peptide

Abstract

A compound comprising a sequence of at least three amino acids or a variant or derivative thereof, wherein the sequence of three amino acids comprises Ser-Arg-Ala, with the proviso that the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln.

Description

[Technical Field]

[0001] The present invention relates to peptides that are MAP kinase inhibitors and uses thereof.

[0002] More particularly, the present invention relates to novel synthetic peptides useful as inhibitors of p38α mitogen-activated protein kinase (p38α MAP kinase or MAPK14). Accordingly, the present invention relates to uses of the novel peptides, therapeutic methods related thereto, and methods for producing such novel peptides. [Background technology]

[0003] p38α MAP kinase is involved in the regulation of inflammatory cell signaling and plays a central role in the control of inflammatory cytokine production.

[0004] Therefore, the novel peptide of the present invention has potential as a therapeutic agent for inflammatory diseases including cancer and autoimmune diseases.

[0005] p38 kinase controls the production of key inflammatory mediators by cells of the innate immune system, including TNFα, IL-1β, and COX-2.

[0006] Because the MAP kinase p38α plays a central role in the inflammatory signaling cascade, its inhibition is thought to play a beneficial role in a variety of human and animal diseases, particularly inflammatory and autoimmune diseases and cancer. This includes, but is not limited to, inflammatory skin diseases such as atopic dermatitis, psoriasis, and acne vulgaris. Activation of p38α MAP kinase may also play a fundamental role in other inflammation-related diseases, such as chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, atherosclerosis, cancer, burns, scar formation, and rheumatoid arthritis.

[0007] European Patent No. 3033094 describes a compound containing the amino acid sequence HKSRALLIFQKIMWLRRQ, which binds to p38α MAP kinase. This compound is useful for binding to and inhibiting p38α MAP kinase, and is useful as a research tool in drug discovery and medicine, particularly for the treatment of inflammatory and autoimmune diseases. Summary of the Invention

[0008] Thus, according to a first aspect of the present invention there is provided a compound comprising at least a sequence of amino acids, wherein the sequence of three amino acids is not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln and variants and derivatives thereof.

[0009] According to a further aspect of the present invention there is provided a compound comprising a sequence of at least 7 amino acids comprising Ser-Arg-Ala-AB-Ile-Phe, wherein A and B may be the same or different and may be any amino acid moiety, and variants and derivatives thereof with the proviso that the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln.

[0010] According to a further aspect of the invention, the compound is

[18] His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg;

[18]

[10] and

[18] and variants and derivatives thereof.

[0011] Unless otherwise specified, the IUB / IUPAC single-letter amino acid code is used herein, and amino acid sequences are presented in the conventional N- to C-terminal direction. Amino acids are typically L-amino acids, although some may be D-amino acids.

[0012] The peptides of the invention may also include variants, e.g., larger peptides with additional amino acids, in which case the peptides of the invention form only a portion of the variant peptide. The amino acids in the variant peptides are typically naturally occurring amino acids, including the 20 amino acids encoded by the genetic code, as well as natural amino acids such as hydroxyproline, selenomethionine, and carnitine. However, one or more of the altered amino acids may also be unnatural amino acids, such as allylaranine or diphenylalanine.

[0013] The novel peptides of the invention described herein are useful for binding to and inhibiting p38α MAP kinase and are useful as research tools, in drug discovery, and in human and veterinary medicine, particularly for the treatment or prevention of proliferative diseases (e.g., cancer), autoimmune diseases, inflammatory diseases, metabolic diseases, and neurological diseases, which may occur in a variety of mammals, including humans and dogs. Advantageously, compounds are provided that are selective for p38α MAP kinase and do not substantially bind to or inhibit other protein kinases.

[0014] The variants and derivatives described herein may comprise any of the described [3], [7],

[10] or

[18] amino acid sequences as contiguous amino acid sequences.

[0015] Typically, when the compound consists of a peptide, its molecular weight will be less than 30,000 daltons, preferably less than 25,000 daltons, more preferably less than 20,000 daltons. Typically, when the compound comprises a peptide moiety linked to another moiety, as described below, the compound will typically have a molecular weight of between 10,000 and 100,000 daltons, for example between 20,000 and 80,000 daltons, for example between 20,000 and 50,000 daltons.

[0016] The amino acid sequence of the compound is a peptide, and the term includes compounds having amino acid residues (H-Cα-[side chain]) that may be linked by peptide (—CO—NH—) or non-peptide bonds.

[0017] Peptides can be synthesized by the Fmoc-polyamide mode of solid-phase peptide synthesis as disclosed by Lu et al. (1981) J. Org. Chem. 46, 3433, incorporated herein by reference. Reagents for peptide synthesis are readily available commercially.

[0018] Compound purification can be achieved by any one or a combination of techniques such as size exclusion chromatography, ion exchange chromatography, and (mainly) reversed-phase high performance liquid chromatography. Analysis of peptides can be achieved using thin layer chromatography, reversed-phase high performance liquid chromatography, amino acid analysis after acid hydrolysis, and fast atom bombardment (FAB) mass spectrometry.

[0019] According to one aspect of the invention the compound comprises the amino acids Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His; and variants and derivatives thereof.

[0020] According to another aspect of the invention, the compound comprises the amino acids His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg; and variants and derivatives thereof.

[0021] According to another aspect of the invention, the compound comprises the amino acids Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile; and variants and derivatives thereof.

[0022] According to another aspect of the invention, the compound comprises the amino acids Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala; and variants and derivatives thereof.

[0023] The compounds of the present invention include variants of the above amino acid sequences or portions thereof having one to five amino acid changes, with the proviso that the amino acid sequence includes the sequence of 3 amino acids Ser-Arg-Ala or the sequence of 7 amino acids Ser-Arg-Ala-AB-Ile-Phe-Phe, in which A and B are as defined herein; with the proviso that the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln.

[0024] Here, the compound binds to the p38α MAP kinase.

[0025] The compounds of the present invention may be N-acetylated, and some or all of the amino acids in the peptide may be N-acetylated.

