Composition containing D-xylose-2-phosphate and its uses as a medicine, food supplement, or cosmetic

Abstract

The invention relates to compositions comprising D-xylose-2-phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-phosphate. These compositions can be used as a medicinal product, particularly in the prevention or treatment of viral infections using syndecanes and / or glypicans as cell receptors. These compositions can also be used in cosmetics or as a food supplement.

Description

Title of the invention: Composition comprising D-xylose-2-phosphate and their uses as a drug, food supplement, or cosmetic

[0001] The invention relates to compositions comprising D-xylose-2-phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-phosphate. These compositions can be used as a medicinal product, particularly in the prevention or treatment of viral infections using syndecanes and / or glypicans as cell receptors. These compositions can also be used in cosmetics or as a food supplement. Previous Art

[0002] Several studies have shown that viral infections, type 2 diabetes, and cancers are accompanied by the degradation of glycosaminoglycans (GAGs), particularly heparan sulfate (HS), dermatan sulfate (DS), and chondroitin sulfate (CS). Several studies have also shown the importance of counteracting HS / CS / DS degradation during viral infections and type 2 diabetes.

[0003] In parallel, several studies have shown that the "core proteins" of proteoglycans (to which HS / CS / DS are attached), more particularly syndecans, increase abnormally (upregulation) in several cancers, such as: hepatocellular carcinoma, colon cancer, breast cancer, prostate cancer... (see Table 1).

[0004] Other studies have noted an excessive loss of syndecanes at the cell surface, as is the case, for example, in lung cancer (see Table 1) [Tables 1] Cancer Type Changes in "core proteins" Heparanase on the cell surface (HPSE) Association with type 2 diabetes Liver carcinoma Glypican-3 is overexpressed in hepatocellular carcinoma [T6]. Syndecan-1 increases in liver dysfunction in HVC hepatocellular carcinoma [T7]. Heparanase overexpression (2 times higher) [T18] There is a strong association between hepatocellular carcinoma and type 2 diabetes [T27;T28;T29] Lung cancer Excessive loss (shedding) of syndecanes-1 is associated with higher grade cancers and a more unfavorable clinical prognosis [T5]. Overexpression of heparanase [T19] Pre-existing diabetes increases the risk of mortality among patients with lung cancer, especially women [T30;T31;T32], Colon / colorectal cancer Upregulation of syndecanes-2 [T4;T10] and decrease of syndecanes-1 [TU] correlation between heparanase expression and serous invasion [T20;T11] Type 2 diabetes increases the risk of colorectal cancer [T33;T34;T35] Breast cancer Upregulation of syndecanes-1, syndecanes-2 and syndecanes-4 is observed in breast cancer and is correlated with poor prognosis and aggressive phenotype."[T1;T2;T3] Heparanase overexpression [T21] Type 2 diabetes increases the risk of breast cancer [T36;T37;T38] Prostate cancer Syndecan-2 and syndecan-1 are overexpressed in prostate cancer and are associated with a poor prognosis [T8;T9]. Heparanase overexpression [T22] Type 2 diabetes increases the risk of prostate cancer [T39;T40;T41] Skin cancer Upregulation of syndecan-2 [T12] Upregulation of heparanase which exerts pro-tumorigenic properties [T23] Type 2 diabetes increases the risk of skin cancer [T42;T43] Pancreatic cancer Upregulation of the Increase in syndecanes-2 [T13] Overexpression of heparanase [T24] Type 2 diabetes increases the risk of cancer. pancreatic cancer [T44; T45; T46; T47] Ovarian cancer Altered expression of syndecanes-1 and perlecan [T15] Overexpression of heparanase [T14] Type 2 diabetes increases the risk of ovarian cancer [T48; T49] Brain cancer Upregulation of syndecanes-1 [T16] Overexpression of heparanase [T25; T26] Esophageal cancer Loss of syndecanes-1 [T17] Overexpression of heparanase [T17] Type 2 diabetes increases the risk of esophageal cancer [T50; T51]

[0005] Several in vitro studies have shown the involvement of GAGs, more specifically HS, in viral attachment. Furthermore, the involvement of HS in the viral attachment of more than a dozen enveloped viruses has been reported in the literature (see Cheudjeu, 2021).

[0006] A literature review (Cheudjeu, 2021) explains why HS / CS / DS binding sites, called "HS attachment sites," are the attachment points of certain viruses (those using core proteins as receptors on the cell surface). "HS attachment sites" are the hydroxyl groups of serine and threonine residues to which D-xylose binds (via UDP-xylose, a free D-xylose molecule, or even xylosides).

[0007] Viruses using syndecans and / or glypicans as cell receptors via core proteins as receptors on the cell surface (thus binding to HS attachment sites, Cheudjeu 2021) are potentially responsible for several cancers. (See Table 2)

[0008] Indeed, several studies have shown that viruses are a probable cause (high prevalence) of several cancers (see Table 2). These viruses use core proteins as receptors to attach to and enter the cell (see Table 2). [Tables 2] Cancer Type Related / Associated Viruses Viruses using core proteins as receptors? Adult T-cell leukemia-lymphoma (ATLL) HTLV-1: Human T-cell leukemia virus type-1 [T53] Yes Burkett's lymphoma in men HSV-2: Herpes simplex virus type 2 [T54] Yes, Syndecaness, [T70] Nasopharyngeal cancer in men HSV-2: Herpes simplex virus type 2 [T54] Cervical cancer HPV-16: Human papillomavirus type 16 [T59; T60] Epidemiologically associated with HSV-2 also [T54; T56] Yes, Syndecaness, [T70] Oral cancer HSV-1: Herpes simplex virus type 1 [T55;[T56] Yes, Syndecaness, [T70] Hepatocellular carcinoma (HCC) HCV: Hepatitis C virus [T58] Yes, Syndecaness, [T70] Kaposi's sarcoma HIV-1: Human immunodeficiency virus type 1 [T57] Yes, Syndecaness, [T70] Human herpesvirus 8 (HHV8) [T57] Breast cancer carcinogenesis HCMV: Human cytomegalovirus [T61] Yes, Syndecaness, [T70] Colorectal cancer HCMV: Human cytomegalovirus [T62] Glioblastoma multiforme (GBM) HCMV: Human cytomegalovirus [T63] Lung carcinoma DENV: Dengue virus [T69] Yes, Syndecaness, [T70] Lung cancer HPV: Human papillomavirus [T64] Yes, Syndecaness, [T70] hepatocellular carcinoma HVB: hepatitis B virus [T65] Yes, Glypicane [T 70]; Burkitt lymphoma and nasopharyngeal carcinoma Epstein-Barr virus [T66;T67] hepatocellular carcinoma HVD: hepatitis D virus [T68] Yes, Glypican [T70]

[0009] This maintains the need for compounds to treat these pathologies. It also maintains the need for new cosmetic compositions and food supplements to increase glycosaminoglycan concentration in healthy individuals.

[0010] The Applicant has previously developed formulations including D-xylose. However, the effectiveness of these formulations was only conceivable at high doses (high EC50).

[0011] The Applicant has thus developed a compound, D-xylose-2-Phosphate, for which no use, medicinal, in food supplement, or in cosmetics, has been reported to date.

[0012] Surprisingly, the Applicant was able to develop a formulation based on modified D-xylose, D-xylose-2-Phosphate or one of its derivatives, enabling the inhibition of viruses using syndecanes and / or glypicans as cellular receptors, more effectively than D-xylose.

[0013] The common inventive concept within the framework of this invention is the use of at least one compound selected from D-xylose-2-Phosphate, its esters, oligosaccharides comprising D-xylose-2-Phosphate, to increase the synthesis of glycosaminoglycans, involved in pathologies, or in healthy subjects in food supplements or cosmetic compositions. Description of the invention

[0014] According to a first aspect, the invention relates to a composition comprising at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate.

[0015] According to another aspect, the invention relates to a composition comprising at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate for use as a drug.

[0016] According to one embodiment, said composition is for use in the prevention or treatment of a viral infection using syndecanes and / or glypicans as cell receptors, preferably said viral infection being chosen from HSV-1, HSV-2, HPV-16, HPV-31, HVB, HCV, HIV-1, HTLV-1, SARS-CoV-2, HCMV, EBOLA, RSV, DENV-1, and DENV-2 infections.

[0017] According to one embodiment, said composition is for use in the treatment of type 2 diabetes.

[0018] According to one embodiment, said composition is for use in the treatment of cancer, preferably colon cancer, lung cancer, breast cancer, liver cancer, adult T-cell leukemia-lymphoma (ATLL), Burkett lymphoma in humans, nasopharyngeal cancer in humans, cervical cancer, oral cancer, hepatocellular carcinoma (HCC), Kaposi's sarcoma, breast cancer carcinogenesis, colorectal cancer, glioblastoma multiforme (GBM), lung carcinoma or nasopharyngeal carcinoma.

[0019] According to one embodiment, said composition is for use in the treatment of joint diseases, preferably osteoarthritis, arthritis, rheumatoid arthritis or gout.

[0020] According to one embodiment, said composition is for use as an anticoagulant.

[0021] According to one embodiment, said composition is for use in the treatment of dermatological diseases.

[0022] According to another aspect, the invention relates to a formulation comprising at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate, in a physiologically acceptable medium for use in a human patient in the stimulation of glycosaminoglycan biosynthesis.

[0023] Even more preferably, said formulation is for use in the prevention or treatment of SARS-CoV-2 infection.

[0024] Even more preferably, said formulation is for use in the prevention or treatment of congenital CMV infection.

[0025] Even more preferably, said formulation is for use in the prevention or treatment of HIV-1 infection.

[0026] According to one embodiment, said formulation is for use in the prevention or treatment of COVID-19.

[0027] According to one embodiment, said formulation is for use in the prevention or treatment of type 2 diabetes.

[0028] According to one embodiment, the compositions for use and the formulations according to the invention are in a form suitable for administration by oral, nasal or parenteral route.

[0029] According to one embodiment, the compositions for use and the formulations according to the invention are in a form suitable for parenteral administration by subcutaneous, intradermal, intravenous or intramuscular route.

[0030] According to one embodiment, the compositions for use and formulations according to the invention are for oral administration, and are formulated in the form of capsules, softgels, tablets, effervescent tablets, powders, granules, oral solutions or suspensions.

[0031] According to one embodiment, the compositions for use and formulations according to the invention are for nasal administration, and are formulated as a solution in aerosol form.

[0032] Preferably, said at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate, more preferably D-xylose-2-Phosphate.

[0033] According to one embodiment, the compositions for use and the formulations according to the invention further comprise at least one other acceptable active pharmaceutical ingredient and / or at least one excipient and / or at least one acceptable pharmaceutical carrier and / or any pharmaceutically acceptable compound.

[0034] Preferably, said at least one other pharmaceutical ingredient is an antiviral active ingredient.

[0035] Preferably, said at least one other pharmaceutical ingredient is an active ingredient enabling the prevention or treatment of COVID-19.

[0036] Preferably, said at least one other pharmaceutical ingredient is an active ingredient enabling the prevention or treatment of type 2 diabetes.

