Muropeptides and peptidoglycans, and their use in the treatment of diseases

Abstract

The present invention relates to an isolated muropeptide of formula (I) GlcNAc-MurNAc-X1-Glu-mDAP-(Ala)Y1-(X2)Y2 as well as peptidoglycans (PG) comprising it and to a composition comprising at least one muropeptide and / or at least one PG and to the implementation of the muropeptide, peptidoglycan or composition in the prevention and / or treatment, in an individual in need thereof, of an immune disorder selected from the group consisting of an inflammatory disorder, graft-versus-host disease (GVHD) and graft rejection; or of an infection; or of a metabolic disorder or of a cancer.

Description

[0001] MUROPEPTIDES AND PEPTIDOGLYCANS, AND THEIR USE IN THE

[0002] TREATMENT OF DISEASES

[0003] FIELD OF THE INVENTION

[0004] This invention relates to novel muropeptides and peptidoglycans, and to their use in methods of treating (i) immune disorders selected from the group consisting of inflammatory disorders, graft-versus-host disease (GVHD) and graft rejection; (ii) cancers, (iii) infections and / or (iv) metabolic disorders.

[0005] BACKGROUND OF THE INVENTION

[0006] Inflammatory and immune disorders represent a significant area of medical concern due to their often chronic nature and the substantial impact they have on patients' quality of life. These conditions encompass a broad range of diseases, each characterized by inflammation and an overactive immune response that targets the body's own tissues.

[0007] Inflammatory disorders are a subset of immune disorders marked by the activation of the immune system, resulting in inflammation that can affect various tissues and organs. Among these, joint inflammation disorders such as rheumatoid arthritis, osteoarthritis, gouty arthritis, and psoriatic arthritis are prevalent, causing pain, swelling, and reduced mobility in affected joints. Skin inflammation disorders like dermatitis, psoriasis, and eczema also pose significant challenges, often leading to discomfort, itching, and longterm skin damage. Gastrointestinal inflammation disorders, including colitis, ulcerative colitis, Crohn’s disease, gastritis, and Irritable Bowel Syndrome (IBS), affect the digestive tract, causing symptoms such as abdominal pain, diarrhea, and malnutrition. Respiratory inflammation disorders such as asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis compromise breathing and overall respiratory health. Systemic inflammatory disorders like systemic lupus erythematosus (SLE), sarcoidosis, and vasculitis have widespread effects, attacking multiple organ systems and leading to severe complications. Musculoskeletal inflammation, including tendinitis, bursitis, and myositis, often results in pain and functional impairment. Neurological inflammation disorders such as multiple sclerosis (MS), meningitis, and Guillain-Barre syndrome impact the nervous system, leading to neurological deficits and disability. Cardiovascular inflammation disorders, including atherosclerosis, myocarditis, and pericarditis, affect heart function and vascular health, contributing to significant morbidity and mortality. Ophthalmic inflammation disorders like uveitis, conjunctivitis, and keratitis can lead to vision impairment and loss, while renal inflammation disorders such as glomerulonephritis, pyelonephritis, and interstitial nephritis affect kidney function, leading to renal failure if untreated.

[0008] Additionally, immune disorders such as graft- versus-host disease (GVHD) and graft rejection are critical concerns in the context of organ and tissue transplantation. GVHD occurs when donor immune cells attack the recipient's body, while graft rejection is the recipient's immune response against the transplanted organ or tissue. Both conditions are serious complications that can significantly hinder the success of transplantation procedures.

[0009] Nucleotide-binding oligomerization domain-containing protein 2 (N0D2) is a pattern recognition receptor (PRR) central to the innate immune response. Expressed in immune cells such as macrophages and dendritic cells, as well as intestinal epithelial cells, N0D2 recognizes bacterial peptidoglycans, particularly muramyl dipeptide (MDP). Upon activation, N0D2 initiates signaling pathways that activate transcription factors like NF-KB and MAPKs, resulting in the production of cytokines and antimicrobial peptides.

[0010] Importantly, N0D2 activation can influence macrophage polarization, promoting or inhibiting the shift toward the Ml phenotype depending on contextual factors since Ml macrophages are associated with pro-inflammatory responses, while M2 macrophages exhibit anti-inflammatory properties.

[0011] Dysregulation of N0D2 has been implicated in several immune disorders. For example, loss-of-function mutations in the N0D2 gene are linked to Crohn’s disease, a chronic inflammatory bowel disease.

[0012] These findings highlight the critical role of N0D2 in maintaining immune balance.

[0013] The ability to modulate N0D2 activity represents a significant therapeutic opportunity. Controlled activation of N0D2 can fine-tune immune responses, potentially reducing pro-inflammatory signaling while promoting anti-inflammatory mechanisms such as the production of IE- 10.

[0014] This makes NOD2 a compelling target for addressing inflammatory and immune-mediated diseases. In the realm of infectious diseases, C. difficile infections, which are characterized by severe intestinal inflammation, could benefit from targeted N0D2 activation to restore immune homeostasis, mitigate inflammation, and promote epithelial repair.

[0015] Metabolic disorders, including obesity and type 2 diabetes, have also been linked to chronic, low-grade inflammation. NOD2’s role in regulating immune responses and maintaining gut microbiota balance supports that modulating its activity should alleviate inflammation-associated metabolic dysfunctions.

[0016] Moreover, N0D2 is also a compelling target for the treatment of cancers. By modulating N0D2 activity, anti-tumor immunity can be enhanced through its influence on macrophage polarization and cytokine production. Specifically, the Ml macrophage phenotype, associated with pro-inflammatory and anti-tumor responses, may be promoted under appropriate conditions via N0D2 activation.

[0017] As an example of the therapeutic relevance of N0D2 activation in the treatment of cancers, Mifamurtide (muramyl tripeptide phosphatidyl ethanolamine, MTP-PE) is a N0D2 activator approved by the European Medicines Agency (EMA) for the treatment of osteosarcoma.

[0018] This illustrates the potential of N0D2 activation-based therapies to address various conditions that involve immune dysregulation, paving the way for further applications in oncology, infectious diseases, and metabolic disorders.

[0019] There is accordingly a constant need for new compounds having the ability to reduce the activity of the immune system in an individual in need thereof, and thus able to prevent and / or treat immune disorders in an individual, in particular to prevent and / or treat inflammatory disorders, graft- versus-host disease (GVHD) and graft rejection.

[0020] There is a need for new compounds having the ability to prevent and / or treat an inflammatory disorder selected from the group consisting of joint inflammation disorder, in particular rheumatoid arthritis, osteoarthritis, gouty arthritis or psoriatic arthritis; skin inflammation disorder, in particular dermatitis, psoriasis or eczema; gastrointestinal inflammation disorder, in particular colitis, ulcerative colitis, Crohn’s disease, gastritis or Irritable bowel syndrome (IBS); respiratory inflammation disorder, in particular asthma, chronic obstructive pulmonary disease (COPD) or allergic thinitis; systemic inflammatory disorder, in particular systemic lupus erythematosus (SLE), sarcoidosis or vasculitis; musculoskeletal inflammation, in particular tendinitis, bursitis or myositis; neurological inflammation disorder, in particular multiple sclerosis (MS), meningitis or Guillain-Barre syndrome; cardiovascular inflammation disorder, in particular atherosclerosis, myocarditis or pericarditis; ophthalmic inflammation disorder, in particular uveitis, conjunctivitis or keratitis; and renal inflammation disorder, in particular glomerulonephritis, pyelonephritis or interstitial nephritis.