[0026] The compound may contain at least one D-amino acid residue, for example, 1, 2, 3, 4, 5, 6, 7, or 8 D-amino acids. Typically, the compound may contain 0, 1, 2, or 3 D-amino acids. The presence of D-amino acids in the compound is useful for preventing the compound from being decomposed by proteases. Another method for making peptides resistant to proteolysis is to block amino acid residues at the N-terminus and / or C-terminus. Thus, the N-terminus and / or C-terminus amino acid residues are blocked. Suitable blocking methods include acetylation of the N-terminus or incorporation of a pyroglutamic acid residue at the N-terminus.

[0027] Although it is preferred that the compounds are peptides as defined, the compounds may also include variants as defined herein in which the peptides of the invention are attached to other sites. Convenient sites for attaching peptides include polyethylene glycol (PEG) and peptide sequences such as TAT ​​and antennapedia, which facilitate delivery to cells.

[0028] PEGylation is a method well known to those skilled in the art in which a peptide or other compound is modified by covalently attaching one or more polyethylene glycol (PEG) molecules to the side chains of one or more amino acids. This is one of the most important molecular modification chemistry (MASC) techniques. Other MASC techniques can also be used. Such techniques can improve the pharmacodynamic properties of a compound, for example, by extending its serum half-life in vivo. PEG-peptide conjugates are formed by first activating the PEG moiety, which reacts and attaches to the compound. PEG moieties vary considerably in molecular weight and conformation, with early moieties (monofunctional PEG; mPEG) being linear with a molecular weight of 12 kDa or less, and later moieties having higher molecular weights. PEG2 is a recent innovation in PEG technology, in which a 30 kDa (or smaller) mPEG is attached to a lysine amino acid (although PEGylation can be extended to PEG addition to other amino acids) and then reacted further to form a branched structure that behaves like linear mPEG with a much higher molecular weight.

[0029] Potential benefits of PEGylation of compounds include reduced renal clearance, which may result in more sustained adsorption after subcutaneous administration for some products, and limited distribution, leading to more consistent plasma concentrations and therefore potentially enhanced clinical efficacy. Further potential benefits include reduced immunogenicity and toxicity of therapeutic compounds.

[0030] There are various approaches to the design and synthesis of mutant peptide compounds that do not contain amide bonds. In one approach, one or more amide bonds can be replaced essentially equivalently with a variety of chemical functional groups.

[0031] Retroinverse peptide mimetics, in which the peptide bonds are reversed, can be synthesized using methods known in the art. This approach creates pseudopeptides that contain changes in the backbone rather than the orientation of the side chains. Retroinverse peptides, which contain NH-CO bonds instead of CO-NH peptide bonds, are more resistant to proteolysis.

[0032] Introducing cyclic moieties into mutant peptide-based scaffolds may be advantageous. The cyclic moieties restrict the conformational space of the peptide structure, which may lead to increased affinity of the peptide for p38α MAP kinase. The advantage of this strategy is that introducing cyclic moieties into the peptide reduces its susceptibility to cellular peptidases.

[0033] The compounds of the present invention are particularly useful because they are capable of binding to p38α MAP kinase. Conveniently, the enzyme can be fused to a polypeptide sequence such as GST and immobilized on a solid substrate.

[0034] Furthermore, the compounds of the present invention are particularly useful because they inhibit p38α MAP kinase. Inhibition of p38α MAP kinase can be determined as follows: Myelin basic protein (MBP) is a substrate for p38α MAP kinase and is phosphorylated in the presence of this enzyme and ATP. The phosphorylation event can be monitored using an antibody that recognizes phosphorylated serine or threonine residues or by measuring the incorporation of radiolabeled phosphate into the protein. Inhibition is measured by a decrease in MBP phosphorylation. The compounds of the present invention can inhibit the activation of p38α MAP kinase by MKK6.

[0035] A suitable method for determining binding to p38α MAP kinase is to use phage display technology. DNA encoding the peptide lead can be cloned into the M13 gplll phagemid vector, transformed into E. coli TG1 cells, and plated on 2% glucose, 2xTY, 100 μg / ml ampicillin plates. Colonies are grown for phage particle production as described in Scott & Smith (1990) Science 249, 386-390. For the assay, 1 μg of p38α MAP kinase is added to 100 μl of PBS in MaxiSorp PBS. TM Polystyrene plates (Nunc TMPlates were coated with 100 μl of phage supernatant per well (Fiberglass-coated 100-μL PBS, Fisher Scientific, Loughborough, UK) for 1 hour at room temperature, washed once with PBS, and blocked with 2% BSA in PBS for 1 hour at room temperature. 100 μl of phage supernatant was added per well and incubated for 1 hour at room temperature. Plates were washed four times with PBS / Tween 20 and twice with PBS. Horseradish peroxidase-conjugated (HRP) anti-M13 secondary antibody (GE Healthcare UK Ltd., Chalfont St. Giles, UK) was diluted 1:5000 in 2% BSA in PBS and incubated for 1 hour at room temperature, followed by washing as above. ELISA assays were performed as described in McGregor & Robins (2001) Anal. Biochem. 294, 108-117. The assay was developed with SureBlue TMB peroxidase substrate (Insight Biotechnology, Middlesex, UK) and read at 450 nm. Peptides bound to p38α MAP kinase are tested for specificity against biotinylated p38α MAP kinase and streptavidin, followed by β-galactosidase, BcIX, anti-FLAG M2 antibody, ovalbumin, and lysozyme coated at 0.5 μg onto streptavidin-coated plates (StreptaWell; Roche Diagnostics Ltd., Burgess Hill, UK) using the same ELISA conditions described above. This method can be used to establish direct, specific peptide binding to p38α MAP kinase, as indicated by an increase in colorimetric signal above background control levels.

[0036] It is particularly preferred if the compound competes for binding to p38α MAP kinase. Whether a compound is capable of competing for binding to p38α MAP kinase can be determined as follows.