[0037] Preferably, said at least one other pharmaceutical ingredient is an active ingredient enabling the prevention or treatment of insulin resistance.

[0038] Preferably, said at least one other pharmaceutical ingredient is an active ingredient enabling the prevention or treatment of HIV.

[0039] Preferably, said at least one other pharmaceutical ingredient is an active ingredient enabling the prevention or treatment of congenital CMV infections.

[0040] Preferably, said at least one other pharmaceutical ingredient is an active ingredient enabling the prevention or treatment of cancer.

[0041] Preferably, the compositions for use and formulations according to the invention further comprise an active ingredient to accelerate the transfer of said at least one compound selected from D-xylose-2-phosphate, its esters, oligosaccharides comprising D-xylose-2-phosphate to the cells, preferably said active ingredient being insulin.

[0042] According to one embodiment of the invention, the compositions for use and the formulations according to the invention also include at least one antibiotic.

[0043] According to one embodiment of the invention, the compositions for use and the formulations according to the invention comprise a hormone accelerating the transport of D-xylose-2-phosphate or its derivatives into the cell, such as insulin or also any pharmaceutically acceptable enzymes facilitating the transport of D-xylose-2-phosphate into the cell, for example xylose transporters.

[0044] According to one embodiment of the invention, the compositions for use and the formulations according to the invention also include a compound enabling the reduction of at least one side effect of taking D-xylose-2-phosphate.

[0045] According to one embodiment of the invention, the compositions and formulations according to the invention also include Vitamin C.

[0046] In the context of compositions for therapeutic uses and formulations, said compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate is in a physiologically acceptable medium for use in a human patient

[0047] According to another aspect, the invention relates to a therapeutic method comprising the administration of a composition or formulation comprising D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate.

[0048] In the context of the compositions for use as a medicinal product, the formulations and therapeutic methods according to the invention, administration by oral, subcutaneous, intradermal, intravenous or intramuscular route is carried out by administering between 1 and 4 doses per day of a composition having a mass of 200 mg to 2 g, of at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate.

[0049] In the context of the compositions for use as a medicinal product, the formulations and therapeutic methods according to the invention, administration by oral, subcutaneous, intradermal, intravenous or intramuscular route is carried out by administering between 1 and 4 doses per day of a composition having a mass of 200 mg to 2 g, of D-xylose-2-Phosphate.

[0050] In the context of the compositions for use as a medicinal product, the formulations and therapeutic methods according to the invention, administration via the nasal route is carried out by administering between 1 and 4 doses per day of a composition having a mass of 200 mg to 2 g of at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate

[0051] In the context of the compositions for use as a medicinal product, formulations and therapeutic methods according to the invention, administration via the nasal route is carried out by administering between 1 and 4 doses per day of a composition having a mass of 200 mg to 2 of D-xylose-2-Phosphate.

[0052] According to another aspect, the invention relates to a non-therapeutic topical cosmetic composition for the care of an area of ​​the skin of a healthy subject comprising at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate.

[0053] Preferably, said cosmetic composition further comprises a cosmetically acceptable medium.

[0054] The cosmetic composition according to the invention may thus be presented in the forms which are usually known for topical administration, that is to say in particular lotions, milks, emulsions, serums, balms, masks, creams, dispersions, gels, foams or sprays.

[0055] Preferably, said cosmetic composition further comprises surfactants, complexing agents, preservatives, stabilizing agents, emulsifiers, thickeners, gelling agents, humectants, emollients, trace elements, essential oils, perfumes, colorants, mattifying agents, chemical or mineral filters, moisturizing agents, or thermal waters.

[0056] According to another aspect, the invention relates to a food supplement composition for oral or nasal administration for healthy subjects, comprising at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate in a physiologically acceptable medium to stimulate the biosynthesis of glycosaminoglycans, preferably at least one selected from heparan sulfate, dermatan sulfate and chondroitin sulfate.

[0057] Preferably, said glycosaminoglycan is a sulfated glycosaminoglycan.

[0058] Preferably, said glycosaminoglycans is at least one selected from heparan sulfate, dermatan sulfate and chondroitin sulfate.

[0059] Preferably, said composition of food supplement for oral or nasal administration in healthy subjects comprises at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate in a physiologically acceptable medium, in the stimulation of glycosaminoglycan biosynthesis.

[0060] Preferably, the food supplement composition is in a form suitable for oral administration by administering between 1 and 2 doses per day of a composition having a mass of 500 mg to 1 g of at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate.

[0061] Preferably, the food supplement composition is in a form suitable for oral administration by administering between 1 and 2 doses per day of a composition having a mass of 500 mg to 1 g of D-xylose-2-Phosphate.

[0062] Preferably, the food supplement composition is in a form suitable for nasal administration by administering between 1 and 2 doses per day of a composition having a mass of 500 mg to 1 g of at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate

[0063] Preferably, the food supplement composition is in a form suitable for administration via the nasal route by administering between 1 and 2 doses per day of a composition having a mass of 500 mg to 1 g of D-xylose-2-Phosphate.

[0064] In all aspects of the invention, said oligosaccharide comprising D-xylose-2-Phosphate may be selected from Galactose-[31-4-D-xylose-2-Phosphate, Galactose-[31-3-Galactose-[31-4-D-xylose-2-Phosphate, or Glucuronic Acid-[31-3-Galactose-[31-3-Galactose-[31-4-D-xylose-2-Phosphate.

[0065] The administered D-xylose-2-phosphate allows the HS, CS, and DS binding sites to occupy the core proteins, thereby increasing glycosaminoglycan synthesis. This inhibits the attachment of viruses using syndecans and / or glypicans as cellular receptors. By binding to the HS / CS / DS binding sites, D-xylose-2-phosphate, its esters, or oligosaccharides containing D-xylose-2-phosphate stimulate GAG ​​biosynthesis.

[0066] Preferably, the biosynthesis of glycosaminoglycans is increased by at least 1%, preferably by at least 5%, preferably by at least 10%, preferably by at least 20%, preferably by at least 30%, preferably by at least 40%, preferably by at least 50%, preferably by at least 60%, preferably by at least 70%, preferably by at least 80%, preferably by at least 90%, preferably by at least 100%, preferably by at least 150%, preferably by at least 200%, preferably by at least 500%, preferably by at least 1000%. Figures

[0067] [Fig.1] are immunofluorescence images of a 96-well plate with a plate arrangement conforming to Table 4 - SARS-CoV-2.

[0068] [Fig.2] are immunofluorescence images of a 96-well plate with a plate arrangement conforming to Table 10 - HIV-1.

[0069] [Fig.3] are immunofluorescence images of a 96-well plate with a plate arrangement conforming to Table 7 - RSV-A2.

[0070] [Fig.4] is a graph showing the percentages of SARS-CoV-2 inhibition as a function of the concentration of SODIUM D-XYLOSE-2-PHOSPHATE or REMDESIVIR (used as a control).

[0071] [Fig.5] is a graph showing the percentages of inhibition of HIV NL43 as a function of the concentration of SODIUM D-XYLOSE-2-PHOSPHATE or AZT (used as a control).

[0072] [Fig.6] is a schematic representation of the experimental procedure allowing the synthesis of D-xylose-2-phosphate. Definitions

[0073] D-Xylose-2-Phosphate is a compound resulting from the phosphorylation of a carbohydrate, D-xylose. It is a five-carbon monosaccharide (a pentose), comprising a phosphate group attached to the second carbon of the xylose. D-Xylose-2-Phosphate is not commercially available.

[0074] D-xylose-2-phosphate can be synthesized by the method shown in Example 3.

[0075] The same applies to oligosaccharides comprising D-xylose-2-phosphate such as: Galactose-[31-4-D-xylose-2-phosphate, Galactose-[31-3-Galactose-[31-4-D-xylose-2-phosphate; Glucuronic acid-[31-3-Galactose-[31-3-Galactose-[31-4-D-xylose-2-phosphate.

[0076] For the purposes of this invention, "D-xylose-2-Phosphate" means D-xylose-2-Phosphate, its esters, and oligosaccharides comprising D-xylose-2-Phosphate.

[0077] In the body, D-xylose, from which D-xylose-2-phosphate is derived, is used in sulfated glycosaminoglycans (GAGs), which are long linear chains made up of disaccharide repeating units present in the extracellular matrix (ECM) on the surface of endothelial cells, epithelial cells, fibroblasts, macrophages, and hepatocytes (RR Vivès, Heparan sulfate: structure, functions, regulation, April 11, 2020). There are six types of glycosaminoglycans: heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate, heparin (Hep), and hyaluronic acid. Among them, HS, CS, DS and Hep share the same binding region, made up of trisaccharides: glucuronic acid-[31-3-galactose-[31-3-galactose-[31-4-xylose-[31 linked to a serine or to a threo-new residue of a protein core (syndecanes, glypicans, etc.).Thus, HS / CS / DS and HP are sugar chains in which D-Xylose is the first element of the chains and is linked via 1-OH to the serine or threonine residue of the core protein. Therefore, HS attachment sites (HSAS) refer to the serine or threonine residues intended to receive the D-xylose molecule to initiate the HS chains.

[0078] The main core proteins of proteoglycans in the extracellular matrix are perlecan (with HS-type chains), agrin (heparan sulfate proteoglycan [HSPG]), aggrecan (chondroitin sulfate proteoglycan [CSPG] / dermatan sulfate proteoglycan [DSPG]) and decorin.

[0079] The core membrane proteins of PGs are classified into two categories: syndecans and glypicans. Syndecans are transmembrane proteins, unlike glypicans, which are entirely extracellular proteins (attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor). Membrane PGs include HSPGs, CSPGs, and DSPGs, but are primarily HSPGs. HSPGs are found on the surface of several cell types, such as endothelial cells, epithelial cells, fibroblasts and neuronal tissues (RR Vivès, Heparan sulfate: structure, functions, regulation, 11 April 2020 & S. Sarrazin, WC Lamanna, JD Esko, Heparan sulfate proteoglycans, Cold Spring Harb. Perspect. Biol. 3 (2011))

[0080] With the exception of KS, all other sulfated GAGs are linked to the core proteins by an identical binding region, consisting of the xylose-galactose-galactose trisaccharide sequence. The biosynthesis of the HS chain (and also of the CS, DS and Hep chains) begins with the attachment of a D-xylose molecule to specific serine and occasionally threonine residues located on the core protein (syndecanes, glypican, decorin, etc.). This initiation of HS / CS / DS biosynthesis is carried out either by the enzymes xylosyltransferase 1 and xylosyltransferase 2 (RR Vivès, Heparan sulfate: structure, functions, regulation, 11 April 2020 & S. Sarrazin, WC Lamanna, JD Esko, Heparan sulfate proteoglycans, Cold Spring Harb. Perspect. Biol. 3 (2011)) or directly by free molecules (unlike UDP-Xyl) of D-xylose (Cheudjeu, 2022).

[0081] After the D-xylose molecule is positioned, two galactose molecules are linked. The chain thus formed constitutes the linking region. This is then completed by a repetition of the same basic unit specific to each type of sulfated GAGs (HS / CS / DS / Hep).

