-terminus, C-terminus, and / or internally, optionally via an isopeptide bond.

66. The peptide of claim 65, wherein the one or more moieties increases the half-life of the peptide.

67. The peptide of claim 65 or 66, wherein the one or more moieties is or comprise an antibody Fc domain (IgG, IgG1, IgG2, IgG3, IgG4), albumin (e.g., human serum albumin), transferrin, polyethylene glycol (PEG), elastin, extended recombinant polypeptide (XTEN), elastin-like peptide (ELP), glycine- 115 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 rich homo-amino-acid polymer (HAP), proline / alanine / serine (PAS) repeats, artificial gelatin-like protein (GLK), and / or C-terminal peptide (CTP) of human chorionic gonadotropin β-subunit.

68. A peptide comprising an amino acid sequence of SEQ ID NO: 1 (FQSE), wherein the amino-terminus is acetylated, and each residue of SEQ ID NO: 1 comprises a D-form amino acid.

69. A peptide comprising an amino acid sequence of SEQ ID NO: 1 (FQSE), wherein the amino-terminus is acetylated, and the serine of SEQ ID NO: 1 comprises a D-serine residue.

70. A peptide comprising an amino acid sequence of SEQ ID NO: 1 (FQSE), wherein the amino-terminus is acetylated, and the glutamine of SEQ ID NO: 1 comprises a D-glutamine residue.

71. A peptide comprising an amino acid sequence of SEQ ID NO: 1 (FQSE), wherein the amino-terminus is acetylated, and the serine of SEQ ID NO: 1 comprises a beta-serine residue.

72. A peptide comprising an amino acid sequence of SEQ ID NO: 22 (FQTE), wherein the amino- terminus is acetylated, and the threonine of SEQ ID NO: 22 comprises a D-threonine residue.

73. A peptide comprising an amino acid sequence of SEQ ID NO: 13 (ESQF), wherein each of the residues of SEQ ID NO: 13 comprises a D-form amino acid.

74. A pharmaceutical composition comprising the peptide of any one of claims 1-72 and one or more pharmaceutically acceptable excipients and / or one or more delivery vehicles.

75. The pharmaceutical composition of claim 74, wherein the one or more pharmaceutically acceptable excipients comprises one or more of water, bicarbonate, carbonate, acetate buffer, citrate buffer, phosphate buffer, ethanol, propylene glycol (PEG, PEG 600), glycerin, sodium chloride, sodium gluconate, sodium acetate, potassium chloride, magnesium chloride, dextrose, dextran, DMSO, serum albumin (human serum albumin), phosphate buffered saline (PBS), cell media, Dulbecco’s Modified Eagle Medium (DMEM), alpha modified Minimal Essential Medium (alpha MEM), Roswell Park Memorial Institute Media 1640 (RPMI Media 1640), HBSS, Ringer’s solution, PLASMA-LYTE, 1,2-propanediol, isopropanol, glycerol, sorbitol, trehalose, creatine, isoleucine, maltose, sucrose, starch, glucose, lactose, sucrose, gelatin, lipid, arginine, glycine, polysaccharide, cyclodextrin, chitosan, cellulose, alginate, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, and combinations thereof. 116 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 76. The pharmaceutical composition of claim 74 or 75, wherein the more pharmaceutically acceptable excipients comprises 5% sodium bicarbonate (NaHCO3).

77. The pharmaceutical composition of any one of claims 74-76, wherein the one or more delivery vehicles comprises a liposome, nanoparticle, and / or dendrimer.

78. The pharmaceutical composition of any one of claims 74-77, wherein the one or more delivery vehicles increases the ability of the peptide to cross the blood-brain barrier.

79. The pharmaceutical composition of any one of claims 74-78, wherein the pharmaceutical composition is formulated into a solution, suspension, gel, emulsion, drop, tablet, chewable tablet, pill, pellet, capsule, capsule containing liquid, powder, granule, sustained-release formulation, cream, paste, ointment, transdermal delivery patch, implant, aerosol, and / or spray.

80. The pharmaceutical composition of any one of claims 74-79, wherein the pharmaceutical composition is formulated into one or more unit doses.