[0037] N-acetylated peptides, which may be fluorescently labeled (i.e., with a fluorophore), bind to p38α MAP kinase. Displacement of this peptide by a compound indicates binding of the compound to p38α MAP kinase and can be measured by fluorescence polarization. Fluorescence polarization is an empirical fluorescence detection technique that measures the vertical and horizontal components of fluorescence emission resulting from plane-polarized excitation. The polarization value (measured in mP) of a fluorescently labeled complex is inversely proportional to the molecular rotation rate of that complex. Because molecular rotation is inversely proportional to molecular volume, a fluorescently labeled peptide will have a higher degree of polarization when it interacts with a molecule large enough to slow its rotation rate (in this case, p38α MAP kinase). Thus, the magnitude of the polarization signal can be used to quantitatively determine the degree of fluorescently labeled peptide binding without the need for filtration or washing separation steps. The principle of this displacement binding assay is competition between a fluorescently labeled peptide and an unlabeled compound for binding to the docking site of p38α MAP kinase using fluorescence polarization detection. Binding of unlabeled compounds displaces the fluorescently labeled peptide, resulting in a loss of mP signal. Loss of signal indicates displacement. A larger loss of signal indicates a larger displacement, whereas a smaller loss of signal indicates a smaller displacement. Any number of fluorescence polarization readers can be used to measure displacement.

[0038] Particularly preferred are compounds of the invention that bind to and inhibit p38α MAP kinase but do not substantially bind to and inhibit Jnnk, PKCd, p38b, AMPK, AurA, GK3b, RAF1, JNK3, VEGF, p38g, p38d, PKCb, PKCa, PDHK2, PDK1, MKK6, p27 KIP, Cdk2 KIP, Prak KIP, Chk1 KIP, Egfr KIP, Kdr KIP, EGF KIP, Zap 70 KIP, IGFR KIP, Src KIP, Fak KIP, Jak3 KIP, Akt CIRA, and Mek CCEK. Commercial services are available to determine whether a compound inhibits these or other protein kinases using standard methods, for example, Merck Millipore's Kinase Profiler. TM and version 54 of its Service Assay protocol.

[0039] The compounds of the present invention have an IC of >1 μM, more preferably >5 μM or >10 μM, against at least one, if not all, of the listed enzymes with substantially no binding. 50 It can have a value.

[0040] The compounds of the present invention have an IC 50 The compounds of the present invention may have an IC of less than 1 μM as measured by the following methodology. 50 The IC may be less than 0.1 μM, preferably less than 0.05 μM, more preferably less than 0.01 μM, and even more preferably less than 0.001 μM. 50 is calculated by testing the degree of inhibition of p38α MAP kinase at a fixed concentration with increasing concentrations of a compound of the invention. Plotting on a logarithmic scale, with the degree of inhibition on the Y-axis and the peptide concentration on the X-axis, typically yields a sigmoidal curve ranging from 0% inhibition at 0 or the lowest concentration to 100% inhibition at the highest dose. The point at which 50% inhibition is achieved is designated the inhibitory concentration 50 or IC 50 and is used to establish the potency of a compound at a given concentration of enzyme.

[0041] The compounds of the present invention may exhibit selectivity for p38α MAP kinase, which is believed to be due in part to the fact that they bind to a site on p38α MAP kinase that is not present in other protein kinases, rather than the ATP-binding pocket. This site is believed to be conserved between human and canine p38α MAP kinase. Compounds that inhibit p38α MAP kinase by binding to an unusual, and perhaps unique, binding pocket offer a much greater chance of selectively inhibiting p38α MAP kinase, thus avoiding off-target side effects and toxicity.

[0042] According to a further aspect of the invention there is provided a method of inhibiting p38α MAP kinase, said method comprising contacting said kinase with a compound of the invention. Typically the method is carried out in vitro.

[0043] Thus, the compounds of the present invention may be useful as reagents for assaying p38α MAP kinase.

[0044] According to a further aspect of the present invention, there is provided a kit of parts for assaying p38α MAP kinase, said kit comprising a compound of the present invention and a substrate for p38α MAP kinase. Suitable substrates for p38α MAP kinase include myelin basic protein (MBP), MK2 / MAPKAPK2, MNK-1, PRAK, and MSK1. MBP is a preferred substrate.

[0045] The use of the compounds of the invention to inhibit p38α MAP kinase is also described.

[0046] Inhibition of p38α MAP kinase is known to be useful, particularly in the treatment of proliferative diseases (e.g., cancer), autoimmune diseases, inflammatory diseases, metabolic diseases, and neurological diseases. Thus, according to a further aspect of the present invention, there are provided compounds described herein for use in the manufacture of a medicament, e.g., for treating an individual. Thus, there are particularly provided compounds as described herein for use in the manufacture of a medicament for the treatment of proliferative diseases (e.g., cancer), autoimmune diseases, inflammatory diseases, metabolic diseases, and neurological diseases. The individual may be a human or an animal, such as a non-human mammal. Due to the amino acid sequence similarity (99.4% identity) to human p38α MAP kinase (MK14_HUMAN SEQ ID NO: 18) and canine p38α MAP kinase (MK14_CANFA SEQ ID NO: 19), the compound is particularly suitable for the treatment of humans and dogs. The compound may also be useful for the treatment of other animals that have p38α MAP kinases with substantial sequence similarity (e.g., 90% or greater identity) to the human enzyme sequence.

[0047] The compounds of the present invention can be used alone or in combination with other therapeutic compounds. Thus, according to a further aspect of the present invention, there are provided compositions comprising a compound of the present invention in combination with one or more other therapeutic compounds, such as an anti-inflammatory compound or an anti-infective compound (e.g., an antibacterial or antiviral compound) or an anti-proliferative compound.

[0048] The therapeutic composition of the present invention can contain pharmaceutically acceptable adjuvants, diluents or carriers.Additives and carriers must be "acceptable" in the sense that they are compatible with the compound and not harmful to its recipient.Appropriate pharmaceutical adjuvants, diluents or carriers can be selected as known in the art depending on the route of administration of the compound or composition and whether the compound or composition is for human or animal use.

[0049] The compounds of the present invention or therapeutic compositions thereof can be administered by any conventional method known in the art. Administration can consist of a single dose or multiple doses over a period of time.