[0082] The basic unit of HS is D-glucuronic acid linked to N-acetylglucosamine. The basic unit of CS is N-acetylgalactosamine linked to D-glucuronic acid. Hyaluronic acid is the only non-sulfated GAG; this type of glycosaminoglycan is not linked to a core protein. The disaccharides that compose it are themselves made up of D-glucuronic acid and DN-acetylglucosamine (RR Vivès, Heparans sulfate: structure, functions, regulation, 11 April 2020).

[0083] HSPGs are rapidly recycled and renewed at the cell surface; their half-life is approximately 2–3 h (M. Egeberg, R. Kjeken, SO Kolset, T. Berg, K. Prydz, Intemalization and stepwise degradation of heparan sulfate proteoglycans in rat hepatocytes, Biochim. Biophys. Acta 1541 (2001) 135–149). The degradation of HSPGs at the cell surface depends on the action of several extracellular and lysosomal enzymes, and in particular on heparanase, which cleaves the HS chains (RR Vivès, Heparan sulfate: structure, functions, regulation, 11 April 2020 & S. Sarrazin, WC Lamanna, JD Esko, Heparan sulfate proteoglycans, Cold Spring Harb. Perspect. Biol. 3 (2011)).

[0084] Type 2 diabetes, insulin resistance and mechanism of action

[0085] Type 2 diabetes (T2DM) is a metabolic disease that is often one of the symptoms of certain viral infections, such as SARS-CoV-2, HIV-1, HCV... (Cheudjeu 2021).

[0086] Several explanations for the occurrence of T2DM during viral infections have been given, such as: inflammation (cytokine storm) due to infections that cause damage to pancreatic cells [3], leading to insulin homeostasis. However, if this were the only explanation, insulin supplementation would be definitively sufficient, but this is not always the case. This inability of insulin to reduce blood glucose is called insulin resistance and is widely reported during viral infections that use core proteins as receptors on the cell surface: SARS-CoV-2 (Govender N et al, 2021: PMID: 33849817), HCV (Desai DV et al, 2010: https: / / doi.org / 10.1096 / fasebj.24.l_supplement.659.4), HIV-1 (Pedro MN et al., 2018: PMID: 30233499), etc. Insulin resistance is also frequently observed in some obese patients with type 2 diabetes (Kahn, BB, and Flier, JS, 2000).The present invention describes for the first time how insulin resistance is linked to the ability of D-xylose to stimulate GAGs. Most of the sugars constituting the GAG ​​chains are glucose metabolites (Cheudjeu 2022).

[0087] In the event of a deficiency of D-xylose in the body (or in the case of certain viral infections), one of the first consequences is an increase in blood glucose. Indeed, certain serine sites that should be occupied by D-xylose on core proteins (syndecans, glypicans, etc.) to initiate the production of GAGs (HS / Hep / CS / DS) are free due to a lack of D-xylose (or are occupied due to viral glycosylation in the case of certain viral infections), thus preventing the initiation of GAG biosynthesis that should take place at these sites. The sugars that should be used in the production of these GAGs (D-glucuronic acid, galactose, N-acetylglucosamine, N-acetylgalactosamine) are found in the bloodstream (Cheudjeu 2020; Cheudjeu 2021; Cheudjeu 2022).

[0088] A 2011 study showed that sulfated GAGs were altered during type 2 diabetes, with HS and chondroitin and dermatan sulfate (CS / DS) levels decreased by about 14% (D. Joladarashi, PV Salimath, ND Chilkunda, Diabetes results in structural alteration of chondroitin sulfate / dermatan sulfate in the rat kidney: effects on the binding to extracellular matrix components, Glycobiology 21 (2011)960-972).

[0089] Several other studies have reported the degradation of HS during diabetes (LM Hiebert, J. Han, AK Mandai, Glycosaminoglycans, hyperglycemia, and disease, Antioxid. Redox Signal. 21 (2014) 1032-1043 & LM Hiebert, Proteoglycans and diabetes, Curr. Pharm. Des. 23 (2017) 1500-1509).

[0090] Also, given the half-life of GAGs on the cell surface, which is 2-3 hours, this degradation contributes to the origin of the accumulation problems of HS / CS / DS chains, sources of certain cardiovascular diseases. Other studies have already shown that the level of N-acetylglucosamine increases during type 2 diabetes and that N-acetylglucosamine can be used as a biomarker of type 2 diabetes (Z. Wang, K. Park, F. Corner, LC Hsieh-Wilson, CD Saudek, GW Hart, Site-specific GlcNAcylation of human erythrocyte proteins: potential biomarker(s) for diabetes, Diabetes 58 (2009) 309-317, & L. Wells, K. Vosseller, GW Hart, A role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance, Cell. Mol. Life Sci. 60 (2003) 222-228).

[0091] Another consequence is the increase of other types of GAGs, such as hyaluronic acid (HA). Indeed, hyaluronic acid not bound to a core protein can act to bind excess sugar not used for the synthesis of HS / CS / Hep / DS. One study showed that hyaluronic acid levels in type 2 diabetes were higher and that these levels could be used as a biomarker (S. Mine, Y. Okada, C. Kawahara, T. Tabata, Y. Tanaka, Serum hyaluronan concentration as a marker of angiopathy in patients with diabetes mellitus, Endocr. J. 53 (2006) 761-766). This accumulation of HA has already been reported in the lung in adult respiratory distress syndrome, where it is about six times higher than in control patients (R. Haßlgren, T. Samuelsson, TC Laurent, J. Modig, Accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome, Am. Rev. Respir. Dis. 139 (1989) 682-687).

[0092] A 2010 study also showed that there is an approximately 66% increase in D-glucuronic acid in the blood of diabetic individuals compared to non-diabetic individuals. Another consequence is a decrease in the activity of xylosyltransferase enzymes (XYLT1, XYLT2) due to a reduction in xylose attachment positions (caused by a lack of D-xylose or by viral glycosylation at these positions). Indeed, Götting et al., in a study of 100 diabetic patients (Type 1 and Type 2) and 100 blood donations from non-diabetic individuals, demonstrated that the serum xylosyltransferase level of diabetic patients was significantly lower than that of non-diabetic patients. These researchers concluded that serum xylosyltransferase activity could be used as a biomarker of reduced GAG biosynthesis in diabetics (C. Gôtting, J. Kuhn, K.Kleesiek, Serum xylosyltransferase activity in diabetic patients as a possible marker of reduced proteoglycan biosynthesis, Diabètes Care31 (2008) 2018-2019). .

[0093] Furthermore, a study in rats showed that such a variation in the activity of the xylosyltransferase 2 enzyme induced lung damage (R. Koslowski, U. Pfeil, H. Fehrenbach, M. Kasper, E. Skutelsky, KW Wenzel, Changes in xylosyltransferase activity and in proteoglycan deposition in bleo-mycin-induced lung injury in rats, Eur. Breathe. J. 18 (2001) 347-356).

[0094] This confirms once again the anti-inflammatory properties of D-xylose and provides an explanation of the process leading to inflammation during diabetes (S. Tsalamandris, AS Antonopoulos, E. Oikonomou, GA Papamikroulis, G. Vogiatzi, S. Papaioannou, S. Deftereos, D. Tousoulis, The role of inflammation in diabetes: current concepts and future perspectives, Eur. Cardiol. 14 (2019) 50-59).

[0095] The antiviral properties of D-xylose, confirmed by tests carried out within the framework of the present invention, corroborate the binding-sites of the SARS-CoV-2 virus using core proteins.

[0096] Based on previous studies, it has been explained why the antiglycemic properties of D-xylose were not related to insulin, but that the reverse was possible. Since insulin increases the penetration rate of D-xylose into cells by two to five times, at equilibrium, in the presence of insulin, xylose is present at 80% instead of 50% to 55% in the cytosol, and 20% in the plasma (Kipnis, DM, 1957).

[0097] The inability of insulin to reduce blood glucose is called insulin resistance (or insulinoresistance) and is widely encountered during viral infections of viruses that use basic proteoglycan (PG) proteins as receptors on the surface of cells, such as SARS-CoV-2, in diabetes in general.

[0098] The notion of insulin resistance thus reflects an underestimation of the storage capacities (weight) of D-xylose-containing GAGs compared to the storage capacities of hepatic glycogen.

[0099] When the liver is full of glycogen and the body does not have enough D-xylose molecules to stimulate the biosynthesis of HS / CS / DS, any insulin supplementation no longer lowers blood glucose, resulting in the situation known as insulin resistance. Indeed, in this condition, GAGs do not act as "reservoirs" of glucose metabolites, and since the other reservoir (the liver, where glycogen is stored) is full, insulin supplementation will have no effect on blood glucose.

[0100] Thus, since the activity of xylosyltransferase enzymes is reduced during T2DM, the increase in free D-xylose molecules helps maintain GAG biosynthesis during insulin resistance and thereby reduce blood glucose levels. This is all the more true since glucose is a competitive inhibitor of D-xylose entry into the cell (where GAGs are biosynthesized in the Golgi apparatus).

[0101] Glycated hemoglobin or glycosylated hemoglobin (HbAlc) is one of the biomarkers of hyperglycemia for diabetes. It is used for assessment, for long-term diabetes control, and for the diagnosis of diabetes. The action of D- The effect of xylose or xylitol, its direct metabolite, on glycated hemoglobin (HbAlc) levels has already been the subject of several previous studies, which have shown that taking D-xylose or xylitol, its direct metabolite, has virtually no effect or very little effect on glycated hemoglobin levels in a healthy person (Bae YJ et al, PMID: 22259678; Bordier V. et al, PMID: 34836205).

[0102] Viruses using syndecanes and / or glypicans as cell receptors (e.g., HSV-1, HSV-2, HPV-16, HPV-3L, HVB, HCV, HIV-1, HTLV-1, SARS-CoV-2, HCMV, DENV-1, and DENV-2) and mechanism of action

[0103] Viruses interact with proteoglycans (PGs) on the surface of host cells to attach to them (A. Jinno, et al. Methods Mol. Biol. 1229 (2015) 567-585; V. Cagno, et al. Viruses 11 (2019) 596). Several studies have focused on these interactions, particularly on the surface molecules glycosaminoglycans (GAGs) and heparan sulfate (HS) (A. Jinno, et al. Methods Mol. Biol. 1229 (2015) 567-585; V. Cagno, et al. Viruses 11 (2019) 596). However, even when viruses interact with HS, the core proteins of most viruses are the viral receptors to which HS binds covalently (Table 1). This indicates that the observed interaction between HS and certain viruses is due to their binding to the same elements: the central proteins (Table 1).Many of these viruses use other molecules as co-receptors in addition to core proteins, as is the case for SARS-CoV-2, which uses syndecans and angiotensin-converting enzyme 2 (ACE2) as co-receptors (M. Bermejo-Jambrina, J. Eder, et al., bioRxiv (2020)). HIV-1 also uses syndecans as well as CD4 as receptors (AC Saphire, et al., J. Virol. 75 (2001) 9187-9200). The hepatitis C virus (HCV) has several other co-receptors in addition to syndecans (Q. Shi, et al., J. Virol. 87 (2013) 6866-6875).