[0021] There is also a need for innovative therapeutic approaches that specifically target N0D2 activation to effectively treat oncology, infectious diseases, and / or metabolic disorders.

[0022] The present invention aims to address these challenges by providing new active compounds, in the form of new muropeptides and peptidoglycans, with potent N0D2 activation properties.

[0023] SUMMARY OF THE INVENTION

[0024] According to a first object, the present invention relates to an isolated muropeptide of formula (I):

[0025] GlcNAc-MurNAc-Xi-Glu-mDAP-(Ala)Yi-(X2)Y2 (I) wherein:

[0026] - GlcNAc represents a N-acetylglucosamine, optionally N-deacetylated;

[0027] - MurNAc represents a N-Acetylmuramic acid, non- substituted or substituted with Acetyl (Ac);

[0028] - Xi is an amino acid selected from the group consisting of Glycine and Alanine;

[0029] - Glu represents a glutamic acid non-substituted with (-NH2), and optionally substituted with a Glycine;

[0030] - mDAP represents a meso-diaminopimelic acid non-substituted with (-NH2);

[0031] - Ala represents an Alanine;

[0032] - Y 1 represents 0 or 1 ;

[0033] - X2 is an amino acid selected from the group consisting of Alanine, Glycine and Serine, the amino acid being non-substituted; and

[0034] - Y2 represents 0 or 1.

[0035] MurNAc may in particular be O-acetylated. The amino acid represented by Xi may in particular be non-substituted.

[0036] Xi may in particular be a Glycine.

[0037] Glu may in particular be non-substituted with a Glycine, and may more particularly be non-substituted. mDAP may in particular be non-substituted.

[0038] In particular, when Y1 is 0 then Y2 is 0.

[0039] X2may in particular be an amino acid selected from the group consisting of Alanine and Glycine, and in particular is Glycine.

[0040] Y2 may in particular be 0.

[0041] The muropeptides according to the invention in particular consist in the formula (I) according to the invention.

[0042] Another object of the invention relates to a peptidoglycan, in particular an oligomer, comprising at least one, in particular at least two, muropeptide(s) according to the invention, more particularly the peptidoglycan being of formula (II):

[0043] [GlcNAc-MurNAc-Xi-Glu-mDAP-(Ala)Yi-(X2)Y2]n (II) in which n represents an integer between 2 and 8, particularly between 2 and 5, inclusive; and

[0044] GlcNAc, MurNAc, Xi, Glu, mDAP, Ala, Yl, X2 and Y2 are as defined herein.

[0045] Another object of the invention relates to a composition, in particular a pharmaceutical composition, comprising, in a physiologically acceptable medium, at least one muropeptide according to the invention and / or at least one peptidoglycan according to the invention.

[0046] The composition according to the invention may be formulated under a form selected from the group consisting of a tablet, a capsule, an oral suspension, an effervescent tablet, a lozenge, a powder, a granule, a solution, a syrup, an emulsion, a gel, a cream, an ointment, a lotion, a patch, a transdermal gel, a transdermal patch, an injectable solution, an intravenous infusion, an intramuscular injection, a subcutaneous injection, an intranasal spray, an inhalation aerosol, a rectal suppository, a vaginal suppository, and a buccal formulation.

[0047] A further object of the invention relates to a muropeptide according to the invention, or a peptidoglycan according to the invention or a composition according to the invention, for use as a medicament. The muropeptide, peptidoglycan or composition for use according to the invention may in particular be for use in the prevention and / or treatment, in an individual in need thereof, of an immune disorder selected from the group consisting of an inflammatory disorder, graft- versus-host disease (GVHD) and graft rejection.

[0048] The inflammatory disorder may in particular be selected from the group consisting of joint inflammation disorder, in particular rheumatoid arthritis, osteoarthritis, gouty arthritis or psoriatic arthritis; skin inflammation disorder, in particular dermatitis, psoriasis or eczema; gastrointestinal inflammation disorder, in particular colitis, ulcerative colitis, Crohn’s disease, gastritis or Irritable bowel syndrome (IBS); respiratory inflammation disorder, in particular asthma, chronic obstructive pulmonary disease (COPD) or allergic thinitis; systemic inflammatory disorder, in particular systemic lupus erythematosus (SLE), sarcoidosis or vasculitis; musculoskeletal inflammation, in particular tendinitis, bursitis or myositis; neurological inflammation disorder, in particular multiple sclerosis (MS), meningitis or Guillain-Barre syndrome; cardiovascular inflammation disorder, in particular atherosclerosis, myocarditis or pericarditis; ophthalmic inflammation disorder, in particular uveitis, conjunctivitis or keratitis; and renal inflammation disorder, in particular glomerulonephritis, pyelonephritis or interstitial nephritis.

[0049] The muropeptide, peptidoglycan or composition for use according to the invention may in particular be for use in the prevention and / or treatment, and in particular in the treatment, in an individual in need thereof, of an infection, in particular of an infection by C. difficile.

[0050] The muropeptide, peptidoglycan or composition for use according to the invention may in particular be for use in the prevention and / or treatment, and in particular in the treatment, in an individual in need thereof, of a metabolic disorder, in particular a metabolic disorder selected from the group consisting of diabetes, insulin resistance, metabolic syndrome and Metabolic dysfunction-Associated Liver Disease.

[0051] The muropeptide, peptidoglycan or composition for use according to the invention may be administered to an individual in need thereof in combination with at least an anti-inflammatory agent different from a muropeptide according to the invention and from a peptidoglycan from the invention.

[0052] The second anti-inflammatory agent may be selected from the group consisting of corticosteroids; probiotics; nonsteroidal anti-inflammatory drugs (NSAIDs); and biologic agents, the biologic agents being in particular selected from the group consisting of tumor necrosis factor inhibitors, in particular Infliximab, Adalimumab, Etanercept, Certolizumab pegol or Golimumab; Interleukin- 1 (IL-1) Inhibitor, in particular Anakinra; Interleukin-6 (IL-6) Inhibitors, in particular Tocilizumab or Sarilumab; Interleukin- 12 / 23 (IL- 12 / 23) Inhibitor, in particular Ustekinumab; Interleukin- 17 (IL- 17) Inhibitors, in particular Secukinumab or Ixekizumab; Interleukin-23 (IL-23) Inhibitors, in particular Guselkumab, Risankizumab or Tildrakizumab; Interleukin-4 / 13 (IL-4 / 13) Inhibitor, in particular Dupilumab; an anti-CD20 antibody, such as Rituximab; and B-Cell Activating Eactor (BALE) Inhibitor, in particular Belimumab.

