Compositions for providing cyclic dipeptides and tripeptides

Abstract

The invention relates to the field of engineered peptides and their use in the manufacture of small peptides compounds. Particularly the invention relates to the manufacture of compositions comprising cyclic dipeptides supplemented with tripeptides that have health benefits, for example in treating, improving or ameliorating a neurological condition such as improving memory, improving cognition or reducing neuroinflammation.

Description

[0001]Title: Compositions for providing cyclic dipeptides and tripeptides Field of the invention The invention relates to the field of engineered peptides and their use in the manufacture of small peptides compounds. Particularly the invention relates to the manufacture of compositions comprising cyclic dipeptides supplemented with tripeptides that have health benefits, for example in treating, improving or ameliorating a neurological condition. Introduction Cyclic dipeptides can be formed of naturally occurring proteins such as collagen. Cyclodipeptides (2,5-Diketopiperazines) can be formed via condensation of two α- amino acids and are synthesized by many organisms including bacteria, fungi, more complex marine microorganisms, and mammals. Further, 2,5-Diketopiperazines are often formed during chemical and thermal processing of food and beverages as the degradation products of polypeptides. They have been detected in many food products. In food, 2,5-diketopiperazines have been shown to be important sensory compounds contributing to the taste of the final products and being perceived as astringent, salty, grainy, metallic or bitter. Although these range from proline, aromatic, aliphatic to polar 2,5-diketopiperazines, the proline 2,5-diketopiperazines are the most abundant and structurally diverse 2,5-diketopiperazines found in food. The most studied of all the simple 2,5-diketopiperazines is the histidyl-proline 2,5- diketopiperazine cyclo(L-His-L-Pro) which is found in a variety of foods, with particularly high concentrations in fish and fish products. It is well absorbed orally, and crosses the blood–brain barrier via a non-saturable mechanism. It also occurs in humans as a metabolite from the thyrotropin-releasing hormone (TRH) and exhibits a wide variety of central nervous system, endocrine, electrophysiological, and cardiovascular effects. Derivatives of cyclo(L-His-L-Pro) have been studied extensively to develop therapeutic agents for neurodegeneration. Recently it has been demonstrated that dietary intake of small peptides have several health benefits (see e.g. Mizushige et al.; Nogimura et al.;). Further JP2020196686A and Yamamoto et al. describe a health benefit specifically derived from cyclic dipeptides such as cyclic (Gly-Pro). For example intake of cyclic Gly-Pro has been linked to neuroprotective and memory regulation effects such as improving cognitive function. It further has been suggested as a potential treatment for multiple neurological disorders such as Angelman syndrome. The latter mechanism of action being related to the Insulin Growth Factor 1 (IGF-1) hormone axis. It is postulated that cyclic Gly-Pro could contribute to the increased bioavailability of free IGF-1 in the central nervous system (CNS), with IGF-1 in its free-form being a potent neurotrophic factor in the brain. Furthermore, free IGF-1 is rapidly metabolised downstream by an acid protease, resulting in the formation of the tripeptide Glypromate (Gly-Pro-Glu). Subsequently, this tripeptide is also further metabolised by carboxypeptidases yielding cyclo Gly-Pro and glutamic acid as metabolites. Lastly, the Glypromate moiety has been reported to interact with N-methyl-D-aspartate (NMDA) receptors in the brain and subsequently is also linked with improvement of neuropathological conditions (see Silva-Reis et al.) This demonstrates that both cyclo Gly-Pro and its precursor tripeptide Gly-Pro-Glu are associated with improvement of neuropathological conditions. Exogenous administration of both compounds could have an influence on CNS disorders through different pathways and interactions. Although cyclic dipeptides may be synthesized de novo, for use as a health product of pharmaceutical composition it would be beneficial to use natural sources. A potential source of cyclic dipeptides is collagen or gelatin derived thereof. Collagen comprises a repetitive sequence of Gly-X-Y triplets where X and Y are frequently Pro or 4- hydroxyproline. When collagen is broken down to tripeptides with the structure Gly-X- Y these tripeptides can be converted to cyclic dipeptides with the structure cyclic-Gly- X by heating as for example described in e.g. JP2014125427A, Taga et al. and Hayasaka et al. Sampaio-Dias et al. describes the synthesis of tripeptides such as Gly-Pro-Glu (GPE). Silva-Reis et al. describes that GPE tripeptides may have a neuroprotective effect. Otsuka et al. show that although cyclic dipeptides may be formed from tripeptides, the sequence of the tripeptides is important as it influences the efficiency of cyclic dipeptide formation. For example cyclic peptides are more efficiently produced if the second amino acid in the tripeptide is proline. In addition the presence of hydroxyproline on the Y position of a Gly-X-Y tripeptide repeat inhibits enzymatic degradation of the polypeptide to tripeptides of the structure Gly-X-Y. Unfortunately in natural sources such as gelatin, the Y position is frequently a hydroxyproline. Moreover the X position cannot be influenced and is frequently not proline. Thus using collagen as a natural source for the production of cyclic dipeptides poses several issues that need to be overcome. For example, the tripeptides obtained from collagen do not have a well-defined structure and thus represent a mixture of many different cyclic dipeptides. In addition collagen comprises many sequence elements that do not easily form cyclic dipeptides, which are either still present in the composition or need to be filtered out which poses great challenges. In addition, further improvements of the health benefit are desired to improve outcomes. The present invention aims to address these limitations, among others, by the compositions, methods and uses as defined in the appended claims. Summary of the invention In a first aspect the invention relates to a composition comprising cyclic Gly-Pro (cGP) and tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu. In a second aspect the invention relates a method for manufacturing a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide as defined in the first aspect of the invention, the method comprising heating a composition comprising tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu, to obtain a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide. In a third aspect the invention relates to a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide obtained or obtainable by the method according to the second aspect of the invention. In a fourth aspect the invention relates to the composition according to the first or third aspect of the invention, for use in the treatment, amelioration or prevention of a neurological disorder in a subject. Definitions A portion of this disclosure contains material that is subject to copyright protection (such as, but not limited to, diagrams, device photographs, or any other aspects of this submission for which copyright protection is or may be available in any jurisdiction.). The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure, as it appears in the Patent Office patent file or records, but otherwise reserves all copyright rights whatsoever. Various terms relating to the methods, compositions, uses and other aspects of the present invention are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art to which the invention pertains, unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred materials and methods are described herein. For purposes of the present invention, the following terms are defined below. As used herein, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. For example, a method for administrating a pharmaceutical agent includes the administrating of a plurality of molecules (e.g., 10's, 100's, 1000's, 10's of thousands, 100's of thousands, millions, or more molecules). As used herein, “about” and “approximately", when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed invention. Unless otherwise clear from context, all numerical values provided herein include numerical values modified by the term “about.” As used herein, “and / or” refers to a situation wherein one or more of the stated cases may occur, alone or in combination with at least one of the stated cases, up to with all of the stated cases. As used herein, "at least" a particular value means that particular value or more. For example, "at least 2" is understood to be the same as "2 or more" i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, …, etc. As used herein, the term "at most" a particular value means that particular value or less. For example, "at most 5" is understood to be the same as "5 or less" i.e., 5, 4, 3, ….-10, -11, etc. As used herein, “comprising” or “to comprise” is construed as being inclusive and open ended, and not exclusive. Specifically, the term and variations thereof mean the specified features, steps or components are included. These terms are not to be interpreted to exclude the presence of other features, steps or components. It also encompasses the more limiting “to consist of”. As used herein, “conventional techniques” or “methods known to the skilled person” refer to a situation wherein the methods of carrying out the conventional techniques used in methods of the invention will be evident to the skilled worker. The practice of conventional techniques in molecular biology, biochemistry, cell culture, genomics, sequencing, medical treatment, pharmacology, immunology and related fields are well-known to those of skill in the art and are discussed, in various handbooks and literature references. As used herein, "exemplary" or “for example” means "serving as an example, instance, or illustration," and should not be construed as excluding other configurations, including those disclosed herein. Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range including both integers and non-integers. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, 6 etc. This applies regardless of the breadth of the range. As used herein, the term “pharmaceutical composition” refers to a composition formulated in pharmaceutically acceptable or physiologically-acceptable compositions for administration to a cell or subject. The compositions of the invention may be administered in combination with other agents as well, provided that the additional agents do not adversely affect the ability of the composition to deliver the intended therapy. The pharmaceutical composition often comprise, in addition to a pharmaceutical active agent, one or more pharmaceutical acceptable carriers (or excipients). As used herein, "treatment", "treating", "palliating", “alleviating” and "ameliorating" in the context of a subject to be treated, all refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. As used herein, “prevention" and "preventing" refers to an approach for reducing in part or in full the change of developing adverse effects, for example normally associated with the use of a particular drug or agent. Within the context of the current invention, for example, the terms may refer to preventing, treating or reducing the effects of a neurological disorder. As used herein the term “nucleic acid” or “polynucleotide” refers to any polymers or oligomers of (contiguous) nucleotides. The nucleic acid may be DNA or RNA, or a mixture thereof, and may exist permanently or transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states. The present invention contemplates any deoxyribonucleotide, ribonucleotide or peptide nucleic acid component, and any chemical variants thereof, such as methylated, hydroxymethylated or glycosylated forms of these bases, and the like. The polymers or oligomers may be heterogeneous or homogenous in composition, and may be isolated from naturally occurring sources or may be artificially or synthetically produced. The term “isolated” thus means isolated from naturally occurring sources or artificially or synthetically produced. As used herein, “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. As used herein, the terms “peptide” and “polypeptide” refer to molecules consisting of a chain of amino acids, without reference to a specific mode of action, size, three dimensional structure or origin. A “fragment” or “portion” or “part” of a polypeptide may thus still be referred to as a “polypeptide”. An “isolated peptide” or isolated polypeptide” is used to refer to a peptide or polypeptide which is no longer in its natural environment, for example in vitro or in a recombinant host cell. As used herein the term “construct” or “nucleic acid construct” or “vector” refers to a man-made nucleic acid molecule resulting from the use of recombinant DNA technology and which is used to deliver exogenous DNA into a host cell, often with the purpose of expression in the host cell of a DNA region comprised on the construct. The vector backbone of a construct may for example be a plasmid into which a (chimeric) gene is integrated or, if a suitable transcription regulatory sequence is already present, only a desired nucleic acid sequence (e.g. a coding sequence) is integrated downstream of the transcription regulatory sequence. Vectors may comprise further genetic elements to facilitate their use in molecular cloning, such as e.g. selectable markers, multiple cloning sites and the like. When used herein the terms GPE and Gly-Pro-Glu are used interchangeably and refer to the tripeptide glycyl-L-prolyl-L-glutamic acid. When used herein the terms cGP and cyclic Gly-Pro, cyclo Gly-Pro, cyclic GP and cyclo GP are used interchangeable and refer to the cyclic dipeptide of glycine and proline as defined below in formula II. Unless specified otherwise the term composition or composition according to the invention refers to a composition comprising cGP and GPE, more specifically composition comprising cyclic Gly-Pro (cGP) and tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly- Pro-Glu. DETAILED DESCRIPTION OF THE INVENTION The invention is defined herein, and in particular in the accompanying claims. Subject- matter which is not encompassed by the scope of the claims does not form part of the present claimed invention. It is contemplated that any method, use or composition described herein can be implemented with respect to any other method, use or composition described herein. Embodiments or preferences discussed in the context of methods, use and / or compositions of the invention may likewise be employed with respect to any other method, use or composition described herein. Thus, an embodiment or preference pertaining to one method, use or composition may be applied to other methods, uses and compositions of the invention as well. Any references in the description to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy. The present invention broadly relates to improved method for manufacturing compositions comprising cyclic dipeptides and medical uses thereof. In particular, the inventors argue that expressing artificial sequences coding for peptides having a defined peptide content improves efficiency, purity and homogeneity of cyclic dipeptide compositions obtained thereof. Moreover, the inventors anticipate that compositions comprising cyclic dipeptides and GPE (Gly-Pro-Glu tripeptides) as defined herein have improved health benefits. The compositions, methods and uses described herein have several unexpected beneficial effects. In particular, an important natural source of tripeptides that can be converted to cyclic dipeptides is collagen. Collagen is rich in [Gly-X-Y] repeats making it an apparent ideal source for cyclic peptides, however has some drawbacks which are not easily overcome. First, for efficient conversion of the tripeptides the X position is preferably a proline (see Otsuka et al.), however this position in collagen is frequently a different position. Second in collagen the Y position is frequently a hydroxyproline, which makes enzymatic degradation to tripeptides challenging. Enzymatic cleavage is inhibited by hydroxyproline at the Y position, so preferably hydroxyproline is not present at the Y position. Furthermore the frequency of naturally occurring Gly-Pro-Glu tripeptides is in the range of 0.3%, therefore gelatin is not a very efficient source for obtaining this specific tripeptide. The present invention allows full control over the peptide structure. By preventing the presence of hydroxyproline at the Y position efficient cleavage of the peptide to tripeptides can be achieved with suitable enzymes. In addition the tripeptide composition can be controlled to be much more homogenous, ensuring proline is present on the X position in the majority of the produced tripeptide (Gly-Pro-Y), and having a high content in Gly-Pro-Glu tripeptides. The inventors found an unexpected high conversion rate of tripeptides to cyclic dipeptides, possibly attributable to the design of the composition having high Gly-Pro-Y and Gly-Pro-Glu content. Lastly the resulting composition which consists mainly of cGP and GPE was found to be more effective in improving cognitive function and memory regulation. Moreover the composition was surprisingly more effective in preventing or reducing scopolamine induced neuroinflammation. In particular in Example 2 the inventors describe two experiments that test the effect of different compositions comprising cPG and GPE with different controls. To this effect, the following controls were tested: non cyclic GP containing di- and tri- and oligopeptides, and compositions comprising non-GPE tripeptides. In addition in the experiments were used synthetic cGP and GPE, as well as cGP and GPE obtained by recombinant expression of a recombinant peptide. The recombinant peptide (SEQ ID NO: 15) has been designed such that its sequence comprises several instances of GPE. The expressed peptide (also referred to herein as Recombinant Peptide or RP GPE) is enzymatically digested to tripeptides (Collagenase RP (CRP) GPE). The tripeptides are heated to convert a fraction of the tripeptides to form cGP to obtain a composition of cGP and GPE (heated Collagenase RP (CRP) GPE). As a further control a different recombinant peptide (SEQ ID NO: 14) comprising no GPE instances in its sequence was treated identically (heated Collagenase RP (CRP) no GPE). In a first experiment the different compositions and control compositions were used to treat rat hippocampal neurons to investigate the effect on neurite outgrowth. As also depicted in Figure 1, the results indicate that GPE or cGP by itself do not have any effect on neurite outgrowth, but that a combination of cGP and GPE significantly increases neurite outgrowth. This is indicated in the graph by GPE:cGP (combination of synthetic GPE and cGP), combination of control peptide + GPE + cGP (alcalase CP + GPE+ cGP, and collagenase CP + GPE + cGP) and heated Collagenase RP (CRP) GPE (also comprising cGP and GPE). This experiment shows a surprising synergetic effect between cGP and GPE in their ability to promote neurite outgrowth. In a second