[0104] The different possibilities of post-translational modifications (PTM) of cell surface proteins may explain the ability of viruses to use different receptors (J. Hu, et al. Front. Microbiol. 11 (2020), 517461), particularly when considering the diversity of glycoproteins present on viral envelopes and the ability of viruses to interact with host target proteins and to use these proteins to enter the cell (S. Maya & A. Ploss, Hepatology 71 (2020) 380-382; K. Azarm, Icahn School of Medicine at Mount Sinai, New York, NY, 2020.).

[0105] Bermejo-Jambrina et al. (M. Bermejo-Jambrina, J. Eder, et al., bioRxiv (2020)) recently showed in an in vitro study that SARS-CoV-2 first binds to heparan sulfate proteoglycans (HSPGs) before interacting with ACE2. However, recent work by Clausen et al. (TM Clausen et al. Cell 183 (2020) 1043-1057) showed that the SARS-CoV-2 spike protein can bind simultaneously to the cell surface via HSPGs and the ACE2 protein receptor. The consensus of the cited studies is that HSPGs are necessary for SARS-CoV-2 to attach to the cell surface. Zhang et al. (Q. Zhang, et al., Cell Discov 6 (2020), 80) also reached the same conclusion after an in vitro study.

[0106] This is also the case for HIV-1. Saphire et al. (AC Saphire, et al., J. Virol. 75 (2001) 9187-9200) showed in an in vitro study that CD4 alone is insufficient for HIV-1 macrophage infection and that attachment to HSPGs is also necessary.

[0107] [Table 3] Virus, core proteins and their associations with type 2 diabetes. Virus Basic proteins of heparan proteoglycans su Ifate Association with diabetes SARS-CoV-2: severe acute respiratory syndrome coronavirus 2 (SARS) Syndecan 1 and 4 as receptors [(M. Bermejo-Jambrina, J. Eder, et al., bioR xiv (2020); A.Hudak et al. Res. Sq, 2020] SARS-induced diabetes S-CoV-2 (F. Rubino et al., N. Engl. J. Med. 383 (2020) 789-790); T. Sathish et al. 1. Prim. Care Diabetes 15 (2020) 194). SARS-CoV HSPGs are preliminary attachment sites of SARS-CoV (J. Lang, et al. PLoS One 6 (2011)). HCoV-NL63: human coronavirus NL63 HSPGs are essential for HCoV-NL63 binding (A. Milewska, et al. J. Virol. 88 (2014) 13221-13230). HSV-1: herpes simplex virus type 1 Syndecanes 1 and 2 as receptors (S. Bacsa, et al. J. Gen. Virol. 92 (2011)733-743). Strong association between HSV-1 infection and type 2 diabetes (Y. Sun et al.Diabetes Care 28 (2) (200 5)435-436) HPV-16: human papillomavirus type 16 Syndecane 1 as a receptor (Z. Surviladze et al J . Gen. Virol. 96 (2015) 223 2) Poor prognosis (A.Sobt i, et al. PLoS One 14 (2019 ),)• . HCV: Hepatitis C virus. Syndecane 1 as a receptor (Q. Shi, et al., J. Virol 1. 87 (2013) 6866-6875). Strong association between HCV infection and a higher prevalence of type 2 diabetes (SS Hammerstad, et al. Front. Endocrinol. 6 (2015) 134). HIV-1: Human immunodeficiency virus type 1. Syndecanes and beta-glycans as receptors (AC Saphire, et al., J. Virol. 75 (2001) 9187-9200). HIV is a high risk factor for the prevalence of type 2 diabetes (AD Duncan, et al. PLoS One 13 (2018)). HCMV: human cytomegalovirus. Strong hypothesis that syndecanes are the receptors for the CMV virus, based on an in vitro study (M. Silvestri, et al. J. Immun ol. 53 (2001) 282-289). Relative risk ratio of up to 12 for having type 2 diabetes for people previously exposed to CMV (BW Roberts, I. Cech, South. Med. J. 98 (2005) 686-692).DENV: Dengue virus. Syndecanes 2 as a receptor (K. Okamoto, et al. J. Gen. Virol. 93 (2012) 761-770). Strong association between diabetes and dengue severity (M. Aamir, et al. Med. Heal. Sci. 9 (2015) 99-101). HTLV-1: Human T-cell leukemia virus type 1. HSPGs are essential for HTLV-1 binding (KS Jones, et al. J. Virol. 79 (2005) 12692-12702). HTLV-1 relative risk ratio greater than 5 for individuals with type 2 diabetes (M. Taghaví et al. Br. J. Diabètes Vas. Dis. 9 (2009) 81-83). HBV: Hepatitis B virus. Glypican-5 as a host cell entry factor for hepatitis B and D (ER Verrier et al., Hepatology (Baltimore, MD.) 63 (2016) 35-48). HBV is associated with the prevalence of diabetes (YS Hong et al. Sci. Rep. 7 (2017), 4606). HVD: Hepatitis D virus.

[0108] According to the invention, the term “Composition” refers to an assembly of compounds, enabling the formation of a mixture having therapeutic, cosmetic, or dietary supplement interest in particular.

[0109] According to the invention, the term "Formulation" indicates the final presentation of a composition, as it will be given to the patient.

[0110] According to the invention, the term "stimulation of glycosaminoglycan biosynthesis" indicates that the biosynthesis of glycosaminoglycans is greater than it was before administration of the formulation or food supplement according to the invention.

[0111] The term "glycosaminoglycan" refers to the family of molecules resulting from the linear polycondensation of osamine and uronic acid units (sometimes replaced by galactose), found primarily in the extracellular matrix of connective tissues. Glycosaminoglycans (GAGs) may be sulfated or unsulfated. There is only one class of unsulfated GAG, hyaluronic acid, but four classes of sulfated GAGs: chondroitin sulfate, dermatan sulfate, keratan sulfate, and heparan sulfate / heparins. Hyaluronic acid is free in tissues, whereas sulfated GAGs are attached to carrier proteins ("core proteins") to form large complexes called proteoglycans. GAGs play an important role in tissue hydration and cell signaling.

[0112] The term "heparan sulfate" refers to these complex polysaccharides belonging to the glycosaminoglycan (GAG) family, which are abundant on the cell surface and in interstitial matrices. It is a high molecular weight sulfated polysaccharide formed by a chain of uronic acids and glucosamines linked by α(1-4) bonds, alternating between D-glucuronic acid or L-iduronic acid and N-acetylated or N-sulfated glucosamine. This mucopolysaccharide or glycosaminoglycan has sulfuric acid residues on the second carbon of the iduronic acids and on the sixth carbon of glucosamine, as well as on the amine group at position 2. This glycan, synthesized in fibroblasts, is a constituent of connective tissue (dermis, aorta), forming part of the basement membrane, in which it is linked to collagen and laminin.

[0113] The term "dermatane sulfate" refers to this sulfated glycosaminoglycan whose polysaccharide structure does not contain glucuronic acid, but rather L-iduronic acid alternating with N-acetylgalactosamine molecules, forming dihexoidal links (L-iduronosido-3-[3-N-acetylgalactosamine]) attached to the C4 of the iduronic acid in the following link. Sulfur radicals are attached to the C4 of the galactosamines. Like most glycosaminoglycans, dermatan sulfates are part of the glycocoprotein structures, the proteoglycans, of connective tissues, particularly the dermis, cartilage, and cornea. Depending on the tissue, the length The chains vary from 10 to 50 links; they are linked to a polypeptide in the same way as the carbohydrate chains of glycoproteins. These dermatan sulfates are either located on the outer surface of cell membranes or associated in macromolecular complexes in the extracellular ground substance.

[0114] The term "chondroitin sulfate" refers to this sulfated glycosaminoglycan whose polysaccharide structure contains glucuronic acids alternating with N-acetylgalactosamine molecules, forming dihexoidal chains (|3-glucuronosido-3-[3-N-acetylgalactosamine]) attached to the C4 of the glucuronic acid of the following chain. The sulfuric acid groups are attached to the C4 or C6 of the galactosamines. Like most glycosaminoglycans, chondroitin sulfates are part of the glycocoprotein structures, the proteoglycans, of connective tissues, particularly the dermis, cartilage, and cornea. Depending on the tissue, the chain length varies from 10 to 50 links; they are linked to a polypeptide in the same way as the carbohydrate chains of glycoproteins.These chondroitin sulfates are located either on the external surface of cell membranes or associated in the form of macromolecular complexes in the extracellular ground substance.

[0115] Regarding joint pathologies [T71], cartilage, with approximately 70 g of chondroitin sulfate, is by far the main contributor to the mass of GAGs with D-xylose as a binding element on core proteins. In 1987, Kleesiek et al. [T72], in an in vivo study, showed that serum xylosyltransferase enzyme, which catalyzes the transfer of D-xylose from UDP-xylose to the hydroxyl group of serine residues of core proteins, was a biomarker of cartilage destruction in chronic joint diseases [T72]. This reflects the importance of CS, which is the only D-xylose-containing GAG present in cartilage, for cartilage protection. Indeed, chondrocyte CS has protective effects by regulating the synthesis of type II collagen and hyaluronic acid, inhibiting cell death, and increasing the production of PG [T73, T74]. Thus, it protects the chondrocyte glycocalyx and reduces inflammation.The anti-inflammatory properties of chondrocyte CS have been well demonstrated [T75, T76].

[0116] Regarding cancers, Table 1 shows that in cancers there is an abnormal increase in core proteins to which HS / CS / DS glycosaminoglycans bind, as well as an overexpression of heparanase in these cancers (Table 1). D-Xylose-2-phosphate, through the stimulation of HS / CS / DS, has antiviral properties (more effective than D-xylose, see examples 1 and 2) against cancer-associated viruses (Table 2).

[0117] Furthermore, stimulation of HS / CS / DS glycosaminoglycan biosynthesis regulates the level of heparanase (HPSE) at the cell surface. Indeed, cells with less HS absorb less HPSE and therefore have more HPSE at the surface cellular (Gingis-Velitski et al., J. Biol. Chem., 279 (2004), pp. 44084-44092). Therefore, D-xylose-2-phosphate, by regulating HPSE levels, contributes to a better prognosis of cancers (Table 1).

[0118] Similarly, stimulation of HS / CS / DS glycosaminoglycan biosynthesis regulates the level of core proteins, particularly syndecans, at the cell surface. Indeed, HS has been shown to regulate syndecan biosynthesis and their shedding from the cell surface (VC Ramani et al., J. Biol. Chem., 287 (2012), pp. 9952-9961; EP Schmidt et al., Nat. Med., 18 (2012), pp. 1217-1223). Therefore, D-xylose-2-phosphate contributes to improved cancer prognosis (Table 1).

[0119] By "esters of D-xylose-2-Phosphate" are understood esters in the sense of the term well known to those skilled in the art, of D-xylose-2-Phosphate.

[0120] Also advantageously included within the scope of the invention are fatty acid esters comprising 16 to 24 carbon atoms, in particular natural fatty acid esters.