[0050] Therapeutic compositions may be in unit dosage form containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a compound of the present invention as the active ingredient.

[0051] The compounds of the present invention are usually administered in the form of pharmaceutical preparations, optionally in the form of non-toxic organic or inorganic acid or base addition salts, in a pharmaceutically acceptable form, topically or orally, or by inhalation, or by any parenteral route. Depending on the disease and individual to be treated and the route of administration, the preparations can be administered in a variety of dosages.

[0052] Thus, the compounds of the invention or therapeutic compositions of the invention can be administered orally, bucally, nasally, ocularly, by inhalation, topically, rectally or sublingually, and are in the form of tablets, capsules, wafers, elixirs, solutions, sprays, gels or suspensions, which may contain flavorings or coloring agents, and which are immediate-release, delayed-release or controlled-release applications.

[0053] Such tablets may contain additives such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and glycine, disintegrants such as starch (preferably corn starch, potato starch, or tapioca starch), disintegrants such as sodium starch glycolate, croscarmellose sodium, and certain complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia, etc. Furthermore, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included.

[0054] Similar solid compositions can also be used as fillers for gelatin capsules.Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols.For aqueous suspensions and / or elixirs, the compound can be combined with various sweeteners or flavorings, colorings or dyes, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0055] The compounds or therapeutic compositions of the present invention can also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intrathoracically, intracranially, intramuscularly, subcutaneously, or intradermally, or by infusion techniques. They may be used in the form of a sterile aqueous solution containing other substances (e.g., sufficient salts or glucose to make the solution isotonic with blood). The aqueous solution should be suitably buffered (preferably pH 3-9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0056] Preparations suitable for parenteral administration include water and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the solution isotonic with the recipient's blood, as well as water and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The preparations may be presented in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored in a lyophilized (lyophilized) state, ready for use by simply adding a sterile liquid carrier, such as water for injection, immediately before use. Ready-to-use injection solutions and suspensions may be prepared from sterile powders, granules, or tablets of the type described above.

[0057] The compounds of the invention or therapeutic compositions of the invention may also be administered intranasally or by inhalation, conveniently in the form of a dry powder inhaler or an aerosol spray in the presence of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane (HFA 134A) or 1,1,1,2,3,3,3-heptafluoropropane (HFA The active compound is administered from a pressurized container, pump, spray, or nebulizer using a gas such as a hydrofluoroalkane (e.g., 227EA3), carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray, or nebulizer may contain a solution or suspension of the active compound, for example, using a mixture of ethanol as a solvent and a propellant, and may also contain a lubricant, such as sorbitan trioleate. Capsules and cartridges (e.g., made from gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mix of the described compound and a suitable powder base, such as lactose or starch.

[0058] Aerosol or dry powder formulations can be adjusted so that each metered dose or "puff" contains at least 1 μg of a compound of the invention or a therapeutic composition of the invention for administration to a patient. It will be understood that the total daily aerosol dose will vary from patient to patient and may be administered in a single dose or, typically, in divided doses throughout the day.

[0059] Alternatively, the compounds or therapeutic compositions of the present invention can be administered in the form of a suppository or pessary, or can be applied topically in the form of a lotion, solution, gel, cream, ointment, or powder. The compounds or therapeutic compositions of the present invention can also be administered transdermally, for example, by the use of a skin patch. They can also be administered via the ophthalmic route, particularly for the treatment of eye diseases.

[0060] For ophthalmic use, the compounds or therapeutic compositions of the invention can be formulated using nanoparticle systems or as micronized suspensions in isotonic, pH-adjusted, sterile saline, or preferably as solutions in isotonic, pH-adjusted, sterile saline, optionally in combination with a preservative such as benzylalkonium chloride, or can be incorporated into an ointment such as petrolatum.

[0061] For topical application to the skin, the compounds or therapeutic compositions of the present invention can be formulated using nanoparticle systems as suitable ointments, for example, by suspending or dissolving the active compound in a mixture with one or more of the following substances: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the compounds or therapeutic compositions can be formulated as suitable sprays, gels, lotions, or creams, for example, by suspending or dissolving the active compound in a mixture with one or more of the following substances: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Nanoparticles with proven tissue and cell penetration properties can also be formulated.

[0062] Additionally, for topical application, the compounds of the invention or therapeutic compositions of the invention (whether alone or in combination with other active ingredients or materials) can be applied to or impregnated into wound dressings to provide dressings that can be used to treat proliferative diseases (e.g., cancer), autoimmune diseases, inflammatory diseases, metabolic diseases, and neurological diseases, or can improve wound healing in an individual.

[0063] Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient, typically with a flavoring such as sucrose and acacia or tragacanth; pastilles containing the active ingredient with an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient with a suitable liquid carrier.

[0064] The compounds of the present invention or therapeutic compositions of the present invention can be delivered using injectable sustained-release drug delivery systems, which are specifically designed to reduce the number of injections. One example of such a system is Nutropin Depot, which encapsulates recombinant human growth hormone (rhGH) in biodegradable microspheres that, upon injection, provide a sustained, slow release of rhGH.

[0065] The compounds of the present invention or therapeutic compositions of the present invention can be administered by a surgically implanted device that releases the drug directly to the required site. For example, Vitrasert releases ganciclovir directly into the eye to treat CMV retinitis. By applying this toxic drug directly to the diseased site, effective treatment can be achieved without the significant systemic side effects of the drug.

[0066] An electroporation therapy (EPT) system can also be used to administer peptides. A device that supplies a pulsed electric field to cells increases the drug permeability of the cell membrane, thereby significantly promoting intracellular drug delivery. Therefore, an electroporation therapy (EPT) system can be used to administer the compound of the present invention or the therapeutic composition of the present invention.

[0067] Peptides can be delivered by electroincorporation (EI). EI occurs when small particles up to 30 microns in diameter on the skin surface experience electrical pulses identical or similar to those used in electroporation. In EI, these particles penetrate through the stratum corneum into deeper layers of the skin. The particles can be loaded or coated with drugs or genes, or they can simply act as "bullets" to generate pores in the skin through which the drugs can enter. Thus, electroincorporation can be used to administer the compounds of the present invention or the therapeutic compositions of the present invention.