experiment the compositions were added to MV2 microglial cells which were stimulated with LPS to induce cytokine (IL-1β) release. It was found that GPE or cGP by itself do not have any effect on suppressing cytokine release, but that a combination of cGP and GPE significantly reduces cytokine release upon stimulating glial cells with LPS. This experiment shows a surprising synergetic effect between cGP and GPE in their ability to reduce neuro-inflammation. The results described in Example 2 and Figures 1 and 2 surprisingly demonstrate a synergetic effect between cGP and GPE. In addition the data shows that cGP or GPE by itself do not significantly increase neurite outgrowth or reduce neuro-inflammation, but do so significantly when combined, for supporting a synergistic instead of an additive effect. Therefore in a first aspect the invention relates to a composition comprising cyclic Gly- Pro (cGP) and tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu. In an alternative embodiment the invention relates to a composition comprising cGP and GPE. Such compositions are useful as they could be used to treat, ameliorate or prevent a neurological disorder in a subject, for example by stimulating neurite outgrowth or by suppressing neuro-inflammation. Further disclosed herein is a composition comprising tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu. Such composition could easily be combined with cGP to obtain a composition according to the first aspect of the invention. Compositions of tripeptides comprising GPE can be readily converted to compositions comprising cyclic dipeptides by heating as described below. The skilled person is aware how such composition can be converted and how the parameters, such as heating time and temperature can be adjusted to achieve the desired effect. For example Taga et al. and Hayasaka et al. describe such process, both of which are hereby incorporated by reference in their entirety. It is understood that by selecting the parameters of the heating reaction the final product can be controlled. For example in case it is desirable to have a not 100% efficient reaction so that some tripeptides remain, the temperature and / or reaction time can be adjusted (for example lowered) accordingly. This may be advantageous as it allows for control of the tripeptide, for example GPE, content in the composition. It is however further envisioned that different compositions are blended to obtain the desired final product. For example one composition in which 100% of the tripeptides have been converted to cyclic dipeptides may be mixed with a composition that comprises partially or even fully tripeptides, such as for example GPE, to obtain the desired final product (such as for example a composition of cyclic dipeptides and a predefined percentage of GPE tripeptide). In an embodiment at least 2%, preferably at least 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the tripeptides in the composition have the formula Gly-Pro-Glu. In an embodiment at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the tripeptides in the composition have the formula Gly-Pro-Y. When used herein the percentages refer to the fraction of specified tripeptides (based on number of molecules) as percentage of the total amount of tripeptides in the composition. In an embodiment the amount of cyclic Gly-Pro in moles per Liter is at least equal to the amount of tripeptides in moles per Liter. In an embodiment cGP and GPE are present in the composition in a molar ratio between 50:1 to 1:50, preferably in a ratio between 45:1- to 1:45, more preferably between 40:1 – 1:40, 30:1 – 1:30, 25:1 – 1:25, 20:1 – 1:20, 15:1 – 1:15, 12:1 – 1:12, 10:1 – 1:10, 8:1 – 1:8, 7:1 – 1:76:1 – 1:6, 5:1 – 1:5, 4:1 – 1:4, 3:1 – 1:3, 2:1 – 1:2, most preferably in a ratio of approximately 1:1 (molar). In an embodiment cGP and GPE are present in the composition in a molar ratio between 100:1 to 1:1, preferably in a ratio between 80:1 – 10:1, 60:1 – 20:1, 50:1 – 40:1. In an embodiment the concentration of cGP in the composition is 10 μm or more, preferably 20 μm, 50 μm, 100 μm, 200 μm, 500 μm, 1 mM or more, more preferably 2 mM, 5 mM, 10 mM, 20 mM, 50 mM, 100 mM, 200 mM, or even 500 mM or more. In an embodiment the concentration of GPE in the composition is 10 μm or more, preferably 20 μm, 50 μm, 100 μm, 200 μm, 500 μm, 1 mM or more, more preferably 2 mM, 5 mM, 10 mM, 20 mM, 50 mM, 100 mM, 200 mM, or even 500 mM or more. In an embodiment the concentration of each of cGP and GPE individually in the composition is 10 μm or more, preferably 20 μm, 50 μm, 100 μm, 200 μm, 500 μm, 1 mM or more, more preferably 2 mM, 5 mM, 10 mM, 20 mM, 50 mM, 100 mM, 200 mM, or even 500 mM or more. In an embodiment the composition is obtained from an animal source. In an embodiment the composition is obtained from a non-animal source such as a plant, a yeast or a unicellular organism such as a bacteria. Because the composition described herein and products derived thereof are a natural product, as opposed to chemically synthesized, they products are suitable for use as a nutraceutical or pharmaceutical composition or supplement for oral administration, e.g. as a food supplement. Thus in an embodiment the tripeptides are not chemically synthesized, as contamination products of the synthesis process may render the product unsafe for administering to humans or animals. When used herein chemical synthesis is the artificial execution of chemical reactions to obtain one or several products. In an embodiment the composition is obtained be expressing a recombinant peptide in a host. In an embodiment the host is a non-animal host such as a plant, a yeast or a unicellular organism such as a bacteria. Therefore, in an embodiment the composition is suitable for vegetarians or vegans. In an embodiment the cGP is obtained by heating the tripeptides to partially convert Gly-Pro-Y to cGP. Alternatively a composition comprising Gly-Pro-Y has been heated to substantially completely convert Gly-Pro-Y to cGP and is subsequently mixed with a composition comprising Gly-Pro-Y (e.g. GPE). In an embodiment the cGP in the composition is not chemically synthesized. In a more preferred embodiment neither the cGP and the GPE in the composition is chemically synthesized. When used herein the term chemically synthesized intends to refer to a compound which is manufactured by chemical synthesis rather than obtained from a natural resource or biological product. Thus in an embodiment the cGP, the GPE, or preferably both, or obtained from a natural or biological product, either directly or by conversion of a natural or biological product. The term biological product also intends to cover recombinant proteins or peptides expressed in a biological system. The terms natural and biological products also intend to cover gelatin converted by natural processing of an animal collagenous starting material. Without wishing to be bound be theory, the applicant anticipates that due to the defined nature the compositions as defined herein allow for a more efficient conversion to cyclic dipeptides due to the defined nature of the compositions. For example gelatin derived compositions may be used to obtain tripeptide containing compositions which subsequently may be converted to compositions comprising cyclic dipeptides, however doing so results in a large presence of non-tripeptides because not every Gly-X-Y tripeptide can be effectively cleaved due to frequent presence of hydroxyproline on the Y position. Furthermore the tripeptides that have formed display large variation in the sequences of the tripeptides. It is anticipated that the compositions described herein have improved efficiency in conversion to cyclic dipeptides, and result in a more pure and homogenous end product. As type I collagen does not comprise any instances of “GPE” in its peptide sequence, enzymatic hydrolysis of natural type I collagen does not result in GPE tripeptides. Therefore collagen type one based recombinant peptides are envisioned as a potential source for GPE containing tripeptide compositions. For example, a partial sequence of collagen type I can be modified to introduce at least a few instances of GPE, allowing the expression of the recombinant peptide in a host and subsequent enzymatic degradation to tripeptides including GPE. An advantage of such method is that it use a biological system to express the peptide, allowing for safe for human consumption production methods. Methods for obtaining tripeptide mixtures according to the invention are described herein. In an embodiment recombinant peptide engineering may be used. Thus according to an embodiment the composition according to the first aspect of the invention is obtained by: - expressing a recombinant peptide in a cell; and - treating the peptide with a peptidase to obtain a composition of tripeptides, wherein the recombinant peptide comprises a peptide sequence [Gly-X-Y]nwherein X and Y are individually for each tripeptide selected from an amino acid, wherein n is an integer between 10 and 1000, and wherein at least 1% of the tripeptides in the recombinant peptide have the formula Gly- Pro-Glu. In an embodiment at least 2%, preferably at least 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the tripeptides in the recombinant peptide have the formula Gly-Pro-Glu. In an embodiment n is an integer between 10 and 1000, for example 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. In an embodiment the recombinant peptide comprises a peptide sequence [Gly-X-Y]nwherein X and Y are individually for each tripeptide selected from an amino acid, wherein n is an integer between 10 and 1000 comprises at least 3, preferably at least 3, 4, 5, 6, 7, 8, 9, 10 or