[0053] The muropeptide, peptidoglycan or composition for use according to the invention may in particular be for use in the prevention and / or treatment, and in particular in the treatment, in an individual in need thereof, of a cancer, in particular of a cancer selected from the group consisting of Melanoma, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Renal Cell Carcinoma, Bladder Cancer, Head and Neck Squamous Cell Carcinoma, Gastric Cancer, Colorectal Cancer (with micro satellite instability-high or mismatch repair-deficient tumors), Rectal Cancer (with microsatellite instability-high or mismatch repair-deficient tumors), Hepatocellular Carcinoma, Cervical Cancer, Ovarian Cancer, Triple-Negative Breast Cancer, Esophageal Cancer, Malignant Pleural Mesothelioma, Prostate Cancer, Pancreatic Cancer and Any Solid Tumor with High Tumor Mutational Burden or Micro satellite Instability-High (MSI-H) / Mismatch Repair Deficiency (dMMR) status.

[0054] The individual in need thereof may be a mammal, and is in particular a human being.

[0055] DETAILED DESCRIPTION OF THE INVENTION

[0056] The inventors have been able to generate a plurality of muropeptides and peptidoglycans having anti-inflammatory properties, and in particular a significant ability to increase the activation of N0D2 and to significantly increase the production of IL- 10. This dual activity illustrates that the muropeptides and peptidoglycans according to the invention are particularly effective in controlling inflammatory responses. As indicated previously, by enhancing NOD2 activation, they engage pathways that can modulate immune cell behavior, potentially reducing pro-inflammatory signalling. Additionally, the increased IL- 10 production supports an anti-inflammatory environment, promoting immune tolerance and minimizing tissue damage associated with inflammation, in particular with chronic inflammation. Together, these properties indicate that the muropeptides and peptidoglycans are useful for therapeutic applications in a range of inflammatory and immune-mediated disorders.

[0057] Definitions

[0058] The term “muropeptide” refers to a structural subunit of peptidoglycan, comprising a disaccharide backbone of N-acetylglucosamine and N-acetylmuramic acid attached to a short peptide chain.

[0059] The term “peptidoglycan” refers to a structural component usually found in the cell walls of bacteria, imparting rigidity and shape to the cell envelope. It consists of linear polysaccharide chains composed of alternating residues of N-acetylglucosamine and N- acetylmuramic acid, cross -linked by short peptide bridges.

[0060] As used herein, the terms “protein”, “peptide”, and “polypeptide” are used interchangeably to refer to a polymer of amino acid residues. All three terms apply to naturally occurring amino acid polymers and non-natural amino acid polymers, as well as to amino acid polymers in which one (or more) amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid. As used herein, the terms encompass amino acid chains of any length, including full-length proteins, wherein the amino acid residues are linked by covalent peptide bonds.

[0061] By “isolated” is meant a biological molecule free from at least some of the components with which it naturally occurs.

[0062] As used herein, the terms “treating”, “treat” or “treatment” include alleviation of the symptoms associated with a specific disorder or condition and / or elimination of said symptoms as well as the complete disappearance of the considered disorder or condition.

[0063] According to the invention, the terms “patient”, “individual” , “patient in need thereof ’ or “individual in need thereof ’ are equivalent and are intended for a human or nonhuman mammal affected or likely to be affected with an immune disorder selected from the group consisting of an inflammatory disorder, graft- versus-host disease (GVHD) and graft rejection. Said individual is preferably a human being.

[0064] As used herein, “prevention” or “preventing” with respect to a disease or disorder relate to prophylactic treatment of the disease or the disorder, e.g., in an individual suspected to have the disease, or at risk for developing the disease. Prevention may include, but is not limited to, preventing or delaying onset or progression of the disease and / or maintaining one or more symptoms of the disease or disorder at a desired or sub-pathological level. The term “prevent” does not require the 100% elimination of the possibility or likelihood of occurrence of the event. Rather, it denotes that the likelihood of the occurrence of the event has been reduced in the presence of a muropeptide, a peptidoglycan or composition according to the invention.

[0065] Types of diseases and disorders that can be prevented and / or treated by methods of the present invention include, but are not limited to, graft-versus-host disease (GVHD), graft rejection and inflammatory disorders, in particular inflammatory disorders selected from the group consisting of joint inflammation disorder, in particular rheumatoid arthritis, osteoarthritis, gouty arthritis or psoriatic arthritis; skin inflammation disorder, in particular dermatitis, psoriasis or eczema; gastrointestinal inflammation disorder, in particular colitis, ulcerative colitis, Crohn’s disease, gastritis or Irritable bowel syndrome (IBS); respiratory inflammation disorder, in particular asthma, chronic obstructive pulmonary disease (COPD) or allergic thinitis; systemic inflammatory disorder, in particular systemic lupus erythematosus (SLE), sarcoidosis or vasculitis; musculoskeletal inflammation, in particular tendinitis, bursitis or myositis; neurological inflammation disorder, in particular multiple sclerosis (MS), meningitis or Guillain-Barre syndrome; cardiovascular inflammation disorder, in particular atherosclerosis, myocarditis or pericarditis; ophthalmic inflammation disorder, in particular uveitis, conjunctivitis or keratitis; and renal inflammation disorder, in particular glomerulonephritis, pyelonephritis or interstitial nephritis.

[0066] Types of diseases and disorders that can be prevented and / or treated by methods of the present invention also include, but are not limited to, infections, in particular C. difficile infection.

[0067] Types of diseases and disorders that can be prevented and / or treated by methods of the present invention also include, but are not limited to, metabolic disorders, in particular selected from the group consisting of diabetes, insulin resistance, metabolic syndrome and Metabolic dysfunction-Associated Liver Disease.

[0068] Types of diseases and disorders that can be prevented and / or treated by methods of the present invention also include, but are not limited to cancers, in particular selected from the group consisting of Melanoma, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Renal Cell Carcinoma, Bladder Cancer, Head and Neck Squamous Cell Carcinoma, Gastric Cancer, Colorectal Cancer (with microsatellite instability-high or mismatch repairdeficient tumors), Rectal Cancer (with micro satellite instability-high or mismatch repairdeficient tumors), Hepatocellular Carcinoma, Cervical Cancer, Ovarian Cancer, TripleNegative Breast Cancer, Esophageal Cancer, Malignant Pleural Mesothelioma, Prostate Cancer, Pancreatic Cancer and Any Solid Tumor with High Tumor Mutational Burden or Micro satellite Instability-High (MSI-H) / Mismatch Repair Deficiency (dMMR) status.

[0069] An individual according to the invention may be selected from the group consisting of human beings; Suidae, in particular pigs, more particularly piglets; Bovinae, in particular cattle, more particularly bulls, and more particularly steers; Canidae, in particular dogs; Equidae, in particular horses; and Phasianidae, in particular poultry, more particularly chickens. In particular, an individual according to the invention is a mammal, in particular a human being.

[0070] The term “physiologically acceptable medium” is intended to denote a medium which is compatible with the body of the individual to whom said composition must be administered. It is, for example, a non-toxic solvent such as water. In particular, said medium is compatible with oral administration.

[0071] Muropeptides and peptidoglycans of the invention

[0072] As previously mentioned, the present invention relates to an isolated muropeptide of formula (I):

[0073] GlcNAc-MurNAc-Xi-Glu-mDAP-(Ala)Yi-(X2)Y2 (I)

[0074] GlcNAc represents a N- acetylgluco s amine.

[0075] GlcNAc may optionally be N-deacetylated.