[0068] Another method for peptide delivery is the thermosensitive ReGel injection system. Below body temperature, ReGel is an injectable liquid; however, upon reaching body temperature, it forms a gel-like reservoir that slowly erodes and dissolves into a known, safe, biodegradable polymer. The active agent is delivered over time as the biopolymer dissolves. Therefore, the ReGel injection system can be used to administer the compounds of the present invention or the therapeutic compositions of the present invention.

[0069] The compounds of the present invention or therapeutic compositions of the present invention can be introduced into cells by "Trojan horse peptides." These are a type of polypeptide called penetratins, which can transport hydrophilic compounds across cell membranes. This system allows for direct targeting of oligopeptides to the cytoplasm and nucleus, is not cell type specific, and is thought to be highly efficient.

[0070] The compounds of the present invention or therapeutic compositions of the present invention can be introduced into cells by "transfection agents," including, but not limited to, polymers, liposomes, poly(lactic-co-glycolic acid) (PGLA, PLA), lipid nanoparticles, gold nanoparticles, and other nanoparticles. As a class, these agents can transport compounds across the cell membrane. These systems can target oligopeptides directly to the cytoplasm and can be cell-type non-specific or cell-type specific and highly efficient.

[0071] The amount of compound administered to an individual is determined by a medical professional (physician or veterinarian) and depends on whether the individual is human or animal (and the type of animal), the condition being treated, and the route and frequency of administration. Conveniently, the compound is administered in an amount of, for example, 100 μg, 1 mg, 5 mg, 10 mg, or 50 mg, within 2 cm of the inflamed area. 2 The compound can be administered to the skin in a carrier formulation to deliver 1 μg to 100 mg of the carrier formulation per skin.

[0072] Also described are methods for treating proliferative diseases (e.g., cancer), autoimmune diseases, inflammatory diseases, metabolic diseases, and neurological diseases in an individual, comprising administering to the individual a compound or composition as described, wherein the individual is administered the described compound and other therapeutic compounds, either sequentially, in any order, or simultaneously.

[0073] According to this aspect of the invention, the method may include the treatment of an inflammatory skin disease; said treatment may include the treatment of burns and / or the prevention of scar formation; or the treatment of atopic dermatitis, the prevention of atopic dermatitis recurrence, and the slowing of skin aging.

[0074] According to a further aspect of the present invention, there is provided a compound or therapeutic composition as described herein for use in treating a proliferative disease (e.g., cancer), an autoimmune disease, an inflammatory disease, a metabolic disease, and a neurological disease in an individual.

[0075] According to this aspect of the invention, the compound or therapeutic composition for use in treating inflammatory diseases may include use in the treatment of burns and / or prevention of scar formation; or use in the treatment of atopic dermatitis.

[0076] According to a further aspect of the invention there is provided the use of a compound of the invention or a therapeutic composition of the invention in the manufacture of a medicament, for example for the treatment or prevention of a proliferative disease (e.g. cancer), an autoimmune disease, an inflammatory disease, a metabolic disease, and a neurological disease in an individual.

[0077] Proliferative diseases (e.g., cancer) include, but are not limited to, breast cancer, prostate cancer, hematological malignancies (e.g., CML, AML, lymphoma), head and neck cancer, colon cancer, bladder cancer, skin cancer, prostate adenocarcinoma, lung cancer, cervical cancer, lymphoma, and the like.

[0078] Autoimmune diseases include, but are not limited to, glomerulonephritis, Good-Specher's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, epidermolysis bullosa, systemic lupus erythematosus, rheumatoid arthritis, arthritis, psoriatic arthritis, eosinophilic esophagitis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0079] Inflammatory diseases include, but are not limited to, inflammatory diseases such as atherosclerosis, arteriosclerosis, stenosis, autoimmune diseases, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthritis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, post-surgical scarring, burns, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, aging, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type 1), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease. Disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, atopic dermatitis, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related vasculitides (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, inflammatory pain, hepatitis, delayed hypersensitivity reactions (such as poison ivy dermatitis), pneumonia, airway inflammation, adult respiratory distress syndrome (ARDS), ventilator-associated pneumonia (VAP), coronavirus pneumonia, encephalitis, immediate hypersensitivity reactions, asthma, hay fever, allergies , acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, graft-versus-host (GvH) rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryocystitis, dermatomyositis, endocarditis, endometritis, enteritis (small intestine), enteritis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastrointestinal inflammation, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, pharyngitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, sialadenitis, sinusitis, stomatitis, sinusitis, orchitis, tonsillitis, urethritis, urinary bladder inflammation, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.Inflammatory diseases can be acute or chronic, resulting from infectious or non-infectious causes.

[0080] Inflammatory diseases to be treated include those in which inflammatory pathways involving p38α MAP kinase are involved in the pathology. Inflammatory diseases to be treated or prevented with the described compounds include, but are not limited to, inflammatory diseases of the skin, such as atopic dermatitis, psoriasis, acne vulgaris, epidermolysis bullosa, skin scarring, and aging. Activation of MAP kinase p38α may also play a fundamental role in other diseases involving inflammation, such as steno-obstructive pulmonary disease, asthma, inflammatory bowel disease, atherosclerosis, cancer, and rheumatoid arthritis, which can also be treated with the described compounds. Inflammatory diseases to be treated can be temporary, chronic, or permanent symptoms experienced by individuals.

[0081] Metabolic disorders include, but are not limited to, metabolic diseases such as obesity and related disorders such as eating disorders, cachexia, diabetes, hypertension, coronary heart disease, peripheral vascular disease, hypercholesterolemia, dyslipidemia, osteoarthritis, cholelithiasis, and sleep apnea.

[0082] Neurological diseases include, but are not limited to, neurodegenerative diseases such as Alzheimer's disease, dementia spectrum disorders (e.g., frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Creutzfeldt-Jakob disease (CJD)), autism, autism spectrum disorders (e.g., Asperger's syndrome, Mendelsohn's syndrome), and myasthenia gravis.