more instances of Gly-Pro-Glu. In an embodiment the recombinant peptide comprises a peptide sequence which comprises a sequence selected from SEQ ID NO: 1-12. When used herein a percentage of the tripeptides in the recombinant peptide having the formula Gly-Pro-Glu intends to define the percentage of GPE of the total (hypothetical) amount of Gly-X-Y tripeptides that can be formed from the peptide. To calculate this the peptide sequence is divided in tripeptides in such a way as yielding the largest number of tripeptides of the sequence Gly-X-Y and then the percentage of is calculated by dividing the theoretical number of GPE tripeptides present by the theoretical number of Gly-X-Y tripeptides in the sequence. A recombinant peptide can be expressed from a suitable expression vector or genetically engineered host in accordance with standard techniques known in the field. One of skill in the art can readily design and synthesize a nucleic acid construct that allows expression of the envisioned peptides using standard techniques. Typically expression of the recombinant peptide is achieved by including the coding sequence in an expression vector comprising a suitable promoter to allow expression in a host cell, however the invention should not be limited to specific ways to express peptide and includes other expression systems such as but not limited to cell free expression systems. An advantage of the present invention is that the peptides may be expressed in non- animal cells allowing for a vegan product. For example the peptides may be expressed in a plant host or a fungus host, including unicellular members of the fungus kingdom such as yeast. Alternatively the peptides may be expressed in microbes such as but not limited to bacteria. The peptide may be expressed in a cell culture system or in a whole organism. Non limiting examples of exemplary recombinant peptides are peptide comprising of the sequences as defined in SEQ ID NO: 1- 12 below, or a variant thereof wherein the variant comprises a sequence with 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identify with a sequence as defined in SEQ ID Nos 1-13 or 15 below. SEQ ID NO: 1 – GPEGPEGPE SEQ ID NO: 2 – GPEGPEGPEGPE SEQ ID NO: 3 – GPEGPEGPEGPEGPE SEQ ID NO: 4 – GPEGPEGPEGPEGPEGPE SEQ ID NO: 5 – GPEGPEGPEGPEGPEGPEGPE SEQ ID NO: 6 – GPEGPEGPEGPEGPEGPEGPEGPE SEQ ID NO: 7 – GPEGPEGPEGPEGPEGPEGPEGPEGPE SEQ ID NO: 8 – GPEGPEGPEGPEGPEGPEGPEGPEGPEGPE SEQ ID NO: 9 – HHHHHHGPEGPEGPE SEQ ID NO: 10 – HHHHHHGPEGPEGPEGPE SEQ ID NO: 11 – HHHHHHGPEGPEGPEGPEGPE SEQ ID NO: 12 – GPEGPEGP SEQ ID NO: 13 – HHHHHHGPEGPEGPEGADGPEGPEGPEGADGPEGPEGPE SEQ ID NO: 15 – HHHHHHGPEGAQGPEGPQGPEGGKGPEGPAGPEGFQGPEGPAGPEGEVGPEGE RGPEGEFGPEGPAGPEGERGPEGESGPEGPAGPEGSRGPEGPPGPEGKSGPEGV LGPEGTAGPEGPSGPEGERGPEGIPGPEGEKGPEGLR Thus in an embodiment the peptide comprises or consist of a sequence [Gly-X-Y]nwherein X and Y are individually for each tripeptide selected from an amino acid, wherein n is an integer between 10 and 1000, and wherein at least 1% of the tripeptides in the recombinant peptide have the formula Gly-Pro-Glu, and wherein the sequence comprises a sequence selected from SEQ ID Nos 1 to 12. A non-limiting exemplary sequence is: SEQ ID NO: 13 – HHHHHHGPEGPEGPEGADGPEGPEGPEGADGPEGPEGPE which comprises a His purification handle, 11 [Gly-X-Y] repeats of which are 9 GPE repeats (81%). A further non limiting exemplary sequence is SEQ ID NO: 15 – HHHHHHGPEGAQGPEGPQGPEGGKGPEGPAGPEGFQGPEGPAGPEGEVGPEGE RGPEGEFGPEGPAGPEGERGPEGESGPEGPAGPEGSRGPEGPPGPEGKSGPEGV LGPEGTAGPEGPSGPEGERGPEGIPGPEGEKGPEGLR which comprises a His purification handle, 46 [Gly-X-Y] repeats of which are 23 GPE repeats (50%). SEQ ID NO: 15 is also used in Example 2 (Figures 1 and 2). It is pointed out that expressing these peptides in a host will in practice lead to compositions with lower percentages of GPE of the total tripeptides as the above indicated theoretical maximum percentages, due loss and inefficiencies in peptide digestion. Thus in an embodiment the invention relates to a composition is obtained by: - expressing a recombinant peptide in a cell; and - treating the peptide with a peptidase to obtain a composition of tripeptides, wherein the recombinant peptide is a peptide comprising a sequence as defined in SEQ ID Nos 1 to 12 or a variant thereof as defined herein. It is appreciated that highly there are several challenges associated with the synthesis and expression of highly repetitive peptide encoding sequences, therefore it is appreciated that for example GPE repeats are alternated with other sequences to avoid such issues. The expressed peptide may be secreted or isolated from the host organism by lysis of the host cell. Preferably the peptide is purified prior to treatment with a peptidase. Therefore, the peptide may further comprise a signal peptide that targets the peptide to a specific cellular location, e.g. the nucleus, cytosol, membrane, or which targets the peptide for secretion. Sequences of signal peptides will depend on the host organism in which the peptide is expressed, such sequences can be identified, selected and incorporated in the peptide using routine techniques and common general knowledge. The peptide may for example be purified by using a purification handle. A purification handle is a tag, usually a short peptide sequence, included in the peptide allowing rapid purification of the peptide by affinity. In addition, the peptide may further comprise a purification handle such as but not limited to a tag selected from ALFA-tag, AviTag, C-tag, Calmodulin-tag, iCapTag™ (intein Capture Tag), polyglutamate tag, polyarginine tag, E-tag, FLAG-tag, HA-tag, His-tag, Gly-His-tag, Myc-tag, NE-tag, Rho1D4-tag, S-tag, SBP-tag, Softag 1, Softag 3, Spot-tag, Strep- tag, T7-tag, TC tag, Ty tag, V5 tag, VSV-tag, or Xpress tag. The sequences of the above referenced tags are known to the skilled person and for example described in Kimple et al. The skilled person is aware how to use these tags to purify a peptide using commonly known techniques. Sequences 9-11 provide three exemplary sequences with a His6 tag, it is however understood that the His tags may be substituted with any other tag suitable for purification purposes. It is further understood that depending on the Tag it should preferably be located on the N- or C-terminal of the peptide. Thus further disclosed herein are peptides comprising any tag selected form the list above and further comprising a peptide sequence as defined in any one of SEQ ID Nos 1 to 12. The peptidase is used to digest to smaller fragments. Preferably the peptide sequence and peptidase are chosen such that the resulting peptidase treatment results in a high percentage of tripeptides with the sequence Gly-X-Y, preferably Gly-Pro-Y. In an embodiment the peptidase is an Gly-N specific endopeptidase or a tripeptidyl peptidase. A Gly-N specific endopeptidase is a peptidase that cuts on the N-terminal side of Gly, and can produce tripeptides of the formula Gly-X-Y when used on peptides having a [Gly-X-Y]n repeat sequence. A tripeptidyl peptidase is a peptidase that cleaves the C-terminal (last) or N-terminal (first) three amino acids of a peptide. Preferably the used tripeptidyl peptidase is an N-terminal peptidase. Thus for peptides having as the last three amino acids of a peptide have the formula Gly-X-Y, treatment with an tripeptidyl peptidase results in tripeptides with the formula Gly-X-Y. Thus a peptide with the formula Z-[Gly-X-Y]n, wherein Z is an arbitrary number of amino acids and n an integer of at least one can treated with a peptidase (e.g. either a Gly-N specific endopeptidase or a tripeptidyl peptidase) to result in n tripeptides of the formula Gly-X-Y and a remaining peptide Z. Alternatively a peptide with the formula Z1--[Gly-X-Y]n-Z2, wherein Z1and Z2are each individually an arbitrary number of amino acids and n is an integer of at least 2 can treated with a Gly-N specific endopeptidase to result in (n-1) tripeptides with the formula Gly-X-Y and two remaining peptides, Z1and Gly-X-Y-Z2. Therefore in an embodiment the peptidase is a tripeptidyl-peptidase I (EC 3.4.14.9), a tripeptidyl-peptidase II (EC 3.4.14.10) or a Glycyl aminopeptidase. An example of a commercially available tripeptidyl-peptidase I is EXWM-4052 (Creative Enzymes). An example of a commercially available tripeptidyl-peptidase II is EXWM-4044 (Creative Enzymes). An example of a commercially available glycyl aminopeptidase is XP-559 (Nagase ChemteX). It is appreciated that these are mere examples of the indicated enzyme classes and the invention is not limited to these specific examples. In an embodiment the peptidase is an alcalase or a subtilisin A based enzyme, or a collagenase. Accordingly in a second aspect the invention relates to a method for manufacturing a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide as defined in the first aspect of the invention, the method comprising heating a composition comprising tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu, to obtain a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide. In an embodiment the method further comprises the step of purifying the cyclic Gly-Pro and the Gly-Pro-Glu tripeptide form the composition. Heating a composition comprising GPE tripeptides results in the conversion of GPE to cGP. The conditions for heating (e.g. temperature, time and pressure) can be chosen such that only part of the GPE in the composition is converted to cGP, or such that all GPE is converted to cGP. In the latter case, the resulting composition comprising cGP can be supplemented with GPE, for example be mixing in additional composition comprising GPE tripeptides that has not been heated to convert GPE to cGP. Thus in an