[0076] “N-deacetylated” refers to a molecule from which one or more acetyl group(s) (CHsCO) have been removed from one or more nitrogen atom(s).

[0077] GlcNAc, N-deacetylated or not, is preferably not substituted.

[0078] Unless otherwise indicated, a “substituted” group has an additional substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include, unless indicated otherwise, substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valences of the heteroatoms and results in the formation of a stable moiety.

[0079] In a particular embodiment, GlcNAc is non- substituted, meaning it does not carry any additional substituents. This is equivalent to stating that GlcNAc “is not substituted” and contains no further modifications.

[0080] MurNAc represents a N-Acetylmuramic acid.

[0081] MurNAc is non- substituted or substituted with Acetyl (Ac) or N-deacetylated. In a particular embodiment, MurNAc is substituted with an Acetyl (Ac) group.

[0082] An “Acetyl” or “Acetyl group” (Ac), the terms being used interchangeably herein, designate a functional group with the chemical structure -COCH3.

[0083] In a particular embodiment, MurNAc is non- substituted.

[0084] A muropeptide of the invention may be such that GlcNAc is non- substituted or N-deacetylated while MurNAC is substituted with an Acetyl (Ac) group.

[0085] A muropeptide of the invention may be such that GlcNAc and MurNAc are both non-substituted.

[0086] A muropeptide of the invention may be such that GlcNAc and MurNAc are both non-substituted with GlcNAc being also N-deacetylated.

[0087] Xi is an amino acid selected from the group consisting of Glycine and Alanine.

[0088] Xi may in particular be a Glycine.

[0089] Xi may in particular be non-substituted, i.e. a non-substituted Glycine or a nonsubstituted Alanine.

[0090] Xi may in particular be a non-substituted Glycine.

[0091] A muropeptide of the invention may be such that GlcNAc and MurNAc are nonsubstituted and Xi is a non-substituted Glycine or a non-substituted Alanine, and in particular is a non-substituted Glycine. A muropeptide of the invention may be such that when Xi is an alanine, in particular a non- substituted alanine, GlcNAc and MurNAc are non-substituted, with GlcNAc being optionally N-deacetylated.

[0092] A muropeptide of the invention may be such that when MurNAc is substituted with an Acetyl (Ac) group, GlcNAc is non-substituted and Xi is a Glycine, in particular a non-substituted Glycine.

[0093] Glu represents a glutamic acid which is non-substituted with (-NH2), i.e. which is non-amidated. “-A / / 2” indeed represents a primary amine group. Glu may be nonsubstituted or substituted with a Glycine (Gly).

[0094] A muropeptide of the invention may be such that when Glu is substituted with a Glycine (Gly), GlcNAc and MurNAc are non-substituted, with GlcNAc being optionally N- deacetylated. A muropeptide of the invention may be such that when Glu is substituted with a Glycine (Gly), Xi is a Glycine. More particularly, a muropeptide of the invention may be such that when Glu is substituted with a Glycine (Gly), GlcNAc and MurNAc are nonsubstituted, with GlcNAc being optionally N-deacetylated, and Xi is a Glycine.

[0095] Glu of formula (I) may preferably be non-substituted with a Glycine and in particular be non-substituted.

[0096] A muropeptide of the invention may be such that when Glu is non-substituted with a Glycine (Gly), and in particular is non-substituted, GlcNAc is non-substituted, and is optionally N-deacetylated.

[0097] A muropeptide of the invention may be such that when Glu is non-substituted with a Glycine (Gly), and in particular is non-substituted, MurNAc is non-substituted or is substituted with Acetyl (Ac), and is in particular substituted with Acetyl (Ac).

[0098] A muropeptide of the invention may be such that when Glu is non-substituted with a Glycine (Gly), and in particular is non-substituted, Xi is an amino acid selected from the group consisting of Glycine and Alanine and is in particular a Glycine.

[0099] A muropeptide of the invention may be such that when Glu is non-substituted with a Glycine (Gly), and in particular is non-substituted, GlcNAc is non-substituted, and is optionally N-deacetylated; MurNAc is non-substituted or is substituted with Acetyl (Ac), and is in particular substituted with Acetyl (Ac); Xi is an amino acid selected from the group consisting of Glycine and Alanine and is in particular a Glycine. mDAP in formula (I) represents a meso-diaminopimelic acid which is nonsubstituted with (-NH2).

[0100] In particular, mDAP of formula (I) is non-substituted.

[0101] Ala in formula (I) represents an Alanine.

[0102] Since Y1 represents 0 or 1, a muropeptide according to the invention may comprise no Alanine linked to mDAP or one alanine linked to mDAP.

[0103] Y 1 may in particular represent 1.

[0104] X2 in formula (I) represents an amino acid selected from the group consisting of Alanine, Glycine and Serine.

[0105] The amino acid represented by X2 is non-substituted.

[0106] X2 may in particular be selected from the group consisting of Alanine and Glycine. X2 may more particularly be a Glycine.

[0107] Y2 represents 0 or 1. It may in particular represent 0.

[0108] In particular, when Y1 is 0, then Y2 is also 0.

[0109] A muropeptide according to the invention may in particular be selected from the group of muropeptides set forth as sequences SEQ ID NO: 1 to SEQ ID NO: 10 as illustrated in the below Table 1.

[0110] As previously mentioned, muropeptides according to the invention may be in a monomeric or polymeric form (i.e. in the form of a peptidoglycan).

[0111] In the context of the present invention, “monomer” or “monomeric form” are used interchangeably and refer to a single, isolated muropeptide molecule, unassociated with other muropeptide molecules.

[0112] In the context of the present invention, “peptidoglycan”, “polymer” or “polymeric form” are used interchangeably and refer to an association of at least two, and in some embodiments at least three, muropeptide molecules bonded together to form a larger, multi-unit structure.

[0113] In the context of the present invention, an “oligomer” refers to a polymeric structure comprising an association of a limited number of muropeptide molecules, specifically between 2 and 9 units. The present invention accordingly also relates to a peptidoglycan (or polymer), in particular an oligomer, comprising at least one, and more particularly at least two, muropeptide(s) according to the invention.

[0114] A peptidoglycan according to the invention in particular comprises 2, 3, 4 or 5 muropeptides according to the invention, more particularly 2 or 3 muropeptides according to the invention, and even more particularly consists in 2, 3, 4 or 5, more particularly 2 or 3, muropeptides according to the invention.

[0115] Accordingly, a peptidoglycan according to the invention is more particularly of formula (II):

[0116] [GlcNAc-MurNAc-Xi-Glu-mDAP-(Ala)Yi-(X2)Y2]n (II) in which n represents an integer between 2 and 8, particularly between 2 and 5, inclusive; and

[0117] GlcNAc, MurNAc, Xi, Glu, mDAP, Ala, Yl, X2 and Y2 are as previously defined.

[0118] When n is indicated as representing an integer between 2 and 8, it is intended to be selected from the group consisting of 2, 3, 4, 5, 6, 7 and 8. When n is indicated as representing an integer between 2 and 5, it is intended to be selected from the group consisting of 2, 3, 4 and 5.

[0119] More particularly, n in a peptidoglycan of the invention of formula (II) may represent 2 or 3.

[0120] A peptidoglycan in which n represents 2 may be herein termed a dimer.