[0121] Among these fatty acid esters, the esters of palmitic, stearic, oleic, linoleic, linolenic, arachidonic, erucic, lignoceric acids will be advantageously chosen.

[0122] By "oligosaccharides containing D-xylose-2-phosphate" are meant holosides consisting of a small number of monosaccharides (2, 3, 4, 5, 6), including D-xylose-2-phosphate. By oligosaccharide within the meaning of the invention is meant chains of sugars containing 2 to 6 sugars.

[0123] Preferably, according to the present invention, the oligosaccharide containing D-xylose-2-Phosphate among the oligosaccharides as defined above comprises at least one xylose or one galactose and 1 to 6 sugars.

[0124] Such oligosaccharides are advantageously chosen from xylobiose, xylobiose hexaacetate, methyl-[3-xylobioside], xylotriose, xylotetraose, xylopentaose and xylohexaose. One or more xyloses have been phosphorylated at position 2 on these oligosaccharides.

[0125] Even more preferably, xylobiose is the oligosaccharide used, which is composed of two molecules of D-xylose-2-Phosphate linked by a 1-4 bond as well as xylobiose acetates such as xylobiose hexaacetate.

[0126] According to one embodiment, said oligosaccharide comprising D-xylose-2-Phosphate is selected from Galactose-[31-4-D-xylose-2-Phosphate, Galactose-[31-3-Galactose-[31-4-D-xylose-2-Phosphate, or Glucuronic Acid-[31-3-Galactose-[31-3-Galactose-[31-4-D-xylose-2-Phosphate.

[0127] The term “human patient” means a human individual suffering from a disease or at risk of suffering from a disease, and whose prevention or treatment is necessary.

[0128] By "healthy subject" is meant a human individual not suffering from a pathology, and therefore not requiring treatment.

[0129] For the purposes of this invention, "non-therapeutic" means a cosmetic application not intended to treat a patient, but which improves the superficial visual appearance of the skin.

[0130] According to the invention, "skin area care" means that the cosmetic composition according to the invention improves the appearance of the skin, preferably of the face.

[0131] For the purposes of this invention, "cosmetically acceptable" means something that is useful in the preparation of a cosmetic composition, that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and that is acceptable for cosmetic use, in particular by topical application to the skin.

[0132] By "administering" is meant the action of introducing into the body of the patient or healthy subject the therapeutic compositions or formulations or the food supplement according to the invention.

[0133] By "number of administrations" is meant the number of times the administration is carried out, for example per day, to the patient or healthy subject of the formulation or food supplement according to the invention.

[0134] By "acceptable active pharmaceutical ingredient" is meant an active medicinal substance known to have a particular therapeutic effect.

[0135] According to the invention, "antiviral active" means a compound known for its virus-eliminating properties, in particular the viruses mentioned in the context of the invention.

[0136] According to the invention, "active ingredient enabling the prevention or treatment of type 2 diabetes" means a compound known for its properties of preventing or treating type 2 diabetes.

[0137] According to the invention, "active ingredient enabling the prevention or treatment of insulin resistance" means a compound known for its properties of preventing or treating insulin resistance.

[0138] According to the invention, "antibiotic" means a compound that acts either by preventing the development of bacteria (bacteriostatic antibiotics) or by killing them (bactericidal antibiotics).

[0139] By "dose" is meant a unit intake of the formulation or food supplement according to the invention.

[0140] By "day" is meant the 24-hour unit beginning at 0000 and ending at 23:59.

[0141] Proteoglycans are glycoproteins composed of a central protein, also called a "carrier protein," "core protein," or "core protein," to which one or more chains of sulfated glycosaminoglycans are attached, generally linked by glycosidic bonds to the alcohol groups of certain serine or, occasionally, threonine amino acids of the protein. Currently, more than 40 different carrier proteins and 5 major classes of proteoglycans are distinguished: 1- Small leucine-rich proteoglycans (SLRPs), which serve primarily to stabilize collagen fibers and regulate cellular activities; the main ones are decorin, lumican and fibromodulin; 2-Large extracellular proteoglycans, some of which are capable of aggregating with hyaluronic acid to form very large complexes allowing tissue hydration and shock absorption; the main ones are versican and agrecan; 3- Proteoglycans associated with basement membranes, which participate in tissue cohesion and the filtration of molecules; the main ones are perlecan and agrin; 4- Cell membrane proteoglycans, which play an important role in cell signaling and promote the action of cytokines and growth factors. This class consists of syndecans, whose carrier protein is transmembrane, and glypicans, for which the carrier protein is anchored to the cell surface; 5- a small proteoglycan called serglycin present in the intracellular granules of mast cells and macrophages, which carries chains of heparin, a major anticoagulant.

[0142] The term "syndecanes" refers to proteoglycans, which are important constituents of the membranes of certain cells, such as the sinusoidal membranes of hepatocytes, muscle cells, and macrophages. Syndecanes form a family of transmembrane molecules with a glycan extracellular domain and an intracellular end in the cytoplasm. Syndecanes are involved in the internalization of atherogenic lipoproteins.

[0143] By "glypican" is meant the proteoglycan for which the carrier protein is anchored to the surface of the cell.

[0144] "HSV-1" is Herpes simplex virus type 1.

[0145] “HSV-2” is Herpes simplex virus type 2.

[0146] “HPV-16” is human papillomavirus 16.

[0147] “HPV-31” is human papillomavirus 31.

[0148] "HBV" is the hepatitis B virus.

[0149] "HCV" is the hepatitis C virus.

[0150] “HIV-1” or HIV-1 is the human immunodeficiency virus.

[0151] The “HTLV-1” is the Human T-lymphotropic Virus 1.

[0152] “SARS-CoV-2” is the virus associated with COVID-19.

[0153] "HCMV" is human cytomegalovirus

[0154] “DENV-1” is the dengue virus in its first serotype.

[0155] “DENV-2” is the dengue virus in its second serotype.

[0156] By "oral administration" or gastrointestinal route or per os (Latin expression meaning "by the mouth") is meant the route of administration for enteral purposes, which consists of swallowing them by the mouth.

[0157] According to the invention, "nasal administration" means the route of administration of drugs to the nose and nasal cavities.

[0158] "Parenteral administration" means administration by means of an injection, through a skin puncture.

[0159] By "subcutaneous route" is meant a continuous or discontinuous injection of into the subcutaneous tissue (hypodermis).

[0160] By "intradermal route" is meant an injection into the skin between the epidermis and the dermis.

[0161] By "intravenous route" is meant an injection into a vein.

[0162] By "intramuscular route" is meant an injection into a muscle.

[0163] According to the invention, the term "prevent" or "prevention" indicates a reduction of risk of developing severe forms of these pathologies.

[0164] According to the invention, the term "treat" or "treatment" means the alleviation of symptoms associated with a specific disorder or condition and / or the elimination of said symptoms.

[0165] By "active ingredient enabling the acceleration of said at least one compound to cells" is meant a molecule enabling the access of said at least one compound selected from D-xylose-2-phosphate, its esters, and oligosaccharides comprising D-xylose-2-phosphate, to target cells through its own action. Preferably, said active ingredient is insulin.

[0166] By "in a suitable form" is meant a pharmaceutical form allowing the proper administration of the formulation or food supplement according to the invention, allowing the active substance to reach the intended organ as quickly and effectively as possible.

[0167] According to the invention, "dietary supplement" means a product that can provide a nutritional benefit. This supplement can be taken alone or formulated with other compounds to make the composition more appealing to consume by being more similar to a regular food product. This supplement may be a contributing factor in preventing or reducing superficial visceral pain that does not require therapeutic treatment.

[0168] The composition according to the invention comprises a "physiologically acceptable medium," that is, one compatible with oral, nasal, or parenteral administration. In other words, the medium used contains compounds that prevent the degradation of d-xylose or its derivatives, and that present no risk to the patient or consumer that might deter them from using this composition, or any risk that could cause adverse side effects.

[0169] In the description and the following examples, unless otherwise stated, percentages are percentages by weight, and value ranges expressed as "between ... and ..." include the specified lower and upper bounds. The following examples are given by way of illustration and are not intended to limit the scope of the invention. Examples

[0170] Example 1: Test of the antiviral and cytotoxic activity of a composition according to the invention against SARS-CoV2, HIV-L RSV.

[0171] Six tests were carried out to study the cytotoxicity of D-xylose-2-phosphate (with 48% purity per mol) and its antiviral action against SARS-CoV-2, HIV-1, RSV.

[0172] The cytotoxicity of D-xylose-2-Phosphate concentrations was determined under the same test conditions, but in the absence of viral infection.

[0173] Introduction

[0174] An 8-point and 2-fold serial dilution of a small molecule compound (Sodium D-Xylose-2-phosphate; highest test concentration: 10 mM) is added to test cells (Vero, A549, and HeLa Tzmbl) concurrently with infection by SARS-CoV-2, RSV-A2, and HIV-1, respectively. The compound is left on the cells for the duration of the experiment (24–48 h, depending on the virus), after which the inhibition of infection is measured by quantifying the percentage of infected cells using an immunofluorescence-based assay. Remdesivir (SARS-CoV-2 and RSV-A2) and AZT (HIV-1) are included as analytical controls.

[0175] In parallel, the cytotoxicity of the same concentrations will be determined under the same test conditions, but in the absence of viral infection using an MTT reading.

[0176] Objective

[0177] The aim of this study is to test the antiviral and cytotoxic properties of 8 concentrations of D-Xylose-2-phosphate, against an early isolate of SARS-CoV2, HIV-1, RSV.

[0178] Controls

[0179] - Untreated and uninfected cells

[0180] - Untreated infected cells

[0181] - HIV-1: AZT

[0182] - SARS-CoV-2: Remdesivir

[0183] - RSV: Remdesivir

[0184] Test system

[0185] - Cells:

[0186] RSV: A549 10000 cells per well

[0187] HIV-1: TZMBL 8000 cells per well

[0188] SARS-CoV-2: Vero AD 8000 cells per well

[0189] - Virus:

[0190] RSV: VRS stock P2, batch 06 / 27 / 2022 (7.8xl06 IFU / ml)

[0191] HIV-1: batch NL4-3 of 12 / 22 / 2023 (4.58xl06 IFU / ml)

[0192] SARS-CoV-2: England 02 / 2020 (stock VRS S2P1, Title 3.2xl06 IFU / ml).

[0193] - Reading: IF for antiviral test; MTT test for cytotoxicity test.

[0194] Reagents

[0195] - Full media:

[0196] RSV / A549: DMEM + 10% FBS + 1% P / S

[0197] HIV-l / TZMBL: DMEM + 10% FBS + 1% P / S

[0198] SARS-CoV-2 / VeroAD: M199 +5% FBS + 1% P / S

[0199] - infection media:

[0200] RSV / A549: DMEM + 0.1% FBS + 20mM HEPES + 0.3% BSA + 1% P / S

[0201] HIV-l / TZMBL: DMEM + 10% FBS + 1% P / S

[0202] SARS-CoV-2 / VeroAD: M199 + 0.4% BSA + 1% P / S

[0203] - Controls

[0204] RSV and SARS-CoV-2: Remdesivir lWOM Stock

[0205] HIV-1: AZT lOmM

[0206] Reagents

[0207] Treatment with the compound

[0208] Experimental method:

[0209] Prepare 400 mM sodium D-Xylose-2-phosphate (Molar mass = 274.07 g / mol; 1.2 g supplied):

[0210] Weigh 200 mg of Sodium D-Xylose-2-phosphate and dissolve in 1824.8 µl of DMEM + w / w (no other supplements).