embodiment the method further comprises a step of supplementing the composition with a composition comprising Gly-Pro-Glu. In an embodiment the supplemented composition comprising Gly-Pro-Glu is also a composition comprising tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu. Thus in an embodiment part of a composition comprising Gly-Pro-Glu is also a composition comprising tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu is heated to convert Gly-Pro-Glu to cyclic Gly-Pro and then mixed back with the part of the composition that is not heated. In a third aspect the invention relates to a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide obtained or obtainable by the method according to the second aspect of the invention. Further described herein is a method for producing the composition according to the first aspect of the invention, the method comprising: - expressing a recombinant peptide in a cell; and - treating the peptide with a peptidase to obtain a composition of tripeptides, wherein the recombinant comprises a peptide sequence [Gly-X-Y]nwherein X and Y are individually for each tripeptide selected from an amino acid, wherein n is an integer between 10 and 1000, and wherein at least 1% of the tripeptides in the recombinant peptide have the formula Gly- Pro-Glu. In an embodiment at least 2%, preferably at least 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the tripeptides in the recombinant peptide have the formula Gly-Pro-Glu. In an embodiment n is an integer between 10 and 1000, for example 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. When used herein the term recombinant peptide denotes an artificially produced peptide, implying the peptide is not naturally occurring. The peptide may be synthesized or expressed from recombinant DNA or RNA. Recombinant DNA or RNA when used herein denotes DNA or RNA that is artificially produced and comprises a nucleotide sequence that is not naturally occurring. In an embodiment the recombinant peptide is a peptide comprising a sequence as defined in SEQ ID Nos 1 to 12 or a variant thereof as defined herein. In a further aspect the invention relates a composition obtained or obtainable by the methods as broadly described above. In a further aspect the invention relates to a method for manufacturing a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide, the method comprising heating the composition according to the first, the second or the fourth aspect of the invention, to obtain a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide. For example Taga et al. describe the production of cycli dipeptides from tripeptides under mild acidic conditions (100 mM sodium acetate @ pH 4.8) by heating to 85 °C for 1, 3 or 8 hours; Hayasaka et al describe heating in pure water at 95 °C for 24 or 48 hours. Thus in an embodiment the heating is performed between 30 minutes to 72 hours, for example between one hour and 60 hours, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 30, 36, 42, 48, 54, or 60 hours. In an embodiment the heating is performed at between 75 and 120 °C, e.g.75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 208, 109, 110, 111, 112, 113, 1145, 115, 116, 117, 118, 119 or 120 °C. In an embodiment the heating is performed at a pH of between 4.0 and 8.0, e.g.4.0, 4.1, 4.2, 4.3, 4.4., 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. In exemplary embodiments the heating is performed at temperature between 80 and 90 °C, for 1 to 12 hour and at a pH of between 4.2 and 5.5. Alternatively the heating is performed at a temperature between 90 and 100 degrees for 18 to 72 hours at a pH between 6.0 and 8.0. The dipeptide glycyl-proline is depicted here with formula I: Formula I The cyclic dipeptide cyclic-glycyl-proline is depicted here with Formula II: Formula II Several health benefits have been identified relating to dietary intake of small peptides. For example Mizushige et al describe that ginger degraded collagen hydrolysate exhibits antidepressant activity in mice. In their study collagen from bovine bone was degraded using ginger rhizome, resulting in collagen hydrolysate with an average molecular weight 816 Da. The effect was tested using the force swim test and Y-maze test in mice. In a follow up study Nogimura et al describe that collagen derived dipeptides such as prolyl-hydroxyproline lead to antidepressant-like mice. JP2020196686A and Yamamoto et al. describe a health benefit specifically derived from cyclic dipeptides such as cyclic (Gly-Pro). E.g. JP2020196686A describes that administering cyclic Gly-Pro to rats results in improved cognitive function. The cyclic Gly-Pro is obtained from collagen. The used collagen tripeptide (Zerais Co., Ltd.) has a cGP content of 20 mg / 4 g (0.5% by weight). Without wishing to be bound by theory, it is expected that the compositions comprising GPE and cyclic dipeptides as described herein or obtained by the methods described herein have improved health advantages over described collagen derived cGP compositions at least for the following reasons: 1. The composition is more defined. As can be seen from the prior art (e.g. JP2020196686A) existing products have very low cGP content (0.5%). Purifying such product is challenging but will inherently result in compositions comprising substantial amount of other cyclic dipeptides, tripeptides and other unknown components, while the compositions defined herein can be carefully controlled to have cyclic Gly-Pro and GPE tripeptides as the main or sole components. 2. The present compositions allow for high purity. In contrast the composition described in JP2020196686A requires administration of 4 g of tripeptide composition to achieve a dose of 20 mg cGP. This means that beneficial effects cannot be unambiguously correlated to a minor component of the composition, moreover adverse effects of the remaining 99.5% of the composition of tripeptides, other cyclic dipeptides and unknown components should not be ruled out. These drawbacks are avoided by the defined compositions described herein. 3. Incorporating GPE into the composition is expected to notably enhance health benefits. While not limited by theory, the applicant foresees that the augmented health benefits may arise from the in vivo conversion of GPE to cGP, alongside GPE's inherent effects, which may also improve neuropathological disorders. In an embodiment the method further comprises the step of purifying the cyclic Gly- Pro and the Gly-Pro-Glu tripeptide form the composition. It is understood that the peptides can be purified before or after the heating step to remove impurities from the composition. For example the impurities may comprise tripeptides which are not GPE or longer peptide fragments resulting from e.g. the purification tag. Thus in an embodiment the invention describes a method comprising the steps: - expressing a recombinant peptide in a cell; and - treating the peptide with a peptidase to obtain a composition comprising tripeptides, - purifying the tripeptides from the composition, and - heating the purified tripeptides to obtain a composition comprising cyclic dipeptides. Alternatively the invention describes a method comprising the steps: - expressing a recombinant peptide in a cell; and - treating the peptide with a peptidase to obtain a composition comprising tripeptides, - heating the tripeptides comprising composition to obtain a composition comprising cyclic dipeptides and optionally tripeptides, and - purifying the cyclic dipeptides and optionally tripeptides from the composition. In a further aspect the invention relates to a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide obtained or obtainable by the method according to the fifth aspect of the invention. In a further aspect the invention relates to a composition comprising cyclic Gly-Pro and tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu. In an embodiment at least 2%, preferably at least 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the tripeptides in the composition have the formula Gly-Pro-Glu. In an embodiment at least 10%, preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the tripeptides in the composition have the formula Gly- Pro-Y. In a further aspect the invention relates to a composition comprising cGP and GPE. In an embodiment the amount of cyclic Gly-Pro in moles per Liter is at least equal to the amount of tripeptides in moles per Liter. In an embodiment cGP and GPE are present in the composition in a molar ratio between 50:1 to 1:50, preferably in a ratio between 45:1- to 1:45, more preferably between 40:1 – 1:40, 30:1 – 1:30, 25:1 – 1:25, 20:1 – 1:20, 15:1 – 1:15, 12:1 – 1:12, 10:1 – 1:10, 8:1 – 1:8, 7:1 – 1:76:1 – 1:6, 5:1 – 1:5, 4:1 – 1:4, 3:1 – 1:3, 2:1 – 1:2, most preferably in a ratio of approximately 1:1 (molar). In an embodiment cGP and GPE are present in the composition in a molar ratio between 100:1 to 1:1, preferably in a ratio between 80:1 – 10:1, 60:1 – 20:1, 50:1 – 40:1. In an embodiment the concentration of cGP in the composition is 10 μm or more, preferably 20 μm, 50 μm, 100 μm, 200 μm, 500 μm, 1 mM or more, more preferably 2 mM, 5 mM, 10 mM, 20 mM, 50 mM, 100 mM, or even 200 mM or more. In an embodiment the concentration of GPE in the composition is 10 μm or more, preferably 20 μm, 50 μm, 100 μm, 200 μm, 500 μm, 1 mM or more, more preferably 2 mM, 5 mM, 10 mM, 20 mM, 50 mM, 100 mM, or even 200 mM or more. In an embodiment the concentration of each of cGP and GPE individually in the composition is 10 μm or more, preferably 20 μm, 50 μm, 100 μm, 200 μm, 500 μm, 1 mM or more, more preferably 2 mM, 5 mM, 10 mM, 20 mM, 50 mM, 100 mM, or even 200 mM or more. In an fourth aspect the invention relates to the composition according to the