81. The pharmaceutical composition of claim 80, wherein the one or more unit doses comprise a mass of about or at least about 0.01 mg to about or at least about 5,000 mg.

82. The pharmaceutical composition of any one of claims 74-81, wherein the pharmaceutical composition is contained within a syringe, autoinjector, pump, patch, nebulizer, and / or capsule.

83. The pharmaceutical composition of any one of claims 74-82, wherein the pharmaceutical composition is suitable for parenteral, oromucosal, intravenous, intranasal, oral, intramuscular, subcutaneous, pulmonary, transdermal, topical, intracranial, intraperitoneal, and / or intrathecal administration.

84. A method of treating and / or ameliorating a psychological, behavioral, and / or cognitive disorder in a subject in need thereof comprising administering to the subject a peptide of any one of claims 1-73 and / or a pharmaceutical composition of any one of claims 74-83.

85. The method of claim 84, wherein the psychological, behavioral, and / or cognitive disorder comprises one or more of a mood disorder, anxiety, generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment- resistant depression (TRD), postpartum depression (PPD), bipolar disorder, bipolar depression, 117 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 schizophrenia, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and stress-related disorders.

86. The method of claim 85, wherein the stress-related disorder comprises conditions and / or behaviors found in humans and / or non-human animals, comprising separation anxiety, social anxiety, noise anxiety, trembling, hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior.

87. The method of claim 84, wherein the psychological, behavioral, and / or cognitive disorder comprises anxiety.

88. The method of claim 84, wherein the psychological, behavioral, and / or cognitive disorder comprises depression.

89. The method of claim 84, wherein the psychological, behavioral, and / or cognitive disorder comprises a stress-related disorder.

90. The method of any one of claims 84-89, wherein the peptide acts through an interaction with and / or modulation of one or more GABAA receptors, voltage-gated calcium channels (VGCC), NMDA receptors, thrombospondin proteins (subtypes 1-4), Neurexin-1a protein, scaffolding protein LRP1, dopamine receptors (D1-5), serotonin receptors, glutamate receptors, and acetylcholine receptors.

91. The method of claim 90, wherein the interaction and / or activation is via receptor-mediated binding.

92. The method of claim 90 or 91, wherein the peptide acts through an interaction with and / or modulation of one or more GABAAreceptors.

93. The method of claim 92, wherein the GABAA receptors comprise one or more isoforms selected from α1β3γ2S, α2β3γ2S, α3β3γ2S, α4β3γ2S, α5β3γ2S, α6β3γ2S, α1β2γ2S, α4β3δ, α6β3δ, α1β2, α1β3, α1β2δ, α4β2δ, α3β3θ, and α3β3ε.

94. The method of any one of claims 90-93, wherein the interaction with and / or modulation of the one or more GABAA receptors comprises binding at a site that is distinct from a binding site of one or more GABAAreceptor ligands selected from isoguvacine, salicylidene salicylhydrazide, bretazenil, SL651498, MK0343, THDOC, TB21007, gaboxadol, FGIN-1-27, and allopregnanolone. 118 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 95. The method of any one of claims 90-94, wherein the interaction with and / or modulation of the one or more GABAA receptors comprises binding at a benzodiazepine binding site.

96. The method of claim 95, wherein the binding at the benzodiazepine binding site increases the affinity of one or more GABAAreceptors to gamma-aminobutyric acid (GABA).

97. The method of any one of claims 90-96, wherein the interaction with and / or modulation of the one or more GABAA receptors comprises binding at an α-β binding site.

98. The method of any one of claims 90-97, wherein the interaction with and / or modulation of the one or more GABAA receptors comprises binding at an α-γ binding site.

99. The method of any one of claims 90-98, wherein the interaction with and / or modulation of the one or more GABAAreceptors comprises binding at both an α-β binding site and an α-γ binding site.

100. The method of any one of claims 90-99, wherein the interaction with and / or modulation of the one or more GABAAreceptors comprises allosteric regulation.