[0211] Heat to 37°C and vortex.

[0212] Filter and sterilize through a 0.22 pM filter. After use, store the remainder at -20°C.

[0213] Prepare 20 mM of sodium D-Xylose-2-phosphate (= 2x final maximum concentration of 10 mM) in 2000 itl:

[0214] - 50 µl of 400 mM sodium D-Xylose-2-phosphate + 950 µl of infection medium (total flight = 1000 seats).

[0215] This is repeated for each virus, in the respective infection media.

[0216] Remdesivir and AZT concentrations are 10 mM in DMSO.

[0217] Prepare 10 pM of Remdesivir (= 2x final maximum concentration of 5 pM):

[0218] - 2 pl of Remdesivir 10 mM + 1998 pl of RSV infection medium.

[0219] Prepare 40 pM of Remdesivir (= 2x final maximum concentration of 20 pM):

[0220] - 3 μl of 10 mM Remdesivir + 747 μl of SARS-CoV-2 infection medium.

[0221] Prepare 10 pM of AZT (= 2x final maximum concentration of 5 pM):

[0222] - 2 μl of 10 mM AZT + 1,998 μl of HIV infection medium

[0223] As this is the control and has a different diluent than the compounds being tested, and The concentration of the diluent is 0.4% at the maximum concentration of Remdesivir, the diluent is not taken into account.

[0224] To wells 4 to 6 of row A on all plates, add 240 µl of 20 mM sodium D-Xylose-2-phosphate.

[0225] To wells 4 to 6 of rows B to H, add 120 µl of virus-specific infection medium.

[0226] Serially dilute the test samples 2 times by moving 120 pl down from row A (wells 4 to 6) to H, mixing 10 times.

[0227] To wells 7 to 9 of row A, add 180 pl of control compound.

[0228] To wells 7 to 9 of rows B to H, add 120 µl of infection medium specific to virus.

[0229] Serially dilute the control compounds 3 times by moving down 60 µl from row A (wells 7 to 9) to H, mixing 10 times.

[0230] In columns 1 to 3 and 10 to 12, add 120 µl of virus-specific infection medium.

[0231] Cytotoxicity

[0232] Remove media from cells in cytotoxicity plate using a multichannel.

[0233] Replace with 50 µl of compound dilutions from the round-bottom plate, immediately followed by 50 µl of infection.

[0234] Incubate the cells for 24 hours (Vero AD) or 48 hours (HeLa Tzmbl and A549) at 37°C and 5% CO2.

[0235] Infection

[0236] Calculate the required virus stock volume using the formula below:

[0237] [(Number of cells / wells*) x (number of wells + >10% excess wells) x MOI] / virus IU / ml

[0238] * Double the number of cells spread out the day before

[0239] RSV = (20,000 x 110 x 0.2) / 7.8 x 10⁶ x 1,000 = 56 µL of virus + 5,444 µL of medium infection

[0240] Thaw an aliquot of virus and add 56 pl of virus + 5,444 pl of infection medium (total volume 110*50 pl = 5,500 pl).

[0241] HIV = (16000x110x0.25) / 4.58x06x000 = 96 µl of virus + 5404 µl of infection medium

[0242] Thaw an aliquot of virus and add 96 pl of virus + 5,404 pl of infection medium (total volume 110*50 pl = 5,500 pl).

[0243] SARS-CoV-2 = (16,000 x 110 x 0.0014 / 3.2 x 105 x 1,000) = 7.7 µL of virus + 5,492.3 µL of infection medium

[0244] Dilute the virus 10 times, by adding 10 pl of virus stock to 90 pl of infection medium for a working titer of 3.2xO5 / IU / ml.

[0245] Add 7.7 pl of diluted virus + 5,492.3 pl of infection medium (total volume 110*50 pl = 5,500 pl).

[0246] Remove the media from the cells in the antiviral plates.

[0247] Replace with 50 µl of compound dilutions from the round-bottom plate, immediately followed by 50 µl of diluted virus or infection media according to the plate arrangement above.

[0248] Incubate RSV and HIV for 48 hours and SARS-CoV-2 for 24 hours at 37°C and 5% CO2.

[0249] Fixation and development

[0250] After 24 or 48 hours of incubation, proceed with the fixation (antiviral test) or the MTT test (cytotoxicity test). For the MTT test, add Triton to column 11 (untreated cells + / - diluent) as a control.

[0251] Immunostaining

[0252] Stain the antiviral plaque using:

[0253] RSV: Staining plate using goat anti-RSV antibody (Abcam AB20745) at 1:500, followed by donkey anti-goat antibody (Abcam

[0254] AB 150135) at 1:800, with nuclear staining by Hoechst at 1:1000.

[0255] SARS-CoV-2: Staining plate using rabbit anti-SARS-CoV-2 Nucleocapsid antibody (HL448) (Thermo Fisher MA5-36271) at 1:500, followed by goat anti-rabbit 488 (Thermo Fisher Al 1034) at 1:800, with nuclear staining by Hoechst at 1:1000.

[0256] HIV: staining plate using rabbit anti-gag p55 p24 antibody (ARP432 NIBSC) at 1:500, followed by the goat anti-rabbit antibody 488

[0257] (Thermo Fisher Al 1034) at 1:800, with nuclear staining by Hoechst at 1:1000.

[0258] Results of cytotoxicity tests.

[0259] Analysis (performed by VRS)

[0260] Cells: VeroAD

[0261] Results for cytotoxicity: absorbance at 570 nm, [Tables 4] Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate (p M) Empty Sodium D-Xylo se-2-phosphate (pM) Remdesivir ( pM) untreated Triton Empty 20.000 10000.0 00 0.26 4 0.24 4 0.25 7 0.23 0.24 0.23 0.24 4 0.040 6.667 5000.000 0.26 9 0.26 8 0.27 3 0.26 0.26 0.25 0.26 3 0.038 2.222 2500.000 0.26 5 0.26 5 0.26 4 0.27 0.27 0.27 0.26 0 0.044 0.741 1250.000 0.27 9 0.26 5 0.27 3 0.27 0.26 0.26 0.26 8 0.039 0.247 625.000 0.26 1 0.25 7 0.26 2 0.26 0.25 0.26 0.24 8 0.040 0.082 312.500 0.27 6 0.26 5 0.26 9 0.27 0.25 0.27 0.25 0 0.054 0.027 156.250 0.25 1 0.25 3 0.25 0 0.24 0.26 0.24 0.23 5 0.045 0.009 78.125 0.22 3 0.22 5 0.22 6 0.21 0.22 0.21 0.19 6 0.048

[0262] Mean for the untreated infected column = 0.246

[0263] Average for the untreated infected column: = 0.044

[0264] Pearson standard deviation for the untreated infected column and the untreated infected column processed: (Standard deviation: 0.023)

[0265] Viability Percentages, Cells = VeroAD [Tables 5] Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate(p M) Empty Sodium D-Xylos e-2-phosphate(p M) Remdesivir (pM) untreated Trit on Empty 20,000 10000.0 00 109. 26 99.3 3 105. 69 92.6 4 98.4 6 92.4 4 99.3 3 -1.68 110. 46 6.667 5000.000 111. 77 111. 15 113. 80 108. 39 106. 95 103. 92 108. 50 -2.89 104. 98 2,222 2,500,000 109.80 109.73 109.18 110.35 111.99 110.02 107.20 0.11 102.96 0.741 1250.000 116.34 109.47 113.80 113.32 106.87 109.00 110.93 -2.07 81.1 0 0.247 625.000 107.81 105.69 108.10 105.30 101.56 105.59 101.14 -1.53 ​​89.7 1 0.082 312.500 115. 10 109. 73 111. 77 111. 48 103. 88 110. 38 102. 40 5.32 89.9 4 0.027 156.250 102. 58 103. 92 102. 08 97.2 6 104. 80 96.7 1 94.9 4 0.70 83.3 4 0.009 78.125 88.7 2 89.6 4 90.1 0 83.5 0 85.0 5 84.3 7 75.5 7 2.04 77.4 7

[0266] Percentages of cytotoxicity, Cells = VeroAD [Tableauxô] Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate(p M) Empty Sodium D-Xylos e-2-phosphate(p M) Remdesivir (pM) untreated Trit on Empty 20.000 10000.0 00 -9.26 0.67 -5.69 7.36 1.54 7.56 0.67 101. 68 -10.4 6 6,667 5000,000 -11.7 7 -11.1 5 -13.8 0 -8.39 -6.95 -3.92 -8.50 102. 89 -4.98 2,222 2500,000 -9.80 -9.73 -9.18 -10.3 5 -11.9 9 -10.0 2 -7.20 99.8 9 -2.96 0.741 1250.000 -16.3 4 -9.47 -13.8 0 -13.3 2 -6.87 -9.00 -10.9 3 102.07 18.9 0 0.247 625.000 -7.81 -5.69 -8.10 -5.30 -1.56 -5.59 -1.14 101.53 10.2 9 0.082 312.500 -15.1 0 -9.73 -11.7 7 -11.4 8 -3.88 -10.3 8 -2.40 94.6 8 10.0 6 0.027 156.250 -2.58 -3.92 -2.08 2.74 -4.80 3.29 5.06 99.3 0 16.6 6 0.009 78.125 11.2 8 10.3 6 9.90 16.5 0 14.9 5 15.6 3 24.4 3 97.9 6 22.5 3

[0267]

[0268] Cells: A549 Results for cytotoxicity: absorbance at 570 nm, [Paintings?] Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate (p M) Empty Sodium D-Xylo se-2-phosphate (gM) Remdesivir (p M) untreated Triton Empty 5.000 10000.0 00 0.40 3 0.39 8 0.39 6 0.32 5 0.32 1 0.34 2 0.34 8 0.041 1.667 5000.000 0.37 9 0.35 9 0.35 3 0.32 9 0.33 2 0.33 3 0.34 2 0.059 0.556 2500.000 0.31 9 0.32 2 0.30 2 0.35 3 0.33 5 0.34 0 0.35 7 0.042 0.185 1250.000 0.35 5 0.34 1 0.31 6 0.34 1 0.31 9 0.35 2 0.34 1 0.042 0.062 625.000 0.33 4 0.33 5 0.33 7 0.35 1 0.32 9 0.34 9 0.33 0 0.044 0.021 312.500 0.34 7 0.35 0 0.33 7 0.38 5 0.36 2 0.40 9 0.41 6 0.043 0.007 156.250 0.34 7 0.34 2 0.35 3 0.43 6 0.32 2 0.40 4 0.44 0 0.045 0.002 78.125 0.27 7 0.29 3 0.27 9 0.36 8 0.32 5 0.33 1 0.35 1 0.042