first or third aspect of the invention for use in treating, ameliorating or preventing a neurological disorder. In an embodiment the invention relates a composition comprising cGP and GPE for use in treating, ameliorating or preventing a neurological disorder. In an embodiment the invention describes a method of treating, preventing, or ameliorating a neurological disorder in a subject in need thereof, the method comprising administering a composition comprising cGP and GPE to the subject. In an embodiment the treating, ameliorating or preventing a neurological disorder comprises improving cognitive functions in a subject. In an embodiment the treating, ameliorating or preventing a neurological disorder comprises improving memory. In an embodiment the treating, ameliorating or preventing a neurological disorder comprises improving cognition. In an embodiment the treating, ameliorating or preventing a neurological disorder comprises reducing neuroinflammation. In an embodiment the treating, ameliorating or preventing a neurological disorder comprises reducing expression of an inflammation marker in a region brain. In an embodiment the inflammation marker is IL-6 and / or TNF-alpha. In an embodiment the region of the brain is the brain cortex and / or the hippocampus. In an embodiment the neurological disorder is one or more selected from the group consisting of central nervous system inflammation and / or injury, movements conditions or disorders, psychotic conditions or disorders, depressive conditions or disorders, anxiety conditions or disorders, nervous system and / or brain damage, cognitive conditions or disorders, personality conditions or disorders, mood conditions or disorders, migraine, epilepsy or convulsive disorders, neurodegenerative condition or disorder, autistic disorders, neuropathy and neurotoxicity. The term neurological disorder also is intended to refer to neuro-motoric functions, neuro-sensoric functions (general neurological functions, not only cognitive). The terms neurological disorder and neurological condition when used herein are used interchangeable and intended to have the same meaning. The subject may be human or a non-human animal such as a vertebrate or a mammal, such as a rodent, a primate or a domesticated animal including dogs, cats, cows and pigs. As demonstrated in Example 2 and Figure 1, the combination of cGP and GPE results in significant increase in neurite outgrowth, while cGP or GPE individually do not have any significant effect. Therefore, in an embodiment neurite outgrowth is increased in the subject. Thus in an embodiment a composition as broadly described herein is administered to a subject in order to promote neurite outgrowth in vivo. In an embodiment the composition as described herein is used to treat, prevent or ameliorate a disease by promoting neurite outgrowth in a subject, preferably a disease associated with reduced or impaired neurite outgrowth. In an embodiment the administration of a composition as broadly described herein results in increased neurite outgrowth in the subject. Positive controls demonstrated a significant effect on neurite outgrowth as expected (not shown). As demonstrated by Example 2 and Figure 2, the combination of cGP and GPE significantly reduces cytokine release upon stimulation with LPS, while cGP or GPE individually do not significantly reduced cytokine release. Therefore, in an embodiment neuro-inflammation is reduced in the subject. In an embodiment cytokine production by glial cells is reduced in the subject. In an embodiment IL-1β production by glial cells is reduced in the subject. Thus in an embodiment a composition as broadly described herein is administered to a subject in order to suppress neuro-inflammation in vivo. In an embodiment the composition as described herein is used to treat, prevent or ameliorate a disease by suppressing neuroinflammation in a subject, preferably a disease associated with neuro-inflammation. Positive controls demonstrated a significant reduction on cytokine release as expected (not shown). In an embodiment the composition as described herein is used to treat, prevent or ameliorate a disease by reducing cytokine production by glial cells in a subject, preferably a disease associated with cytokine production by glial cells. In an embodiment the composition as described herein is used to treat, prevent or ameliorate a disease by reducing IL-1β production by glial cells in a subject, preferably a disease associated with IL-1β production by glial cells. In an embodiment the administration of a composition as broadly described herein results in decreased neuro-inflammation, reduced cytokine production by glial cells, or reduced IL-1β production by glial cells in the subject. EXAMPLES Example 1 – exemplary peptides Below is a list of exemplary peptides in accordance with the invention: SEQ ID NO: 1 – GPEGPEGPE SEQ ID NO: 2 – GPEGPEGPEGPE SEQ ID NO: 3 – GPEGPEGPEGPEGPE SEQ ID NO: 4 – GPEGPEGPEGPEGPEGPE SEQ ID NO: 5 – GPEGPEGPEGPEGPEGPEGPE SEQ ID NO: 6 – GPEGPEGPEGPEGPEGPEGPEGPE SEQ ID NO: 7 – GPEGPEGPEGPEGPEGPEGPEGPEGPE SEQ ID NO: 8 – GPEGPEGPEGPEGPEGPEGPEGPEGPEGPE SEQ ID NO: 9 – HHHHHHGPEGPEGPE SEQ ID NO: 11 – HHHHHHGPEGPEGPEGPEGPE SEQ ID NO: 12 – GPEGPEGP SEQ ID NO: 13 – HHHHHHGPEGPEGPEGADGPEGPEGPEGADGPEGPEGPE Prophetic Example 1 Nucleic acid constructs expressing peptides comprising a sequence selected from SEQ ID NOs 1-11. The encoded peptides further comprise a purification handle and a signal peptide targeting the peptides for secretion. The nucleotides were introduced in yeast and the yeast was allowed to express the peptides. The peptid es were isolated form the culture medium using the purification handles. Peptides were treated glycyl aminopeptidase (XP-559, Nagase ChemteX) to produce a composition comprising tripeptides with the sequence Gly-Pro-Glu. The composition was subsequently heated to 100°C for 24 hours to create a composition consisting primarily of cyclic Gly-Pro and Gly-Pro-Glu. It is anticipated that the methods described here strongly increase efficiency of cyclic dipeptide production and result in a more homogenous and defined composition. Prophetic Example 2 Improvement of rodent neurological function as determined by the Morris Water Maze test in rodents along with measurement of neuroinflammation. Study setup The study will use naïve adult male rodents housed and grown under standard conditions. Water and food will be available ad libitum. Animals will be assigned to treatment groups prior to the experiment: I negative control group (naïve), II positive control scopolamine group, III control group scopolamine + [medication] IV scopolamine + natural source cyclic peptide group V scopolamine + tripeptide group (non-heat treated) VI scopolamine + cyclic dipeptide group (heat treated) VII scopolamine + tripeptide / cyclic dipeptide group (mixed heat treated non heat treated). In this experimental setup four control groups are defined: I animals not treated with scopolamine, II animals only receiving scopolamine, III animals receiving scopolamine and either a CNS stimulant such as methylphenidate or cholinesterase inhibitor such as donepezil (or a combination thereof) which inhibits the effect of scopolamine and IV animals receiving scopolamine complemented with a natural source of cyclic dipeptides (hydrolysate of collagen and / or whey powder). The experimental groups are defined as V: animal receiving scopolamine complemented with a tripeptide composition as defined herein which has not been heat treated (so no cyclic peptides are present, mainly comprising Gly-Pro-Y / Gly- Pro-Glu); VI: animal receiving scopolamine complemented with a tripeptide composition as defined herein which has been heat treated (so predominantly cyclic peptides are present, mainly comprising cPG and some residual Gly-Pro-Y / Gly-Pro- Glu); and VII animal receiving scopolamine complemented with a mixture of heat treated and non-heat treated as described above (50:50). Scopolamine disrupts memory and cognition in animals due to blockage of cholinergic neurotransmission (Laczo et al. 2016). Furthermore, administration of scopolamine also causes neuroinflammation. It is anticipated that providing a source of cyclic peptides will at least reduce the effect of scopolamine to some extent. Two conditions will be tested: a gelatin derived source of cyclic peptides, and a recombinant source of cyclic peptides as described herein. A Morris water maze (MWM) test will be used to evaluate long-term spatial learning and memory. A circular water tank will be filled with approximately 25 ◦C water and made opaque by adding non-toxic white paints. An escape platform will be randomly placed on one of the four quadrants, divided into the same size, and hidden by submerging it 1 cm below the water surface. Different visual cues of different shapes will be randomly designated and placed in the north, south, east, and west. The animals will be trained in four different areas, every day for several days, during the training period. The latency required to reach the submerged platform will be recorded. When the animals are able to reach the platform within 60 sec, they will be allowed to rest on the platform for 20 sec. If the animals do not reach the platform, they will be guided to the platform by an experimenter for 20 sec. In the test session, the animals will be placed in a random area other than the last training session and will be allowed to navigate for 90 sec without the platform. All of the experiments will recorded using a video camera installed on the top of the tank. Furthermore parameters indicating neuroinflammation will be measured at the end of the study upon euthanasia of the animals. Parameters