[0083] According to a further aspect of the present invention, there is provided a method for identifying a molecule that binds to p38α MAP kinase, the method comprising determining whether the molecule binds to p38α MAP kinase at the position at which a compound of the present invention binds to p38α MAP kinase.

[0084] This method can be used to identify molecules that selectively inhibit p38α MAP kinase and are useful in anti-inflammatory and autoimmune therapies. There are various ways to determine whether a test molecule binds to p38α MAP kinase at the same site as a compound of the present invention. One method is to perform a biochemical competition assay between the test molecule and a compound of the present invention to determine whether the test molecule can displace a peptide bearing a compound of the present invention from its binding site on p38α MAP kinase, using, for example, the fluorescence polarization method described herein. Compounds of the present invention can be labeled with a detectable, e.g., fluorescent, label. Affinity-based assays or enzyme-linked immunosorbent assays (ELISAs) can be used. Another method is to use computational chemistry. High-resolution structural information obtained by X-ray crystallography or two-dimensional nuclear magnetic resonance could be used to construct accurate computational models of p38α MAP kinase.

[0085] The invention will now be described in a non-limiting manner with reference to the following figures, in which peptides are referred to in the following manner: JEL0305 is Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala; and JEL2603 is Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His; and JEL2603 is His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg; and JEL0802 is Ser-Arg-Ala-Leu-Ile-Phe-Gln-Lys-Ile.

[0086] In the figures below, statistically significant differences were observed with *p<0.05, ***p<0.01, ***p<0.001, and ***p<0.0001 (N=2). [Brief explanation of the drawings]

[0087] [Figure 1] The activity of JEL0305 at baseline and after 4 weeks under two storage conditions (4°C and room temperature (RT)) is shown. Both showed similar activity at TO, indicating that the biological activity of JEL0305 is stable when stored at RT or 4°C for both peptide and polymer formulations. [Figure 2] JEL2603 is shown, showing some loss of anti-inflammatory activity between TO and 4 weeks when stored at 4°C. Both the peptide and polymer formulations lose activity after 4 weeks. [Figure 3] The activity of the JEL1103 peptide is maintained at 4°C and room temperature, but the JEL1103-polymer formulation loses activity when stored at room temperature, indicating the drawback of this polymer formulation. [Figure 4] This shows that JEL0802, as a peptide (JEL0802) alone, exhibits TO activity at 4°C and RT for 4 weeks. The peptide-polymer formulation provides no benefit, but demonstrates the pro-inflammatory effect of the polymer; Figure 1-4: M0 refers to non-activated macrophages. M1 refers to inflammatory macrophages after LPS stimulation. Polymer-JEL is a combination of the peptide (JEL) and a polymeric transfection agent. JEL refers to the peptide alone. [Figure 5] Particle intensity versus size at weeks T0, T1, T2, T3, and T4 is shown, showing secondary peaks due to the polymer. [Figure 6] Figure 1 shows particle count versus particle size at weeks TO, T1, T2, T3, and T4, demonstrating the consistency of the nanoparticle formulation over 4 weeks at both 4°C and RT. [Example]

[0088] Each peptide was encapsulated into an appropriate nanoparticle formulation, purified, characterized for physicochemical properties, and evaluated for anti-inflammatory biological activity in vitro. Other transfection methods were used, including, but not limited to, proprietary polymers, PGLA, liposomes, and lipid nanoparticles. Optimized formulations were prepared and stored at two conditions (room temperature and 4°C) for up to 4 weeks for stability testing. Key stability parameters were assayed by ELISA and anti-inflammatory activity. Additionally, vesicle stability was evaluated.

[0089] vesicle stability Formal FDA guidance on the stability of pharmaceutical nanoparticles (primarily lipid nanoparticles) requires extensive evaluation of vesicle integrity. This can be done by measuring vesicle stability, which provides a measure of vesicle membrane integrity and is useful in development efforts to understand functionality.

[0090] Vesicle stability was assessed by two measures. - A graph of number versus size gives equal weight to each particle: the magnitude of a peak is directly proportional to the number of particles corresponding to that peak. - The intensity vs. size graph weights particles based on the intensity of the scattered light, i.e. the larger the particle the higher the scattered light intensity. The stability of the vesicles was measured using dynamic light scattering (DLS).

[0091] In vitro anti-inflammatory activity (ELISA method) The anti-inflammatory response of each free peptide and peptide-polymer formulation was measured using TNFα as a marker. Anti-inflammatory bioactivity was assessed using an enzyme-linked immunosorbent assay (ELISA) to quantitatively detect human TNFα in activated M1-macrophages. THP1 human monocytes were differentiated into macrophages (M0) and then activated (overnight) with lipopolysaccharide (LPS) to generate M1-macrophages. LPS stimulates macrophages to produce many inflammatory cytokines, including TNFα, which actively contribute to the inflammatory response.

[0092] At time points T0 and T4 (after 4 weeks of storage at RT or 4°C), each JEL peptide and each JEL polymer formulation was incubated in M1 macrophages preactivated with LPS for 24 hours at 37°C. After incubation, the supernatants were collected, centrifuged, and stored at -80°C for enzyme-linked immunosorbent assay (ELISA).

[0093] Each supernatant sample was thawed and subjected to ELISA assay according to the Invitrogen protocol.

[0094] Figures 1-4 show the concentrations of human TNFα detected by ELISA after incubation with free and polymer-bound peptides at a concentration of 100 ng / mL.

[0095] The Skimune® Skin Extraction Assay Models Graft-Versus-Host Disease (GvHD) and Cytokine Responses Using an HLA (human leukocyte antigen)-mismatched GvHD model that produces grade III to IV graft-versus-host reactions, grade III reactions were observed in all tests using an LNP formulation of the compound of the present invention (JEL0305, JEL2603, JEL1103, or JEL0802) and a positive control assay, and no inhibition of the reaction was observed when the compound was added to a whole mixed lymphocyte reaction and spiked into a skin pick (Skimune®) assay.