101. The method of claim 90 or 91, wherein the peptide acts through an interaction with and / or modulation of one or more voltage-dependent calcium channels.

102. The method of claim 101, wherein the one or more voltage-dependent calcium channels comprise a L-type, N-type, P / Q type, and / or R-type.

103. The method of claim 101 or 102, wherein the interaction with and / or modulation of the one or more voltage-dependent calcium channels comprises binding, or competing with binding to, an α2δ calcium channel subunit, optionally one or more of the α2δ calcium channel subunit isoforms (α2δ1- 4).

104. The method of claim 103, wherein the peptide functions as an α2δ-2 modulator.

105. The method of claim 103, wherein the peptide does not interact with and / or modulate a function of α2δ-1.

106. The method of claim 103, wherein the binding, or competing with binding to, is at a binding site shared with gabapentin.

107. The method of claim 106, wherein the binding, or competing with binding to, comprises one or more gabapentin binding sites in the α2δ-2 calcium channel isoform. 119 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 108. The method of claim 107, wherein the binding, or competing with binding to, is substantially localized to brain tissue.

109. The method of claim 106, wherein the binding, or competing with binding to, does not comprise one or more gabapentin binding sites in the α2δ-1 calcium channel isoform.

110. The method of any one of claims 106-109, wherein the binding, or competing with binding to, is not substantially localized to cardiac tissue.

111. The method of any one of claims 84-110, wherein the peptide decreases presynaptic α2δ-2-VGCC representation.

112. The method of any one of claims 84-111, wherein the peptide reduces GABAA receptor level.

113. The method of any one of claims 84-112, wherein the peptide enhances AMPA receptor postsynaptic level.

114. The method of any one of claims 84-112, wherein the peptide induces long-term potentiation (LTP).

115. The method of any one of claims 84-112, wherein the peptide supports synaptogenesis and axon regeneration.

116. The method of any one of claims 84-115, wherein the peptide does not bind, or does not substantially overlap with a binding site thereof, of pregnenolone sulfate (PREGS).

117. The method of any one of claims 84-116, wherein the peptide does not bind, or does not substantially overlap with a binding site thereof, of one or more GABAAreceptor binding sites shared with diazepam, muscimol, bicuculline, gabazine, and / or CGS-9895.

118. The method of any one of claims 84-117, wherein the peptide does not bind, or does not substantially overlap with a binding site thereof, of one or more binding sites for one or more ligands selected from neurotransmitter receptor ligands; dopamine receptors ligands (haloperidol, sulpiride, spiperone, 7- OH-DPAT); serotonin receptors ligands (ketanserin); acetylcholine receptor ligands (nicotine); and glutamate receptor ligands (glutamate, glycine, Ro-256981, LY-354740, MK-801, spermine, arkain).

119. The method of any one of claims 84-118, wherein the peptide acts through an interaction with and / or modulation of one or more receptors with an affinity of less than about 1 nM, less than about 5 nM, less than about 10 nM, less than about 50 nM, less than about 0.1 µM, less than about 0.5 µM, less 120 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 than about 1.0 µM, less than about 1.5 µM, less than about 2.0 µM, less than about 2.5 µM, less than about 5.0 µM, less than about 10 µM, less than about 15 µM, less than about 20 µM, less than about 25 µM, less than about 50 µM, or less than about 100 µM.

120. The method of any one of claims 84-119, wherein the peptide exhibits a half-life of about or at least about 0.5 hours, about or at least about 1 hour, about or at least about 2 hours, about or at least about 3 hours, about or at least about 4 hours, about or at least about 5 hours, about or at least about 6 hours, about or at least about 7 hours, about or at least about 8 hours, about or at least about 9 hours, about or at least about 10 hours, about or at least about 12 hours, about or at least about 14 hours, about or at least about 16 hours, about or at least about 18 hours, about or at least about 20 hours, about or at least about 25 hours, about or at least about 30 hours, about or at least about 35 hours, about or at least about 40 hours, about or at least about 45 hours, about or at least about 50 hours, about or at least about 60 hours, about or at least about 70 hours, about or at least about 80 hours, about or at least about 90 hours, about or at least about 100 hours, about or at least about 120 hours, about or at least about 140 hours, about or at least about 160 hours, about or at least about 180 hours, about or at least about 200 hours, about or at least about 220 hours, about or at least about 240 hours, about or at least about 260 hours, about or at least about 280 hours, or about or at least about 300 hours.