can include but are not limited to interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). Sampling areas can include but are not limited to brain cortex and hippocampus. Samples will be frozen, mixed and dispersed in phosphate buffered saline (PBS) completed with protease inhibitors. The homogenate will be centrifuged and the supernatant will be analysed immediately by specific enzyme-linked immunosorbent assays (ELISA). It is anticipated that the recombinant source of cyclic peptides more profoundly reduces the effect of scopolamine compared to the gelatin derived source of cyclic peptides. Example 2 neuronal effects of composition of cPG and GPE Assay information Neurite outgrowth assay Neurons create connections via extensions of their cellular body called axons and dendrites, which are commonly referred to as “neurites”. This biological phenomenon is referred to as neurite outgrowth and is regulated by complex intracellular signaling events. Neurite outgrowth is a commonly used assay to study neuronal development and neuronal degeneration in vitro. The neurite outgrowth study has been performed in primary hippocampal cells from rats. Because both cPG and GPE peptides are speculated to be linked to the PI3-Akt pathway, which generally support neuronal development through the release of BDNF, these neurite outgrowth assays are extremely well suited to evaluated neurogenetic properties of the compounds. Neuro-inflammation assay The immortalized mouse microglia cell line BV-2 is a fast high-throughput tool. Cytokine release by the mouse microglial cell line BV-2 is stimulated by LPS. This assays is considered a valuable tool to evaluate potential anti-inflammatory aspects of the compounds under investigation. In this specific study, quantification of cytokines (IL-1β) has been performed. Test compound information Products tested A standard gelatin (250PS8, Rousselot, Gent, Belgium) was digested with alcalase (alcalase digested gelatin (ACP)) or Microbial Collagenase (collagenase digested gelatin (CCP)). These hydrolysates do not comprise GPE sequences. Two recombinant proteins (seq.14 and seq.15, below) have been expressed in P. pastoris and his-tag purified according to standard protocols. The purified recombinant proteins were further digested with microbial collagenase and heated according to standard protocols (Collagenase digested recombinant protein 1 (CRPP1) and Collagenase digested recombinant protein 2 (CRPP2)). For CRPP2, the heating step was carried out at an appropriate pH and temperature for an appropriate time ensuring that the formed levels of cGP were half those of GPE on a weight-to-weight basis (ppm w / w). %GPE on [GXY tripeptides] [GPE] [cGP] total GXY (ppm) (ppm) (ppm) tripeptides pure synthetic GPE (GPE) 987106 987106 BLD 100% pure synthetic cGP (cGP) BLD BLD 993282 NA Alcalase digested gelatin (ACP) 5673 BLD 86 0% Collagenase digested gelatin (CCP) 254405 BLD 1783 0% Heated collagenase digested recombinant protein 1 (HCRPP1) 77109 BLD 43999 0% Heated collagenase digested recombinant protein 2 (HCRPP2) 104788 64769 33215 62% Pure synthetic GPE (GPE) 987106 987106 BLD 100% Pure synthetic cGP (cGP) BLD BLD 993282 0% Overview of the contents of the different compositions tested. BLD indicates below detection limit. Sequences of recombinant protein SEQ ID NO.: 14 HHHHHHGPDGNNGAQGPPGPQGVQGGKGEQGPAGPPGFQGLPGPAGTAGEVGKPGERGIPGEF GLPGPAGPRGERGPPGESGAAGPAGPIGSRGPSGPPGPDGNKGEPGVLGAPGTAGPSGPSGLP GERGAAGIPGGKGEKGETGLRGD Number of amino acids: 149 Molecular weight: 13699 SEQ ID NO.: 15 HHHHHHGPEGAQGPEGPQGPEGGKGPEGPAGPEGFQGPEGPAGPEGEVGPEGERGPEGEFGPE GPAGPEGERGPEGESGPEGPAGPEGSRGPEGPPGPEGKSGPEGVLGPEGTAGPEGPSGPEGER GPEGIPGPEGEKGPEGLR Number of amino acids: 144 Molecular weight: 13761 RESULTS Neurite outgrowth Materials and methods Primary culture of hippocampal neurons Rat hippocampal neurons were cultured as follows; pregnant female rats of 17 days gestation (Wistar) were euthanized with a CO2 chamber and a cervical dislocation. Embryos were removed from the uterus and placed in L15 Leibovitz medium with a 2 % penicillin (10,000 U / mL) and streptomycin (10 mg / mL) solution (PS) and 1 % bovine serum albumin (BSA). Hippocampal tissues were treated for 20 min at 37 °C with a trypsin-EDTA solution. The dissociation was stopped by addition of Dulbecco’s modified Eagle’s medium (DMEM) with 4.5 g / L of glucose, containing grade II DNA-se I and 10 % fetal bovine serum (FBS). Cells were mechanically dissociated. The supernatant was discarded, and the pellet was resuspended in a culture medium consisting of Neurobasal medium with a 2 % solution of B27 supplement, 2 mM of L- glutamine, 2 % of PS solution, and 10 ng / mL of brain-derived neurotrophic factor (BDNF). Cells were seeded in 96-well plate precoated with poly-L-lysine and were cultured at 37 °C with 5% CO2. Application of test compounds On day 0 of culture, test or reference compound (or vehicle) was dissolved in the culture medium and applied on the culture for 120 hours. The concentrations of the different test compounds were adjusted to obtain the same concentrations of cGP and / or GPE in each test condition, namely 50 µM. The gelatin hydrolysates were tested at a concentration of 0.112 mg / ml. Immunostaining After 72 hours of treatment, hippocampal neurons were fixed by a cold solution of ethanol (95 %) and acetic acid (5 %). The cells were washed twice in PBS, and then permeabilized. The cultures were incubated with chicken polyclonal antibody anti Microtubule-associated protein 2 (MAP-2) at dilution of 1 / 400 in PBS. Readouts Pictures per well were automatically taken. From images, analyses were directly and automatically performed. The following read-outs were investigated: - Total neurite network (length of MAP-2 positive neurites, in µm) Statistics Statistical analysis was performed by one-way ANOVA followed by Fisher’s LSD test. A p< 0.05 was considered significant. Dataset The above described compounds have been tested with the potential to promote neurogenesis. This study aimed to evaluate the effects of various test compounds on neurite outgrowth in primary hippocampal neurons. The concentrations of cGP and / or GPE were standardized across all test conditions to 50 µM. The results are depicted in Figure 1. The gelatin hydrolysates ACP and CCP, as well as ACP and CCP spiked with GPE, and ACP spiked with cGP, did not enhance neurite outgrowth compared to the control. However, CCP spiked with cGP did promote neurite outgrowth, suggesting an unexpected synergy between specific tripeptides in CCP and the added cGP. Notably, the combination of GPE and cGP yielded the most pronounced effect on neurite outgrowth, an unprecedented finding not previously documented in prior research. The highest increase was observed in the recombinant construct enriched in cGP and GPE, highlighting a significant and novel synergistic interaction. Neuro-inflammation Materials and methods BV-2 cell culture and treatment BV2 microglial cells were cultured in a high-glucose Dulbecco's Modified Eagle Medium solution containing approximately 1% streptomycin, penicillin and 10% fetal bovine serum, at 37 °C in an incubator with 5% CO2 until reaching 90% confluency. The cells were then seeded into 96-well plates at a density of approximately 2x104cells / well and incubated along with the different test compounds. The concentrations of the different test compounds were adjusted to obtain the same concentrations of cGP and / or GPE in each test condition, namely 10 µM. The gelatin hydrolysates were tested at a concentration of 0,0224 mg / ml. Following the pre-treatment period with compounds, the cells were stimulated with 100 ng / ml LPS for 24 hours. The experiment was performed in 5 technical replicates per condition. Analyses Supernatant of all samples was collected at one time point (24 hours after LPS stimulation). Afterwards, levels of cytokines (IL-1β) were evaluated in the supernatant of all samples using an ELISA kit. ELISA was carried out according to the manufacturer’s instructions. The results were expressed as picogram per milliliter and converted based on the measured levels in the negative control. Statistics Statistical analysis was performed by one-way ANOVA followed by Fisher’s LSD test. A p< 0.05 was considered significant. Dataset The above described compounds have been tested for potential to reduce neuro- inflammation. The aim of the study was to investigate the effect of different test compounds in an immortalized mouse microglia BV-2 cell line that was stimulated with LPS. The concentrations of the different test compounds was adjusted to obtain the same concentrations of cGP and / or GPE in each test condition, namely 10 µM. The results are depicted in Figure 2. Apart from the gelatin hydrolysates, ACP and CCP, all treatments effectively reduced IL-1β levels compared to the positive control group. The recombinant product enriched in cGP and GPE exhibited the lowest reduction in inflammation, demonstrating a clear synergistic effect compared to the conditions where cGP and GPE were administered separately LITERATURE Mizushige et al., J Nutr Sci Vitaminol, 65, 251-257, 2019 Taga et al., J. Agric. Food Chem.2017, 65, 9514-9521 Nogimura et al., The FASEB Journal 2020:34, 5715-5723 Hayasaka et al., Food Science and Technology Research, 22 (4), 477_483, 2016 Yamamoto et al., Oyo Yakuri (Pharmacometrics) (0300-8533), May 2023, Vol. 104 Issue 3 / 4, p41-54. Laczo et al., Psychopharmacology (Berl).2017 Feb;234(4):535-547. Kimple ME, et al., Curr Protoc Protein Sci.2013 Sep 24;73:9.9.1-9.9.23. Otsuka et al., Bioscience, Biotechnology, and Biochemistry, 83:12, 2355-2363. Sampaio-Dias et al., Green Chemistry, vol.22, no.11, pages 3584-3596.