[0269] Mean for the untreated infected column = 0.366

[0270] Average for the untreated infected column: = 0.045

[0271] Pearson standard deviation for the untreated infected column and the untreated infected column: (Standard standard deviation: 0.040)

[0272] Viability Percentages, A549 Cells [Tables 8] Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate(p M) Empty Sodium D-Xylos e-2-phosphate(p M) Remdesivir (pM) untreated Trit on Empty 5.000 10000.0 00 111. 54 110. 04 109. 27 87.4 0 86.0 1 92.6 2 94.5 5 -1.24 1.667 5000.000 104. 25 97.8 9 96.0 3 88.6 7 89.5 6 89.7 5 92.7 0 4.32 0.556 2500.000 85.4 9 86.4 9 80.1 4 95.9 5 90.3 8 91.9 8 97.3 9 -0.97 0.185 1250.000 96.7 5 92.1 9 84.4 5 92.2 5 85.5 7 95.7 8 92.1 7 -0.70 0.062 625.000 90.2 0 90.4 1 91.1 3 95.3 7 88.5 2 94.7 9 88.9 6 -0.08 0.021 312.500 94.0 3 95.0 1 90.9 9 106.02 98.8 2 113.54 115.53 -0.56 0.007 156.250 94.1 9 92.6 8 95.8 9 121. 97 86.4 7 111. 98 123. 24 0.06 0.002 78.125 72.4 8 77.4 6 72.9 0 100. 58 87.3 2 89.2 2 95.4 5 -0.83

[0273] Percentages of cytotoxicity, A549 cells [Tables 9] Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate(p M) Empty Sodium D-Xylos e-2-phosphate(p M) Remdesivir (pM) untreated Trit on Empty 5.000 10000.0 00 -11.5 4 -10.0 4 -9.27 12.6 0 13.9 9 7.38 5.45 101.24 1.667 5000.000 -4.25 2.11 3.97 11.3 3 10.4 4 10.2 5 7.30 95.6 8 0.556 2500.000 14.5 1 13.5 1 19.8 6 4.05 9.62 8.02 2.61 100.97 0.185 1250.000 3.25 7.81 15.5 5 7.75 14.4 3 4.22 7.83 100.70 0.062 625.000 9.80 9.59 8.87 4.63 11.4 8 5.21 11.0 4 100.08 0.021 312.500 5.97 4.99 9.01 -6.02 1.18 -13.5 4 -15.5 3 100.56 0.007 156.250 5.81 7.32 4.11 -21.9 7 13.5 3 -11.9 8 -23.2 4 99.9 4 0.002 78.125 27.5 2 22.5 4 27.1 0 -0.58 12.6 8 10.7 8 4.55 100.83

[0274] Cells: HeLa TZM-bl

[0275] Results for cytotoxicity: absorbance at 570 nm, [Tables 10] AZT (g M) Sodium D-Xylo se-2-pho sphate (p M) Empty Sodium D-Xylo se-2-phosphate (gM) AZT (pM) untreated Triton Empty 5.000 10000.0 00 0.75 0 0.84 8 0.72 5 0.88 1 0.77 7 0.74 5 0.76 1 0.052 1.667 5000.000 0.88 7 0.93 7 0.80 4 1.05 2 0.84 5 0.82 0 0.89 5 0.058 0.556 2500.000 1.03 7 0.90 7 0.77 7 1.08 7 1.00 2 0.79 7 0.81 8 0.071 0.185 1250.000 0.79 1 0.78 7 0.77 3 1.05 5 0.86 7 0.81 2 0.75 9 0.053 0.062 625.000 0.81 2 0.77 0 0.78 1 0.97 0 0.82 4 0.78 7 0.75 4 0.057 0.021 312.500 0.94 8 0.87 9 0.82 7 0.99 3 0.84 3 0.85 4 0.80 8 0.057 0.007 156.250 0.88 9 0.85 6 0.84 2 0.73 7 0.85 2 0.82 6 0.81 9 0.064 0.002 78.125 0.83 0 0.90 1 0.82 8 0.99 0 0.85 8 0.88 0 0.82 0 0.068

[0276] Mean for the untreated infected column = 0.804

[0277] Average for the untreated infected column: = 0.060

[0278] Pearson standard deviation for the untreated infected column and the untreated infected column processed: (Standard deviation: 0.047)

[0279] Viability percentages, HeLa TZM-bl cells [Tableauxll] AZT (g M) Sodium D-Xylo se-2-pho sphate(p M) Empty Sodium D-Xylos e-2-phosphate(p M) AZT (pM) untreated Trit on Empty 5.000 10000.0 00 92.7 6 105. 84 89.4 2 110. 32 96.3 4 92.0 9 94.1 9 -1.08 1.667 5000.000 111.08 117.82 99.9 9 133.26 105.55 102.16 112.17 -0.32 0.556 2500.000 131.28 113. 88 96.2 8 137. 96 126. 53 98.9 7 101. 82 1.41 0.185 1250.000 98.2 2 97.7 0 95.7 5 133. 70 108. 40 101. 07 93.8 9 -0.89 0.062 625.000 101. 07 95.3 8 96.8 5 122. 28 102. 72 97.7 0 93.2 1 -0.36 0.021 312.500 119. 33 110. 08 103. 11 125. 33 105. 25 106. 66 100. 53 -0.36 0.007 156.250 111. 44 106. 92 105. 11 90.9 9 106. 47 102. 93 102. 03 0.49 0.002 78.125 103. 46 112. 96 103. 25 124. 92 107. 26 110. 20 102. 16 1.12

[0280] Percentages of cytotoxicity, HeLa TZM-bl [Tables 12] AZT (p M) Sodium D-Xylo se-2-pho sphate(p M) Empty Sodium D-Xylos e-2-phosphate(p M) AZT (pM) untreated Trit on Empty 5.000 10000.0 00 7.24 -5.84 10.5 8 -10.3 2 3.66 7.91 5.81 101.08 1.667 5000.000 -11.0 8 -17.8 2 0.01 -33.2 6 -5.55 -2.16 -12.1 7 100.32 0.556 2500.000 -31.2 8 -13.8 8 3.72 -37.9 6 -26.5 3 1.03 -1.82 98.5 9 0.185 1250.000 1.78 2.30 4.25 -33.7 0 -8.40 -1.07 6.11 100.89 0.062 625.000 -1.07 4.62 3.15 -22.2 8 -2.72 2.30 6.79 100.36 0.021 312.500 -19.3 3 -10.0 8 -3.11 -25.3 3 -5.25 -6.66 -0.53 100.36 0.007 156.250 -11.4 4 -6.92 -5.11 9.01 -6.47 -2.93 -2.03 99.5 1 0.002 78.125 -3.46 -12.9 6 -3.25 -24.9 2 -7.26 -10.2 0 -2.16 98.8 8

[0281] Results for antiviral tests

[0282] Results for SARS-CoV-2

[0283] Raw data: [Tables 13] Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate (p M) Empty Sodium D-Xylo se-2-phosphate (pM) Remdesivir (p M) Infected untreated Uninfected untreated Triton Empty 20,000 10000.0 00 12.5 9 11.3 5 6.29 0.00 0.46 0.30 28.3 4 0.18 6.667 5000.000 33.0 6 34.9 1 14.0 2 3.09 2.36 2.46 62.7 0 0.01 2,222 2,500,000 19.1 1 28.4 7 29.7 2 18.4 4 20.6 7 36.9 3 48.2 7 0.00 0.741 1,250,000 35.3 0 33.9 2 55.9 2 49.1 8 30.0 3 84.6 4 42.0 8 0.01 0.247 625,000 47.5 2 50.4 0 46.3 8 49.2 1 73.0 2 49.7 4 60.6 9 0.74 0.082 312,500 37.6 5 42.1 5 48.0 2 65.2 6 53.8 3 54.7 2 40.4 8 0.00 0.027 156.250 45.7 4 60.4 8 54.2 8 51.9 1 56.1 4 60.0 1 49.5 9 0.00 0.009 78.125 42.5 0 61.0 3 76.7 5 56.9 7 80.0 1 79.5 1 90.0 5 0.35

[0284] Analyses (performed by VRS)

[0285] Absorbance - SARS-CoV-2

[0286] Average for the untreated infected column: 52.78

[0287] Standard deviation for the untreated infected column: 18.68

[0288] Average for the uninfected, untreated column: 0.16

[0289] Standard deviation for the untreated, uninfected column: 0.26

[0290] Percentages of inhibition [Tables 14] Remdesivir (pM) Sodium D-Xylose-2-phosphate (pM) Void Sodium D-Xylose-2-phosphate (pM) Remdesivir (pM) Infected untreated Non-infected untreated Triton Void 20,000 10,000 0 0 76.3 8 78.7 3 88.3 5 100.31 99.4 3 99.7 4 46.43 99.97 6,667 5,000,000 37.4 7 33.9 5 73.6 6 94.4 3 95.8 2 95.6 4 -18.85 100.2 8 2,222 2,500,000 63.9 9 46.2 0 43.8 3 65.2 5 61.0 3 30.1 2 8.57 100.3 1 0.741 1250.000 33.2 2 35.8 4 -5.9 8 6.84 43.2 3 -60.57 20.33 100.2 8 0.247 625.000 10.0 0 4.51 12.1 6 6.77 -38. 47 5.78 -15.04 98.91 0.082 312.500 28.7 5 20.1 9 9.03 -23.7 3 -2.0 1 -3.7 0 23.36 100.3 1 0.027 156.250 13.3 7 -14. 64 -2.8 5 1.65 -6.3 9 -13. 74 6.05 100.3 1 0.009 78.125 19.5 3 -15. 69 -45. 57 -7.97 -51. 76 -50. 81 -70.84 99.64 [Table 15] Number of cells Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate (p M) Empty Sodium D-Xylose-2-phosphate (pM) Remdesivir (pM) Infected untreated Non-infected untreated Tri ton Empty 20,000 10000.0 00 1359 3 13951 1413 1 1379 6 1344 7 1366 1 1341 7 1408 6 6,667 5000,000 1566 4 15054 1507 8 1474 5 1457 7 1470 4 1468 2 1475 3 2,222 2500,000 1515 2 15573 1521 4 1486 2 1508 7 1469 3 1509 9 1543 6 0.741 1250.000 1484 6 14959 1505 0 1461 9 1444 1 1442 9 1501 9 1464 9 0.247 625.000 1527 9 15234 1493 1 1458 5 1491 0 1461 5 1462 7 1586 8 0.082 312.500 1493 5 14903 1464 7 1439 0 1436 1 1548 0 1476 2 1497 3 0.027 156.250 1429 6 14218 1387 0 1432 5 1395 5 1407 7 1416 3 1482 6 0.009 78.125 1283 6 12733 1261 3 1272 4 1161 6 1203 9 1158 8 1349 1

[0291] A photograph of the plate described in Table 15 is shown in [Fig. 1].