[0121] A peptidoglycan in which n represents 3 may be herein termed a trimer.

[0122] A peptidoglycan in which n represents 4 may be herein termed a tetramer.

[0123] A peptidoglycan in which n represents 5 may be herein termed a pentamer.

[0124] GlcNAc, MurNAc, Xi, Glu, mDAP, Ala, Yl, X2 and Y2 are defined, independently or in combination, as per the above developments.

[0125] In an embodiment, each muropeptide of formula (I) comprised in a peptidoglycan according to the invention of formula (II) is identical.

[0126] In an embodiment, at least two muropeptides of formula (I) comprised in a peptidoglycan according to the invention of formula (II) are identical. In such an embodiment, when n is superior to 2, and for example is 3, the two identical muropeptides may be linked to one another or may be linked by the intermediate of one or more, in particular one in a trimer, muropeptide according to the invention.

[0127] In a particular embodiment, each muropeptide of formula (I) comprised in a peptidoglycan according to the invention of formula (II) is different. Accordingly, in such embodiment, in the case of a dimer, the two muropeptides of formula (I) are different.

[0128] Accordingly, in such embodiment, in the case of a trimer, the three muropeptides of formula (I) are different, i.e. the peptidoglycan according to the invention comprises three different muropeptides of formula (I). In a particular embodiment, a peptidoglycan according to the invention comprises at least one, and in particular at least two, muropeptides having a sequence selected from the group of sequences consisting of the sequences set forth as SEQ ID NO: 1 to SEQ ID NO: 10.

[0129] A peptidoglycan according to the invention may in particular be selected from the dimers and trimers having a sequence selected from the group of sequences consisting of the sequences set forth as SEQ ID NO: 11 to 27.

[0130] Preferably, a peptidoglycan according to the invention consists in 2 to 8 muropeptides of formula (I) according to the invention, i.e. consists in a peptidoglycan of formula (II).

[0131] TABLE 1

[0132] Methods of producing peptidoglycans and muropeptides of the invention

[0133] Peptidoglycans (or polymers) and muropeptides according to the invention may be prepared using well known methods such as for example through chemical synthesize as described in Adamson et al., Chem Commun (Camb). 2024 Feb 20;60(16):2212-2215 or through chemoenzymatic synthesis as described in Giradin et al., J Biol Chem. 2003 Oct 24;278(43):41702-8).

[0134] Alternatively, muropeptides as per the invention may be obtained from the peptidoglycans after digestion of a peptidoglycan (the polymer) by mutanolysin, a peptidoglycan hydrolase that cleaves the glycan strands between MurNAc and GlcNAc. Composition of the invention

[0135] The present invention also relates to a composition, in particular a pharmaceutical composition, comprising, in a physiologically acceptable medium, at least a muropeptide and / or at least a peptidoglycan according to the invention.

[0136] According to an embodiment, a composition according to the invention can comprise at least one muropeptide according to the invention and at least one peptidoglycan according to the invention.

[0137] In a particular embodiment, a composition according to the invention can comprise at least two muropeptides according to the invention and at least two peptidoglycans according to the invention.

[0138] According to an embodiment, a composition according to the invention can comprise:

[0139] - at least one muropeptide, and in particular at least two muropeptides and more particularly all the muropeptides of Table 1; and / or

[0140] - at least one peptidoglycan, and in particular at least two peptidoglycans and more particularly all the peptidoglycans of Table 1.

[0141] A composition according to the invention may be chosen from an oral or rectal composition and is in particular an oral composition.

[0142] A composition of the invention being an oral composition is intended for oral administration to an individual.

[0143] A composition of the invention being a rectal composition is intended for rectal administration to an individual.

[0144] An oral composition may be in the form of a suspension, a tablet, a pill, a capsule, a granule or a powder.

[0145] A composition according to the invention for oral administration may be chosen from the group consisting of a food product, a beverage, a pharmaceutical product, a nutraceutical, a food additive, a food supplement or a milk product and is, in particular, a pharmaceutical product.

[0146] A composition according to the invention may in particular be a pharmaceutical product. A pharmaceutical product for oral administration may be present in capsules, gel capsules, soft capsules, tablets, sugar-coated tablets, pills, pastes, lozenges, gums, oral solutions or emulsions, a syrup or a gel.

[0147] For example, a pharmaceutical product according to the invention for oral administration may be in a capsule, in particular in a capsule under the form of a lyophilizate, more particularly together with physiologically acceptable excipients.

[0148] Advantageously, a composition according to the invention intended for oral administration may be provided with a gastric -juice-resistant coating, in order to ensure that the muropeptide(s) and / or peptidoglycan(s) of the invention included in said composition can pass through the stomach. The release of the muropeptide(s) and / or peptidoglycan(s) of the invention may thus take place for the first time in the upper intestinal tract.

[0149] A pharmaceutical product for oral use according to the invention may also comprise a sweetener, a stabilizer, an antioxidant, an additive, a flavoring agent and / or a dye.

[0150] The formulation thereof is carried out by means of the usual methods for producing sugar-coated tablets, gel capsules, gels, controlled-release hydrogels, emulsions, tablets or capsules.

[0151] A composition of the invention may be administered intrarectally.

[0152] A rectal administration may in particular be carried out in the form of a suppository, an enema or a foam, in particular an enema.

[0153] A composition according to the invention may also be in the form of a nutritional composition.

[0154] A nutritional composition according to the invention may be in the form of a yogurt, a cereal bar, breakfast cereals, a dessert, a frozen food, a soup, a pet food, a liquid suspension, a powder, a tablet, a gum or a candy.

[0155] The composition according to the invention may in particular be formulated under a form selected from the group consisting of a tablet, a capsule, an oral suspension, an effervescent tablet, a lozenge, a powder, a granule, a solution, a syrup, an emulsion, a gel, a cream, an ointment, a lotion, a patch, a transdermal gel, a transdermal patch, an injectable solution, an intravenous infusion, an intramuscular injection, a subcutaneous injection, an intranasal spray, an inhalation aerosol, a rectal suppository, a vaginal suppository, and a buccal formulation. In particular, a composition of the invention may be suitable for the administration of a daily dose representing from 0.1 pg to 10 g of at least one muropeptide according to the invention and / or of at least one peptidoglycan according to the invention, preferably a daily dose equivalent to 1g.

[0156] A composition according to the invention may be administered to an individual requiring it from 1 to 10 times a day, each dose containing at least one muropeptide of the invention and / or at least one peptidoglycan according to the invention in an amount of for example between 0.1 pg and 10 g so that the total daily dose of muropeptide(s) of the invention and / or of peptidoglycan(s) according to the invention administered to the individual is as indicated above.

[0157] In particular, a composition according to the invention may be administered to an individual for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 10 days, 14 days, 15 days, 3 weeks, 1 month or for more than 1 month. When a composition according to the invention is administered for more than 1 day, the same daily amount of muropeptide(s) of the invention and / or of peptidoglycan(s) according to the invention can be administered every day or the daily amount can vary along the treatment period. In particular, the daily dosage of the muropeptide(s) of the invention and / or of peptidoglycan(s) according to the invention may be higher during the first days of the treatment and then gradually decrease.