[0096] Measurement of cytokine levels from the Skimune® assay revealed very high levels of pro-inflammatory cytokines, including Th1 cytokines (IFNγ, TNFα, IL-1β) and Th2 cytokines (IL-13, IL-4). This finding explains the Grade III reaction to Skimune® and suggests that the reaction to the lipid NP formulation, especially at high concentrations, is due to an excess of lipid. For example, formulating the peptide with a different nanoparticle formulation, a lower lipid dose, or a polymer could reduce the lipid effect and allow the peptide to exert its potency (as demonstrated by T cell proliferation assays) that is currently masked by the formulation.

[0097] Atopic dermatitis (AD) model The AD phenotype was assessed by measuring the intensity of "vitiligo" within the biopsies. This increased from 20% in vehicle-only controls to 80% upon AD induction and reduced to 40% with clobetasol (topical corticosteroid). All concentrations of the compounds (JEL0305, JEL2603, JEL1103, or JEL0802) reduced vitiligo by 50–60%, following a similar trend as clobetasol. Three additional donors (ALC1373, ALC1366, and ALC1365) were treated with activated PBMCs and a cytokine cocktail model to develop atopic dermatitis. The phenotype and biomarkers (filagrin, involucrin, and TSLP) were assessed immunohistochemically. In two donors (ALC1366 and ALC1365), filaggrin and involucrin levels were reduced compared to non-AD-induced skin biopsies treated with vehicle alone. This is the expected response to AD induction. In the presence of the control drug, clobetasol, filaggrin and involucrin expression increased, reversing the AD phenotype. All concentrations (0.1 μg / ml, 1.0 μg / ml, 2.5 μg / ml) of the compounds (JEL0305, JEL2603, JEL1103, or JEL0802) showed similar increases in expression, consistent with phenotypic ("vitiligo") analysis demonstrating improvement and reversal of damage in treated samples. However, this was less pronounced than with clobetasol, likely due to the lipid formulation causing cytokine upregulation. In a third donor, ALC1373, phenotypic improvement was observed with 0.1 and 1.0 μg / ml of the compounds (JEL0305, JEL2603, JEL1103, or JEL0802), although the results were inconclusive. This appeared to be an improvement over the control drug, clobetasol. The results of Filaggrin were inconclusive. TSLP expression in all donors was inconclusive.

[0098] The main overall conclusion is that the compounds of the present invention (JEL0305, JEL2603, JEL1103, or JEL0802) at their current concentrations and formulations cause a significant increase in inflammatory cytokines, masking the effects of the peptides, when tested for their inhibitory properties in a "complex" GvHD-type assay. However, when tested in a less complex tissue model of atopic dermatitis, these compounds (JEL0305, JEL2603, JEL1103, or JEL0802) showed a similar response to the known drug clobetasol. This result indicates that the compounds (JEL0305, JEL2603, JEL1103, or JEL0802) have potential as immunomodulators in atopic dermatitis.

Claims

1. A compound comprising a sequence of at least three amino acids, or a variant or derivative thereof, wherein the sequence of three amino acids comprises the sequence Ser-Arg-Ala, However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln.

2. the compound comprises a sequence of 7 amino acids comprising Ser-Arg-Ala-A-B-Ile-Phe or a variant or derivative thereof, wherein A and B in the sequence may be the same or different and may be any amino acid moiety; 2. The compound of claim 1, wherein the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln.

3. The compound is the following amino acid Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His; His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg; Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile; and Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala; 3. The compound of claim 1 or 2, selected from the group comprising:

4. 10. A compound according to any one of the preceding claims, wherein the compound comprises a variant comprising a larger peptide with additional amino acids, and wherein the peptide according to claim 1 forms only a part of the variant peptide.

5. 10. The compound of any one of the preceding claims, wherein in the variant peptide, the additional amino acid is a naturally occurring amino acid.

6. 10. The compound of claim 1, wherein in the variant peptide, the additional amino acids are unnatural amino acids such as allylalanine and diphenylalanine.

7. 10. A compound according to any one of the preceding claims, having a molecular weight of less than 30,000 daltons.

8. 10. A compound according to any one of the preceding claims, wherein the amino acids are linked by peptide (-CO-NH-) bonds.

9. 10. A compound according to any one of the preceding claims, comprising at least one non-peptide bond between amino acids.

10. 10. The compound according to any one of claims 1 to 9, wherein the compound comprises the amino acid sequence Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His or a variant or derivative thereof.

11. 10. The compound of any one of claims 1 to 9, wherein the compound comprises the amino acid sequence His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg or a variant or derivative thereof.

12. 10. The compound according to any one of claims 1 to 9, wherein the compound comprises the amino acid sequence Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile or a variant or derivative thereof.

13. 10. The compound of any one of claims 1 to 9, wherein the compound comprises the amino acid sequence Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala or a variant or derivative thereof.

14. 10. The compound of any one of the preceding claims, wherein the compound binds to p38α MAP kinase.

15. 10. A compound according to any one of the preceding claims, wherein some or all of the amino acids in the peptide are N-acetylated.

16. 10. The compound according to any one of the preceding claims, wherein the compound comprises at least one D-amino acid residue.

17. 10. A compound according to any one of the preceding claims, wherein the N-terminal and / or C-terminal residues are blocked.

18. 10. The compound of any one of the preceding claims, wherein the compound is substantially resistant to proteolysis.

19. 10. A compound according to any one of the preceding claims for use in binding to p38α MAP kinase.

20. 10. A compound according to any one of the preceding claims for use in inhibiting p38α MAP kinase.

21. 10. The compound according to any one of the preceding claims, wherein the compound competes for binding to p38α MAP kinase.

22. 1. A method of inhibiting p38α MAP kinase, comprising contacting the kinase with a compound comprising a sequence of at least three amino acids or a variant or derivative thereof, wherein the sequence of three amino acids comprises the sequence Ser-Arg-Ala; 1. A method wherein the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln.

23. the compound comprises a sequence of at least seven amino acids or a variant or derivative thereof, the sequence of seven amino acids comprising Ser-Arg-Ala-A-B-Ile-Phe, wherein A and B may be the same or different and may be any amino acid moiety; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln, 23. The method of claim 22.