121. The method of claim 120, wherein the half-life is a serum half-life.

122. The method of claim 120 or 121, wherein the half-life is a half-life as measured in humans.

123. The method of claim 120 or 121, wherein the half-life is a half-life as measured in dogs.

124. The method of any one of claims 84-123, wherein the administration results in a change in the intensity of and / or occurrence of anxiolytic-like behavior, Anxiety Index (AI), depressive behavior, deficits associated with schizophrenia, intensity of one or more sleep disorders or changes in sleep, appetite fluctuation, body weight fluctuation, fatigue, feelings of low mood or sadness, hopelessness, helplessness, low self-esteem, tearfulness, guilt, irritability, intolerance, restlessness, lack of motivation, difficulty in decision-making, cognitive dysfunction, difficulty concentrating, persistent aches and pains, exit frustration, social panic, redirected frustration, reactive communication, immediate frustration, noise sensitivity, separation anxiety, social anxiety, noise anxiety, trembling, 121 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior.

125. The method of claim 124, wherein the change is a reduction, amelioration, or ablation.

126. The method of any one of claims 84-125, further comprising measuring a change in one or more of anxiolytic-like behavior, Anxiety Index (AI), depressive behavior, deficits associated with schizophrenia, intensity of one or more sleep disorders or changes in sleep, appetite fluctuation, body weight fluctuation, fatigue, feelings of low mood or sadness, hopelessness, helplessness, low self-esteem, tearfulness, guilt, irritability, intolerance, restlessness, lack of motivation, difficulty in decision-making, cognitive dysfunction, difficulty concentrating, persistent aches and pains, exit frustration, social panic, redirected frustration, reactive communication, immediate frustration, noise sensitivity, separation anxiety, social anxiety, noise anxiety, trembling, hiding attempts, compulsive licking and grooming, self-injuring, diarrhea, vomiting, reduced activity, and / or destructive behavior.

127. The method of claim 126, wherein the measuring comprises using a Hamilton Anxiety Scale (HAM- A), a Beck Anxiety Inventory (BAI), a Beck Depression Inventory (BDI-II), an Anxiety Symptoms Questionnaire (ASQ), a Hamilton Rating Scale for Depression (HAM-D), a Montgomery Asberg Depression Rating Scale (MADRS), a Clinical Global Impression-Severity (CGI-S), using one of more diagnostic tests as outlined in the Diagnostic and Statistical Manual of Mental Disorders 4thEdition (DSM-IV), 5thEdition (DSM-V), and / or DSM-5TR (2022), one or more neuropsychological tests comprising saccadic eye movements, saccadic reaction time, saccadic peak velocity, and saccadic inaccuracy, smooth pursuit eye movements, adaptive tracking, body sway, pupil size, visual analogue scale (VAS) to assess mood, alertness, and / or calmness, cognitive assessment VVLT (Learning and Immediate Recall, Delayed Recall, and Delayed Recognition), and / or qEEG (quantitative electroencephalogram).

128. The method of any one of claims 124-126, wherein the change occurs within about or at least about 1 day to about 2 days, within about or at least about 2 days to about 4 days, within about or at least about 4 days to about 6 days, within about or at least about 6 days to about 8 days, within about or at least about 8 days to about 10 days, within about or at least about 10 day to about 20 days, within about or at least about 20 day to about 40 days, or within about or at least about 40 day to about 60 days from an initial administration. 122 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 129. The method of any one of claims 84-128, wherein the method does not substantially result in one or more adverse events in comparison to a subject that was not administered the peptide.

130. The method of claim 129, wherein the one or more adverse events is or comprises drowsiness, sedation, trouble sleeping (insomnia, restlessness), appetite fluctuation (suppressed appetite, increased appetite), binge eating, nausea, diarrhea, constipation, loss of muscle tone, memory issues (memory loss, false memories), psychosis, confusion, peptide intolerance, and / or peptide dependence.