Claims

CLAIMS 1. A composition comprising cyclic Gly-Pro (cGP) and tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu (GPE).

2. The composition according to claim 1, wherein at least 2%, preferably at least 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the tripeptides in the composition have the formula Gly-Pro-Glu.

3. The composition according to claim 1 or 2, wherein at least 10%, preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the tripeptides in the composition have the formula Gly-Pro-Y.

4. The composition according to any one of the preceding claims, wherein the amount of cyclic Gly-Pro in moles per Liter is at least equal to the amount of tripeptides in moles per Liter.

5. The composition according to any one of the preceding claims, wherein the cGP is obtained by heating the tripeptides to partially convert Gly-Pro-Glu to cGP.

6. The composition according to any one of the preceding claims, wherein cGP and GPE are present in the composition in a molar ratio between 50:1 to 1:

50.

7. The composition according to any one of the preceding claims, wherein the concentration of each of cGP and GPE individually in the composition is 1 mM or more 8. A method for manufacturing a composition comprising cyclic Gly-Pro and Gly- Pro-Glu tripeptide as defined in any one of claims 1 to 7, the method comprising heating a composition comprising tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid,wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro- Glu, to obtain a composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide.

9. The method according to claim 8 wherein the method further comprises a step of supplementing the composition with a composition comprising Gly-Pro-Glu, preferably wherein the supplemented composition comprising Gly-Pro-Glu is also a composition comprising tripeptides according to the formula Gly-X-Y, wherein X and Y are individually for each tripeptide selected from an amino acid, wherein at least 1% of the tripeptides in the composition have the formula Gly-Pro-Glu.

10. The method according to claim 8 or 9, wherein the method further comprises the step of purifying the cyclic Gly-Pro and the Gly-Pro-Glu tripeptide form the composition.

11. A composition comprising cyclic Gly-Pro and Gly-Pro-Glu tripeptide obtained or obtainable by the method according to any one of claims 8 to 10.

12. The composition according to any one of claims 1 to 7, or claim 11, for use in the treatment, amelioration or prevention of a neurological disorder in a subject.

13. The composition for use according to claim 12, wherein the treatment, amelioration or prevention of a neurological disorder comprises improving cognitive functions in a subject, preferably the neurological disorder is one or more selected from the group consisting of central nervous system inflammation and / or injury, movements conditions or disorders, psychotic conditions or disorders, depressive conditions or disorders, anxiety conditions or disorders, nervous system and / or brain damage, cognitive conditions or disorders, personality conditions or disorders, mood conditions or disorders, migraine, epilepsy or convulsive disorders, neurodegenerative condition or disorder, autistic disorders, neuropathy and neurotoxicity.

14. The composition for use according to claim 12 or 13, wherein neurite outgrowth is increased in the subject.

15. The composition for use according to claim 12 or 13, wherein neuro- inflammation is reduced in the subject, preferably wherein cytokine production by glial cells is reduced in the subject, more preferably wherein IL-1β production by glial cells is reduced in the subject.

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