[0158] A muropeptide according to the invention, a peptidoglycan according to the invention and / or a composition according to the invention may be administered to an individual in need thereof in combination with at least an anti-inflammatory agent different from a muropeptide of formula (I) according to the invention and from a peptidoglycan according to the invention.

[0159] Such at least one anti-inflammatory agent, also termed herein additional antiinflammatory agent, may be for example selected from the group consisting of corticosteroids; probiotics; nonsteroidal anti-inflammatory drugs (NSAIDs); and biologic agents, the biologic agents being in particular selected from the group consisting of tumor necrosis factor inhibitors, in particular Infliximab, Adalimumab, Etanercept, Certolizumab pegol or Golimumab; Interleukin- 1 (IL-1) Inhibitor, in particular Anakinra; Interleukin-6 (IL-6) Inhibitors, in particular Tocilizumab or Sarilumab; Interleukin- 12 / 23 (IL- 12 / 23) Inhibitor, in particular Ustekinumab; Interleukin- 17 (IL- 17) Inhibitors, in particular Secukinumab or Ixekizumab; Interleukin-23 (IL-23) Inhibitors, in particular Guselkumab, Risankizumab or Tildrakizumab; Interleukin-4 / 13 (IL-4 / 13) Inhibitor, in particular Dupilumab; an anti-CD20 antibody, such as Rituximab; and B-Cell Activating Factor (BAFF) Inhibitor, in particular Belimumab.

[0160] Such at least one anti-inflammatory agent, also termed herein additional antiinflammatory agent, may be for example a steroidal anti-inflammatory, a non-steroidal antiinflammatory, an anti-TNF alpha antibody and combinations thereof.

[0161] For example, steroidal anti-inflammatory agents include, without limitation, cortisone, triamcinolone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, prednisolone hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, funisolide, fluoromethalone, fluperolone, fuprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof.

[0162] Steroidal anti-inflammatory agents may be formulated for inhalation therapy and may accordingly be, without limitation, beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, triamcinolone or mixtures thereof.

[0163] Non-steroidal anti-inflammatory drugs (NSAIDs) represent a large group of therapeutic agents with analgesic, anti-inflammatory, and anti-pyretic properties. NSAIDs typically reduce inflammation by blocking the cyclooxygenase 1 and / or cyclooxygenase 2 (COX 1 and COX 2) enzymes. NSAIDs that selectively inhibit COX 2 enzymes are more sparing of the gastric mucosa, where C0X1 is predominant. Representative NSAIDs may be, without limitation, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aspirin, azapropazone, benzydamine (prostaglandin synthase inhibitor), butibufen, celecoxib, chlorthenoxacin, choline salicylate, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole, etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, fenoprofen, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamizole, mefenamic acid, metiazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxaprozin, piroxicam, pranoprofen, propyphenazone, proquazone, protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid, tolmetin, valdecoxib and mixtures thereof.

[0164] Antibody based anti-inflammatory agents may be, without limitation, infliximab, etanercept, alemtuzumab, adalimumab, omalizumab, efalizumab, alefacept, natalizumab, abatacept, certolizumab pegol, golimumab, canakinumab, tocilizumab, ustekinumab, Vedolizumab, talizumab, abrilumab, inclacumab, anifrolumab, anrukinzumab, benralizumab, brodalumab, clazakizumab, clenoliximab, eldelumab, etrolizumab, gomiliximab, mavrilimumab, oxelumab, pateclizumab, perakizumab, quilizumab, rontalizumab, sirukumab, tezepelumab, Tildrakizumab, zanolimumab and mixtures thereof.

[0165] A muropeptide according to the invention and / or a peptidoglycan according to the invention, and the at least one additional anti-inflammatory agent, may be administered to the individual in the same composition (i.e. in a composition according to the invention).

[0166] A muropeptide according to the invention and / or a peptidoglycan according to the invention, and the at least one additional anti-inflammatory agent may be administered in separate compositions.

[0167] When the muropeptide(s) according to the invention and / or the peptidoglycan(s) according to the invention, and the at least one additional anti-inflammatory agent are administered in separate compositions, the compositions can be administered to the individual simultaneously or separately through the same route of through different routes.

[0168] By simultaneously, it is understood that the muropeptide(s) according to the invention and / or the peptidoglycan(s) according to the invention, or composition comprising it / them can be administered at the same moment or up to the same day or couple of days as the at least one additional anti-inflammatory agent or composition comprising it.

[0169] By separately, it is understood that the muropeptide(s) according to the invention and / or the peptidoglycan(s) according to the invention, or composition comprising it / them, can be administered with at least several days, for example at least three days of difference, compared to the administration of the at least one additional anti-inflammatory agent or of the composition comprising it.

[0170] The dosage and frequency of administration of a muropeptide according to the invention and / or of a peptidoglycan according to the invention, may be adapted depending on the administered individual’s response.

[0171] For illustrative purposes only, the frequency of administration of one or more muropeptide(s) according to the invention and / or one or more peptidoglycan(s) according to the invention, or composition comprising it / them, may be a daily administration for 5 to 15 consecutive days. The administration can alternatively be every 2, 3, 4, 5, 6 or 7 days for a period of up to several months.

[0172] As is known in the art, adjustments for protein degradation, systemic versus localized delivery, as well as the age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and is easily determined with routine experimentation by those skilled in the art.

[0173] A composition according to the invention may also comprise at least one among: antioxidants, fish oils, DHA, EPA, vitamins, minerals, phytonutrients, a protein, a lipid, probiotics, and combinations thereof.

[0174] Therapeutic uses

[0175] As previously mentioned, a muropeptide according to the invention, a peptidoglycan according to the invention, or a composition of the invention, may be used as a medicament.

[0176] Accordingly, the present invention relates to a muropeptide according to the invention, a peptidoglycan according to the invention, or a composition of the invention, for its use as a medicament. The invention also relates to the use, in an individual in need thereof, of a muropeptide according to the invention, a peptidoglycan according to the invention, or a composition of the invention, as a medicament.

[0177] In particular, a muropeptide according to the invention, a peptidoglycan according to the invention, or a composition of the invention, may be for use in the prevention and / or treatment, in an individual in need thereof, of an immune disorder selected from the group consisting of an inflammatory disorder, graft-versus-host disease (GVHD) and graft rejection.

[0178] The present invention accordingly also relates to a method for preventing and / or treating an immune disorder selected from the group consisting of an inflammatory disorder, graft-versus-host disease (GVHD) and graft rejection by administering to an individual in need thereof at least a muropeptide according to the invention, at least a peptidoglycan according to the invention, or a composition of the invention.

[0179] The present invention also relates to the use of a muropeptide according to the invention, a peptidoglycan according to the invention, or a composition of the invention, for the preparation of a medicament for the prevention and / or treatment of an immune disorder selected from the group consisting of an inflammatory disorder, graft-versus-host disease (GVHD) and graft rejection.