131. The method of any one of claims 84-130, wherein the administering is performed by parenteral, oromucosal, intravenous, intranasal, oral, intramuscular, subcutaneous, oral, pulmonary, transdermal, topical, intracranial, intraperitoneal, and / or intrathecal routes.

132. The method of claim 131, wherein the administering is intranasal and / or oromucosal.

133. The method of claim 131, wherein the administering is oral.

134. The method of claim 131, wherein the administering is intravenous.

135. The method of any one of claims 84-134, wherein the administering comprises providing one or more unit doses of the peptide and / or pharmaceutical compositions.

136. The method of claim 135, wherein the one or more unit doses comprise a total mass of the peptide of about or at least about 0.01 mg to about or at least about 5,000 mg.

137. The method of claim 136, wherein the one or more unit doses comprise a total mass of the peptide of about or at least about 0.01 mg, about or at least about 0.1 mg, about or at least about 0.5 mg, about or at least about 1.0 mg, about or at least about 5.0 mg, about or at least about 10 mg, about or at least about 15 mg, about or at least about 25 mg, about or at least about 50 mg, about or at least about 100 mg, about or at least about 150 mg, about or at least about 200 mg, about or at least about 300 mg, about or at least about 400 mg, about or at least about 500 mg, about or at least about 1,000 mg, about or at least about 1,500 mg, about or at least about 2,000 mg, about or at least about 2,500 mg, about or at least about 3,000 mg, about or at least about 3,500 mg, about or at least about 4,000 mg, about or at least about 4,500 mg, or about or at least about 5,000 mg.

138. The method of any one of claims 84-137, wherein the administering comprises providing a mass range of peptide of about 0.001 mg / kg to about 200 mg / kg body weight, about 0.01 mg / kg to about 123 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 100 mg / kg body weight, about 0.01 mg / kg to about 50 mg / kg body weight, about 0.01 mg / kg to about 40 mg / kg body weight, about 0.01 mg / kg to about 30 mg / kg body weight, about 0.01 mg / kg to about 20 mg / kg body weight, about 0.01 mg / kg to about 5 mg / kg body weight, about 0.01 mg / kg to about 10 mg / kg body weight, about 0.1 mg / kg to about 10 mg / kg body weight, about 0.1 mg / kg to about 20 mg / kg body weight, about 0.1 mg / kg to about 30 mg / kg body weight, about 0.1 mg / kg to about 40 mg / kg body weight, about 0.1 mg / kg to about 50 mg / kg body weight.

139. The method of any one of claims 84-138, wherein the administering comprises a dosage frequency of about or at least about thrice daily, about or at least about twice daily, about or at least about once daily, about or at least about every 2 days, about or at least about every 3 days, about or at least about every 4 days, about or at least about every 5 days, about or at least about every 6 days, about or at least about weekly, about or at least about biweekly, about or at least about once every three weeks, or about or at least about monthly.

140. The method of any one of claims 84-139, further comprising administering one or more additional therapeutic agents.

141. The method of claim 140, wherein the one or more additional therapeutic agents comprises a therapeutic agent for an anxiety disorder, a depression disorder, a stress-related disorder, a bipolar disorder, and / or a mood disorder.