24. The compound is the following amino acid Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His; His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg; Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile; and Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala; 23. The method of claim 21 or 22, wherein the nucleotide sequence is selected from the group comprising: nucleotides 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,

25. 23. The method of claim 21 or 22, comprising the treatment of proliferative diseases (e.g. cancer), autoimmune diseases, inflammatory diseases, metabolic diseases, and neurological diseases.

26. 26. The method of claim 25, wherein the treatment of an inflammatory disease includes the treatment of burns and / or the prevention of scar formation.

27. 26. The method of claim 25, wherein the treatment of inflammatory diseases includes treatment of atopic dermatitis, prevention of recurrence of atopic dermatitis, and delay of skin aging.

28. 1. Use of a compound comprising a sequence of at least three amino acids or a variant or derivative thereof for inhibiting p38α MAP kinase, wherein the sequence of three amino acids comprises the sequence Ser-Arg-Ala; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln.

29. 1. Use of a compound comprising a sequence of at least seven amino acids or a variant or derivative thereof for inhibiting p38α MAP kinase, wherein the sequence of seven amino acids comprises Ser-Arg-Ala-A-B-Ile-Phe, wherein A and B may be the same or different and may be any amino acid moiety; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln, 29. The use according to claim 28.

30. 30. The use according to claim 28 or 29, wherein the compound is selected from the group comprising the following amino acids: Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His; His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg; Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile; and Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala; or a variant or derivative thereof.

31. 1. A compound comprising a sequence of at least three amino acids or a variant or derivative thereof for use in the manufacture of a medicament, wherein the sequence of three amino acids comprises the sequence Ser-Arg-Ala; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln.

32. 1. A compound comprising a sequence of at least seven amino acids or a variant or derivative thereof for use in the manufacture of a medicament, wherein the sequence of seven amino acids comprises Ser-Arg-Ala-A-B-Ile-Phe, wherein A and B may be the same or different and may be any amino acid moiety; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln, 32. The compound of claim 31.

33. The compound is the following amino acid Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His; His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg; Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile; and Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala; and variants and derivatives thereof 33. The compound of claim 31 or 32, selected from the group comprising:

34. 34. A compound according to any one of claims 31 to 33 for use in the manufacture of a medicament for the treatment of proliferative diseases (e.g. cancer), autoimmune diseases, inflammatory diseases, metabolic diseases and neurological diseases.

35. 35. A compound according to claim 34, wherein the treatment of inflammatory diseases includes the treatment of burns and / or the prevention of scar formation.

36. 35. The compound of claim 34, wherein the treatment of inflammatory diseases includes the treatment of atopic dermatitis, prevention of recurrence of atopic dermatitis, and delay of skin aging.

37. 1. A kit of parts for assaying p38α MAP kinase, said kit comprising a compound comprising a sequence of at least three amino acids or a variant or derivative thereof, wherein the sequence of three amino acids comprises the sequence Ser-Arg-Ala; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln, Parts kit.

38. the compound includes a compound comprising a sequence of at least seven amino acids or a variant or derivative thereof, wherein the sequence of seven amino acids comprises Ser-Arg-Ala-A-B-Ile-Phe, wherein A and B may be the same or different and may be any amino acid moiety; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln, 38. The kit of parts of claim 37.

39. The compound is the following amino acid Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His; His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg; Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile; and Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala; and variants and derivatives thereof 39. The kit of parts according to claim 37 or 38, selected from the group comprising:

40. 1. A composition comprising a compound comprising a sequence of at least three amino acids, or a variant or derivative thereof, for use in combination with one or more other therapeutic compounds, wherein the sequence of three amino acids comprises the sequence Ser-Arg-Ala; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln, composition.

41. 1. A composition comprising a compound comprising a sequence of at least seven amino acids, or a variant or derivative thereof, for use in combination with one or more other therapeutic compounds, wherein the sequence of seven amino acids comprises Ser-Arg-Ala-A-B-Ile-Phe, wherein A and B may be the same or different and may be any amino acid moiety; However, the amino acids are not His-Lys-Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile-Met-Trp-Leu-Arg-Arg-Gln, 41. The composition of claim 40.

42. The compound is the following amino acid Ser-Arg-Ala-Leu-Lys-Ile-Phe-Leu-Ala-Thr-Arg-Lys-Asp-Arg-Ser-Pro-Trp-His; His-Lys-Ser-Arg-Ala-Arg-Leu-Ile-Phe-His-Glu-Gly-Pro-Cys-Gly-Val-Arg-Arg; Ser-Arg-Ala-Leu-Leu-Ile-Phe-Gln-Lys-Ile; and Val-Ser-Arg-Ala-Thr-Arg-Ile-Phe-Lys-Leu-Ser-Gln-Leu-Arg-Gly-Gln-Cys-Ala; and variants and derivatives thereof 42. The composition of claim 40 or 41, selected from the group comprising:

43. 43. The composition of any one of claims 40 to 42, wherein the one or more other therapeutic compounds is an anti-inflammatory compound, an anti-infective compound (e.g., an antibacterial or antiviral compound), an autoimmune suppressive compound, an anti-metabolic compound, an anti-neurological compound, or an anti-proliferative compound.

44. The composition of any one of claims 40 to 43, wherein the composition comprises a pharmaceutically acceptable adjuvant, diluent or carrier.

45. A compound according to claims 1 to 21 or a composition according to claims 36 to 40 for use in treating a proliferative disease (e.g. cancer), an autoimmune disease, an inflammatory disease, a metabolic disease and a neurological disease in an individual.

46. 46. ​​A compound according to claim 45, wherein the treatment of inflammatory diseases includes the treatment of burns and / or the prevention of scar formation.

47. 46. ​​The compound of claim 45, wherein the treatment of inflammatory diseases includes the treatment of atopic dermatitis, prevention of recurrence of atopic dermatitis, and delay of skin aging.

48. A compound, method, use, kit, or composition herein described with reference to the accompanying examples.

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