[0180] An inflammatory disorder may in particular be selected from the group consisting of joint inflammation disorder, in particular rheumatoid arthritis, osteoarthritis, gouty arthritis or psoriatic arthritis; skin inflammation disorder, in particular dermatitis, psoriasis or eczema; gastrointestinal inflammation disorder, in particular colitis, ulcerative colitis, Crohn’s disease, gastritis or Irritable bowel syndrome (IBS); respiratory inflammation disorder, in particular asthma, chronic obstructive pulmonary disease (COPD) or allergic thinitis; systemic inflammatory disorder, in particular systemic lupus erythematosus (SLE), sarcoidosis or vasculitis; musculoskeletal inflammation, in particular tendinitis, bursitis or myositis; neurological inflammation disorder, in particular multiple sclerosis (MS), meningitis or Guillain-Barre syndrome; cardiovascular inflammation disorder, in particular atherosclerosis, myocarditis or pericarditis; ophthalmic inflammation disorder, in particular uveitis, conjunctivitis or keratitis; and renal inflammation disorder, in particular glomerulonephritis, pyelonephritis or interstitial nephritis. The muropeptide, peptidoglycan or composition for use according to the invention may also be for use in the prevention and / or treatment, and in particular in the treatment, in an individual in need thereof, of an infection, in particular of an infection by C. difficile.

[0181] The muropeptide, peptidoglycan or composition for use according to the invention may moreover be for use in the prevention and / or treatment, and in particular in the treatment, in an individual in need thereof, of a metabolic disorder, in particular a metabolic disorder selected from the group consisting of diabetes, insulin resistance, metabolic syndrome and Metabolic dysfunction-Associated Liver Disease.

[0182] Types of diseases and disorders that can be prevented and / or treated by methods of the present invention also include, but are not limited to cancers, in particular selected from the group consisting of Melanoma, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Renal Cell Carcinoma, Bladder Cancer, Head and Neck Squamous Cell Carcinoma, Gastric Cancer, Colorectal Cancer (with microsatellite instability-high or mismatch repairdeficient tumors), Rectal Cancer (with micro satellite instability-high or mismatch repairdeficient tumors), Hepatocellular Carcinoma, Cervical Cancer, Ovarian Cancer, TripleNegative Breast Cancer, Esophageal Cancer, Malignant Pleural Mesothelioma, Prostate Cancer, Pancreatic Cancer and Any Solid Tumor with High Tumor Mutational Burden or Micro satellite Instability-High (MSI-H) / Mismatch Repair Deficiency (dMMR) status.

[0183] The muropeptide, peptidoglycan or composition for use according to the invention may in particular be for use in the prevention and / or treatment, and in particular in the treatment, in an individual in need thereof, of a cancer, in particular of a cancer selected from the group consisting of selected from the group consisting of Melanoma, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Renal Cell Carcinoma, Bladder Cancer, Head and Neck Squamous Cell Carcinoma, Gastric Cancer, Colorectal Cancer (with microsatellite instability-high or mismatch repair-deficient tumors), Rectal Cancer (with micro satellite instability-high or mismatch repair-deficient tumors), Hepatocellular Carcinoma, Cervical Cancer, Ovarian Cancer, Triple-Negative Breast Cancer, Esophageal Cancer, Malignant Pleural Mesothelioma, Prostate Cancer, Pancreatic Cancer and Any Solid Tumor with High Tumor Mutational Burden or Micro satellite Instability-High (MSI-H) / Mismatch Repair Deficiency (dMMR) status. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

[0184] EXAMPLES

[0185] The muropeptides detailed above have been tested individually in batches in the following examples as well as in the form of peptidoglycan, in particular of oligomers, also detailed above.

[0186] EXAMPLE 1:

[0187] HEK CELLS PROTOCOL: MEASUREMENT OF NOD2 ACTIVATION

[0188] HEK reporter cells (N0D2 and null2) were cultured in RPMI medium supplemented with FBS (Fetal Bovine Serum), [3-mercaptoethanol and Penicillin / Streptomycin. The day of confluency, the cells were collected and plated in 96- well plates. In parallel, muropeptides and peptidoglycans of Table 1 were thawed then treated by ultrasound before being diluted at different concentrations (0.05pg / mE, O.lpg / mE, 0.5pg / mE, Ipg / mE, 5pg / mE and lOpg / mE) in the same medium than HEK cells. The diluted muropeptides and peptidoglycans were then added to the HEK reporter cells, and the plates were incubated for 18 hours at 37°C and 5% CO2. After the incubation, the absorbance was measured with a spectrophotometer at 620 nm to determine the SEAP (Secreted Embryonic Alkaline Phosphatase activity, production induced by NOD2 agonists). The ratio between the absorbance results obtained for NOD2 and null2 HEK cells is calculated to determine the activation of NOD2.

[0189] This experiment illustrates the capacity of the muropeptides according to the invention to induce NOD2 activation.

[0190] EXAMPLE 2:

[0191] NOD2 KO DENDRITIC CELLS PROTOCOL: ANALYSIS OF IL-10 PRODUCTION INDUCED BY MUROPEPTIDES OF THE INVENTION IN NOD2 KO MICE The bone marrow from NOD2 KO and WT mice from Institut Pasteur was collected to obtain stored in DMSO at - 80°C until further use.

[0192] For the experiment, N0D2 KO and WT DC cells were thawed and plated in 6- well plates in RPMI medium supplemented with FBS, [3-mercaptoethanol, Penicillin / Streptomycin and GM-CSF for 6 days at 37°C, 5% CO2. The DC were then plated in 24- well plates at 2.105or 4.105cells / well. In parallel, muropeptides and peptidoglycans according to Table 1 (and thus according to the invention) were thawed, then treated by ultrasound before being diluted in the same medium than DC. The muropeptides and peptidoglycans were then added to DC in 24- well plate at various concentrations. The plates were incubated for 24 hours at 37°C, 5% CO2. After the co-incubation, supernatant was collected and stored at -20°C until the samples were tested for IL- 10 production by ELISA.

[0193] This experiment illustrates the fact that the ability of the muropeptides and peptidoglycans according to the invention to induce IL- 10 production in DC is linked to NOD2, which materializes by the observations of a decrease of IL- 10 production induced by the muropeptides and peptidoglycans according to the invention in NOD2 KO DC compared with WT DC.

[0194] EXAMPLE 3:

[0195] CARD9 KO DENDRITIC CELLS PROTOCOL: ANALYSIS OF IL-10 PRODUCTION INDUCED BY PEPTODOGLYCAN OF THE INVENTION IN CARD9 KO MICE

[0196] The bone marrow from CARD9 KO mice and WT mice was collected to obtain DC, as explained above. The cells were stored in DMSO at -80°C until further use.

[0197] For the experiment, CARD9 KO and WT DC cells were thawed and cultured as described above. An IL- 10 and TNF-a dosage by ELISA was then performed as indicated in example 2.

[0198] This experiment illustrates the fact that the IL- 10 production induced by the muropeptides and PGs according to the invention in DC is link to CARD9 which materializes by a decrease of IL- 10 production by the muropeptides and PGs according to the invention in CARD9 KO DC compared to the production in WT DC.