142. The method of claim 140 or 141, wherein the one or more additional therapeutic agents comprises one or more of benzodiazepines selected from alprazolam (XANAX), dexmedetomidine (SILEO), clonazepam (KLONOPIN), diazepam (VALIUM), lorazepam (ATIVAN), oxazepam (SERAX), and chlordiazepoxide (librium); beta blockers selected from propranolol (INDERAL) and atenolol (TENORMIN); tricyclic antidepressants selected from imipramine (TOFRANIL), desipramine (NORPRAMIN, PERTOFRANE), nortriptyline (AVENTYL or PAMELOR), amitriptyline (ELAVIL), doxepin (SINEQUAN or ADAPIN), clomipramine (ANAFRANIL); monoamine oxidase inhibitors (MAOIs) selected from phenelzine (NARDIL), tranylcypromine (PARNATE); selective serotonin reuptake inhibitors (SSRIs) selected from fluoxetine (PROZAC), fluvoxamine (LUVOX), sertraline (ZOLOFT), paroxetine (PAXIL), escitalopram oxalate (LEXAPRO), citalopram (CELEXA); serotonin- norepinephrine reuptake inhibitors (SNRIs) selected from venlafaxine (EFFEXOR), venlafaxine extended release (EFFEXOR XR) and duloxetine (CYMBALTA); mild tranquilizers such as buspirone 124 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 (BUSPAR); and anticonvulsants selected from valproate (DEPAKOTE), pregabalin (LYRICA), and gabapentin (NEURONTIN), CYMBALTA oral, LEXAPRO oral, EFFEXOR XR oral, ZOLOFT oral, CELEXA oral, TRAZODONE oral, PROZAC oral, WELLBUTRIN XL oral, CITALOPRAM oral, PRISTIQ oral, AMITRIPTYLINE oral, SAVELLA oral, VIIBRYD oral, PAXIL CR oral, WELLBUTRIN oral, PAXIL oral, SERTRALINE oral, REMERON oral, NORTRIPTYLINE oral, VENLAFAXINE oral, FLUOXETINE oral, BUPROPION HCL oral, MIRTAZAPINE oral, RITALIN oral, PAROXETINE oral, WELLBUTRIN SR oral, DOXEPIN oral, METHYLPHENIDATE oral, SYMBYAX oral, ESCITALOPRAM OXALATE oral, PAMELOR oral, IMIPRAMINE oral, BRINTELLIX oral, DULOXETINE oral, NARDIL oral, FETZIMA oral, EMSAM TRANSDERMAL, PARNATE oral, PEXEVA oral, BRISDELLE oral, CLOMIPRAMINE oral, ANAFRANIL oral, TOFRANIL oral, FLUVOXAMINE oral, ZYBAN oral, DESIPRAMINE oral, SARAFEM oral, PROZAC WEEKLY oral, APLENZIN oral, METHYLIN oral, NEFAZODONE oral, QUILLIVANT XR oral, TOFRANIL-PM oral, NORPRAMIN oral, REMERON SOLTAB oral, BUPROPION HBR oral, OLEPTRO ER oral, DESVENLAFAXINE SUCCINATE oral, BUPROBAN oral, IMIPRAMINE PAMOATE oral, VILAZODONE oral, MILNACIPRAN oral, PAROXETINE MESYLATE oral, SURMONTIL oral, MAPROTILINE oral, PROTRIPTYLINE oral, PHENELZINE oral, MARPLAN oral, OLANZAPINE- FLUOXETINE oral, TRANYLCYPROMINE oral, SELEGILINE TRANSDERMAL, AMOXAPINE oral, FORFIVO XL oral, ISOCARBOXAZID oral, DESVENLAFAXINE oral, KHEDEZLA oral, LEVOMILNACIPRAN oral, VORTIOXETINE oral, DESVENLAFAXINE FUMARATE oral, bestatine, comostate amylase, leupeptin, aprotinin, bacitracin, amastatine, boroleucine, puromycin, a bile salt, and a fusidic acid (disodium ethylene-diaminetetraacetate).

143. The method of claim 142, wherein the one or more additional therapeutic agents comprises dexmedetomidine (SILEO).

144. The method of any one of claims 84-143, wherein the subject is human.

145. A method of treating and / or ameliorating a mood disorder in a subject in need thereof comprising administering to the subject a peptide comprising an amino acid sequence of SEQ ID NO: 1 (FQSE), optionally wherein the amino-terminus is acetylated, and wherein the serine of SEQ ID NO: 1 comprises a D-serine residue.

146. The method of claim 145, wherein the mood disorder is a depression disorder. 125 DB1 / 149168710.1Attorney Docket No.: LACT-003PC / 121851-5003 147. The method of claim 145, wherein the mood disorder is an anxiety disorder. 126 DB1 / 149168710.1

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