Claims

CLAIMS1. An isolated muropeptide of formula (I):GlcNAc-MurNAc-Xi-Glu-mDAP-(Ala)Yi-(X2)Y2 (I) wherein:- GlcNAc represents a N-acetylglucosamine, optionally N-deacetylated;- MurNAc represents a N-Acetylmuramic acid, non- substituted or substituted with Acetyl (Ac);- Xi is an amino acid selected from the group consisting of Glycine and Alanine;- Glu represents a glutamic acid non-substituted with (-NH2), and optionally substituted with a Glycine;- mDAP represents a meso-diaminopimelic acid non-substituted with (-NH2);- Ala represents an Alanine;- Y 1 represents 0 or 1 ;- X2 is an amino acid selected from the group consisting of Alanine, Glycine and Serine, the amino acid being non-substituted; and- Y2 represents 0 or 1.

2. The muropeptide according to claim 1, wherein MurNAc is O-acetylated.

3. The muropeptide according to claim 1 or 2, wherein the amino acid represented byXi is non-substituted.

4. The muropeptide according to any one of claims 1 to 3, wherein Xi is a Glycine.

5. The muropeptide according to any one of claims 1 to 4, wherein Glu is nonsubstituted with a Glycine, and is more particularly non-substituted.

6. The muropeptide according to any one of claims 1 to 5, wherein mDAP is nonsubstituted.

7. The muropeptide according to any one of claims 1 to 6, wherein when Y1 is 0 then Y2 is 0.

8. The muropeptide according to any one of claims 1 to 7, wherein X2is an amino acid selected from the group consisting of Alanine and Glycine, and in particular is Glycine.

9. The muropeptide according to any one of claims 1 to 8, wherein Y2 is 0.

10. Peptidoglycan, in particular oligomer, comprising at least one, in particular at least two, muropeptide(s) as defined in any one of claims 1 to 9, more particularly the peptidoglycan being of formula (II):[GlcNAc-MurNAc-Xi-Glu-mDAP-(Ala)Yi-(X2)Y2]n (II) in which n represents an integer between 2 and 8, particularly between 2 and 5, inclusive; andGlcNAc, MurNAc, Xi, Glu, mDAP, Ala, Yl, X2 and Y2 are as defined in any one of claims 1 to 9.

11. A composition, in particular a pharmaceutical composition, comprising, in a physiologically acceptable medium, at least one muropeptide as defined in any one of claims 1 to 9 and / or at least one peptidoglycan according to claim 10.

12. The composition according to claim 11, the composition being formulated under a form selected from the group consisting of a tablet, a capsule, an oral suspension, an effervescent tablet, a lozenge, a powder, a granule, a solution, a syrup, an emulsion, a gel, a cream, an ointment, a lotion, a patch, a transdermal gel, a transdermal patch, an injectable solution, an intravenous infusion, an intramuscular injection, a subcutaneous injection, an intranasal spray, an inhalation aerosol, a rectal suppository, a vaginal suppository, and a buccal formulation.

13. A muropeptide according to any one of claims 1 to 9, a peptidoglycan according to claim 10 or a composition according to claim 11 or 12, for use as a medicament.

14. The muropeptide, peptidoglycan, or composition for use according to claim 13, for use in the prevention and / or treatment, in an individual in need thereof, of an immune disorder selected from the group consisting of an inflammatory disorder, graft- versus-host disease (GVHD) and graft rejection.

15. The muropeptide, peptidoglycan, or composition for use according to claim 13 or 14, wherein the inflammatory disorder is selected from the group consisting of joint inflammation disorder, in particular rheumatoid arthritis, osteoarthritis, gouty arthritis or psoriatic arthritis; skin inflammation disorder, in particular dermatitis, psoriasis or eczema; gastrointestinal inflammation disorder, in particular colitis, ulcerative colitis, Crohn’s disease, gastritis or Irritable bowel syndrome (IBS); respiratory inflammation disorder, in particular asthma, chronic obstructive pulmonary disease (COPD) or allergic thinitis; systemic inflammatory disorder, in particular systemic lupus erythematosus (SLE), sarcoidosis or vasculitis; musculoskeletal inflammation, in particular tendinitis, bursitis or myositis; neurological inflammation disorder, in particular multiple sclerosis (MS), meningitis or Guillain-Barre syndrome; cardiovascular inflammation disorder, in particular atherosclerosis, myocarditis or pericarditis; ophthalmic inflammation disorder, in particular uveitis, conjunctivitis or keratitis; and renal inflammation disorder, in particular glomerulonephritis, pyelonephritis or interstitial nephritis.

16. The muropeptide, peptidoglycan, or the composition for use according to claim 13, for use in the prevention and / or treatment, in an individual in need thereof, of an infection, in particular of an infection by C. difficile.

17. The muropeptide, peptidoglycan, or the composition for use according to claim 13, for use in the prevention and / or treatment, in an individual in need thereof, of a metabolic disorder, in particular selected from the group consisting of diabetes, insulin resistance, metabolic syndrome and Metabolic dysfunction-Associated Liver Disease.

18. The muropeptide, peptidoglycan, or the composition for use according to any one of claims 13 to 17, wherein the muropeptide, peptidoglycan, or composition is administered to an individual in need thereof in combination with at least an anti-inflammatory agent different from a muropeptide as defined in any one of claims 1 to 9 and from a peptidoglycan as defined in claim 10.

19. The muropeptide, peptidoglycan, or composition for use according to claim 18, wherein the anti-inflammatory agent is selected from the group consisting of corticosteroids; probiotics; nonsteroidal anti-inflammatory drugs (NSAIDs); and biologic agents, the biologic agents being in particular selected from the group consisting of tumor necrosis factor inhibitors, in particular Infliximab, Adalimumab, Etanercept, Certolizumab pegol or Golimumab; Interleukin- 1 (IL-1) Inhibitor, in particular Anakinra; Interleukin-6 (IL-6) Inhibitors, in particular Tocilizumab or Sarilumab; Interleukin- 12 / 23 (IL- 12 / 23) Inhibitor, in particular Ustekinumab; Interleukin- 17 (IL- 17) Inhibitors, in particular Secukinumab or Ixekizumab; Interleukin-23 (IL-23) Inhibitors, in particular Guselkumab, Risankizumab or Tildrakizumab; Interleukin-4 / 13 (IL-4 / 13) Inhibitor, in particular Dupilumab; an anti-CD20 antibody, such as Rituximab; and B-Cell Activating Eactor (BALE) Inhibitor, in particular Belimumab.

20. The muropeptide, peptidoglycan, or the composition for use according to claim 13, for use in the prevention and / or treatment, in an individual in need thereof, of a cancer, in particular of a cancer selected from the group consisting of Melanoma, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Renal Cell Carcinoma, Bladder Cancer, Head and Neck Squamous Cell Carcinoma, Gastric Cancer, Colorectal Cancer (with micro satellite instability-high or mismatch repair-deficient tumors), Rectal Cancer (with micro satellite instability-high or mismatch repairdeficient tumors), Hepatocellular Carcinoma, Cervical Cancer, Ovarian Cancer, Triple-Negative Breast Cancer, Esophageal Cancer, Malignant Pleural Mesothelioma, Prostate Cancer, Pancreatic Cancer, and Any Solid Tumor with High Tumor Mutational Burden or Micro satellite Instability-High (MSI-H) / Mismatch Repair Deficiency (dMMR) status.

21. The muropeptide, peptidoglycan, or composition for use according to any one of claims 13 to 20, wherein the individual in need thereof is a mammal, and is in particular a human being.

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