[0292] Results for HIV-1

[0293] Raw data: [Tables 16] AZT (g M) Sodium D-Xylo se-2-pho sphate (p M) Empty Sodium D-Xylo se-2-phosphate (pM) AZT (pM) Infected untreated Uninfected untreated Triton Empty 5.000 10000.0 00 37.6 3 34.0 5 33.7 9 1.41 1.89 1.86 46.6 0 0.26 1.667 5000,000 36.3 3 34.5 2 35.1 6 3.65 3.24 3.84 41.0 7 0.21 0.556 2500,000 37.9 5 36.8 3 34.6 2 8.65 7.19 9.04 39.9 3 0.02 0.185 1250.000 26.0 6 30.8 0 29.6 3 16.4 5 15.9 8 16.4 0 39.5 4 0.07 0.062 625.000 31.3 0 24.6 1 29.7 8 22.0 6 23.9 4 27.2 8 41.6 7 0.08 0.021 312.500 33.5 9 35.5 4 39.4 7 31.6 2 34.3 9 33.1 6 41.4 6 0.05 0.007 156.250 38.3 3 38.0 0 41.5 9 36.7 8 37.6 3 37.8 2 45.8 7 0.09 0.002 78.125 44.8 4 41.6 0 44.0 8 43.5 2 46.6 2 50.5 0 46.3 1 0.24

[0294] Analyses (performed by VRS)

[0295] Absorbance - HIV-1

[0296] Average for the untreated infected column: 42.81

[0297] Standard deviation for untreated infected column: 2.95

[0298] Average for the uninfected, untreated column: 0.13

[0299] Standard deviation for the untreated, uninfected column: 0.09

[0300] Percentages of inhibition [Tables 17] AZT (pM Sodium Void Sodium D-Xylo AZT (pM) Infect Non-Vid ) D-Xylo se-2-phosphate é non-infect e se-2-pho (pM) treated é non phate(p M) -trait é Tri tone 5.000 10000.0 00 12.1 2 20.5 1 21.1 2 96.9 9 95.8 6 95.9 3 -8.88 99.69 1.667 5000.000 15.1 8 19.4 1 17.9 1 91.7 4 92.7 1 91.2 9 4.07 99.81 0.556 2500,000 11.3 8 14.0 1 19.1 8 80.0 3 83.4 5 79.1 1 6.74 100.2 6 0.185 1250,000 39.2 5 28.1 3 30.8 8 61.7 5 62.8 6 61.8 6 7.64 100.1 3 0.062 625.000 26.9 6 42.6 4 30.5 1 48.6 2 44.2 1 36.3 7 2.67 100.1 1 0.021 312.500 21.5 9 17.0 3 7.81 26.2 1 19.7 3 22.6 0 3.15 100.1 8 0.007 156.250 10.4 8 11.2 7 2.85 14.1 3 12.1 3 11.6 9 -7.18 100.0 9 0.002 78.125 -4.7 7 2.82 -2.9 8 -1.68 -8.9 2 -18.02 -8.22 99.74 [Table 18] Number of cells AZT (g M) Sodium D-Xylo se-2-pho sphate (p M) Empty Sodium D-Xylose-2-phosphate (pM) AZT (pM) Infected untreated Non-infected untreated Tri ton Empty 5.000 10000.0 00 1466 0 14506 1534 4 2536 7 2129 1 2302 6 9902 2735 7 1.667 5000.000 1503 0 16471 1594 6 3010 7 2826 2 2673 9 1037 7 2646 0 0.556 2500.000 1586 5 15599 1424 9 2988 3 2710 3 2459 8 1087 2 2532 8 0.185 1250.000 1462 2 15158 1397 8 2297 2 2146 2 2253 6 1166 8 2514 3 0.062 625.000 1541 8 15033 1462 5 1757 7 1692 6 1794 9 1102 5 2450 6 0.021 312.500 1302 1 13503 1368 8 1396 3 1350 2 1386 9 1151 4 2575 8 0.007 156.250 1296 0 13291 1268 5 1355 7 1257 8 1252 8 1223 9 3249 8 0.002 78.125 1142 9 11973 1267 3 1222 3 9928 1054 1 1063 4 3047 0

[0301] A photograph of the plate described in Table 18 is shown in [Fig.2].

[0302] Results for RSV-A2

[0303] Raw data: [Tables 19] Remdesi vir (pM) Sodium D-Xylo se-2-pho sphate (p M) Empty Sodium D-Xylo se-2-phosphate (pM) Remdesivir (p M) Infected untreated Uninfected untreated Triton Empty 5.000 10000.0 00 47.8 2 51.0 4 55.0 9 1.07 1.32 1.38 44.3 0 0.04 1.667 5000,000 44.8 3 45.9 8 49.7 4 4.37 3.63 3.42 50.0 7 0.03 0.556 2500,000 30.2 9 32.1 0 36.6 0 6.45 6.44 3.67 51.2 8 0.00 0.185 1250.000 33.0 5 43.6 3 42.5 7 15.9 7 13.6 8 14.0 2 46.7 5 0.00 0.062 625.000 43.9 4 46.1 9 46.1 0 32.5 5 29.6 9 25.5 5 56.2 9 0.04 0.021 312.500 55.9 7 60.1 4 57.7 9 52.8 5 50.3 3 44.5 1 60.6 7 0.00 0.007 156.250 51.6 6 57.3 9 58.4 9 51.1 5 47.3 9 49.0 8 54.0 3 0.01 0.002 78.125 51.6 2 57.9 0 59.5 2 50.8 8 48.2 8 46.7 8 49.0 0 0.03

[0304] Analyses (performed by VRS)

[0305] Absorbance - RSV-A2

[0306] Average for the untreated infected column: 51.55

[0307] Standard deviation for untreated infected column: 5.29

[0308] Average for the uninfected, untreated column: 0.02

[0309] Standard deviation for the uninfected, untreated column: 0.02

[0310] Percentages of inhibition [Tables 20] Remdesivir (pM) Sodium D-Xylose-2-phosphate (pM) Empty Sodium D-Xylose-2-phosphate (pM) Remdesivir (pM) Infected untreated Non-infected untreated Triton Empty 5.000 10000.0 00 7.24 1.00 -6.8 7 97.9 7 97.4 7 97.3 7 14.07 99.96 1.667 5000.000 13.0 4 10.8 2 3.51 91.5 5 93.0 0 93.4 0 2.86 99.98 0.556 2500.000 41.2 6 37.7 4 29.0 1 87.5 3 87.5 3 92.9 2 0.52 100.0 4 0.185 1250.000 35.9 0 15.3 7 17.4 2 69.0 4 73.4 8 72.8 2 9.31 100.0 4 0.062 625.000 14.7 7 10.4 1 10.5 8 36.8 7 42.4 2 50.4 5 -9.19 99.96 0.021 312.500 -8.5 7 -16. 66 -12. 12 -2.53 2.36 13.6 6 -17.70 100.0 4 0.007 156.250 -0.2 2 -11.34 -13.48 0.77 8.07 4.79 -4.81 100.0 2 0.002 78.125 -0.1 4 -12.32 -15.46 1.30 6.34 9.25 4.95 99.98 [Table 21] Number of cells Remdesi Sodium Vid Sodium D-Xylose- Remdesivir (pM) Infec Non- Vid vir (pM) D-Xylo e 2-phosphate(pM) te no infect e se-2-pho n tra é non sphate(p M) ity -trait é Tri tone 5.000 10000.0 00 1314 5 13269 1290 6 1359 8 1348 1 1338 1 1278 3 1061 0 1.667 5000.000 1499 3 14338 1542 8 1373 9 1378 6 1319 0 1295 9 1036 9 0.556 2500,000 1496 0 13813 1459 0 1368 3 1408 9 4691 1386 4 1057 3 0.185 1250,000 1363 1 14463 1419 2 1481 9 1414 1 1394 8 1380 0 1077 2 0.062 625.000 1387 0 13842 1431 8 1445 1 1387 0 1432 9 1325 0 1009 4 0.021 312.500 1425 5 14301 1366 4 1490 9 1466 6 1413 4 1311 0 1043 6 0.007 156.250 1280 2 12841 1249 2 1311 7 1221 9 1311 5 1291 4 1146 4 0.002 78.125 1020 9 10106 1158 5 1187 1 1058 4 1155 5 1159 8 9839

[0311] A photograph of the plate described in Table 21 is shown in [Fig.3].

[0312] Interpretation of results

[0313] SARS-CoV-2

[0314] Previous tests of the antiviral activities of D-xylose (unmodified) against SARS-CoV-2 carried out by the same laboratory had revealed an EC50 = 26.22 mM

[0315] Such a concentration is very high (if converted into a dose).

[0316] The results obtained with Sodium D-xylose-2-Phosphate give an EC50 concentration of the unpurified product of 4.411 mM. ([Fig.4])

[0317] The purity of the product obtained from APEX molecular is 46%, i.e. EC50 = 2.03 mM (For Sodium D-xylose-2-Phosphate)

[0318] The antiviral properties of Sodium D-xylose-2-Phosphate against SARS-CoV-2 are therefore: EC50(D-xylose) / EC50(D-xylose-2-Phosphate) = 12.9 times more effective than those of D-xylose.

[0319] HIV-1NL4-3

[0320] Previous tests of the antiviral activities of D-xylose (unmodified) against HIV-1 NL4-3 carried out by the same laboratory had revealed an EC50 = 124.4 Mm.

[0321] The maximum concentration of D-xylose-2-phosphate sodium tested in this example is 10 mM, and at this concentration, the concentration that inhibits 30% of the virus is EC30, which is between 0.625 mM and 1.25 mM.

[0322] The results obtained with D-xylose (unmodified): EC30 around 104 Mm (inhibition of 28.85%, mean of 3 wells) ([Fig.5]).

[0323] The purity of the product obtained from APEX molecular is 46%, i.e. EC30 around = 0.43 mM (For Sodium D-xylose-2-Phosphate).

[0324] The antiviral properties of Sodium D-xylose-2-Phosphate against HIV-1 are therefore: EC30(D-xylose) / EC30(D-xylose-2-Phosphate) = 241.9 times more effective than those of D-xylose.

[0325] Example 2: In vitro test of the antiviral and cytotoxic activity of a compound alone or in combination with a second compound against HCMV.

[0326] This test was carried out to study the cytotoxicity of D-xylose-2-phosphate (with a purity per mol of 46%).

[0327] The cytotoxicity of Sodium-D-xylose-2-Phosphate concentrations was determined under the same test conditions, but in the absence of viral infection.

[0328] The simultaneous administration of Sodium-D-xylose-2-phosphate (unpurified) and the virus allows the competitive inhibitory properties of D-xylose to be studied against HCMV.

[0329] The maximum concentration tested was ImM.

[0330] Introduction

[0331] A serial dilution of 8 points, with a dilution factor of 2 times one small molecule compound (Sodium-D-Xylose-2-phosphate with a purity of 46%; (highest test concentration: 10 mM), added to test cells (Human foreskin fibroblasts (HFFs)) concurrently with HCMV infection, following the dilution scheme below: [Tables22] Sodium-D-Xylose-2-Phosphate (mM) 10.000000 10.000000 10.000000 1.000000 1.000000 1.000000 0.100000 0.100000 0.100000 0.010000 0.010000 0.010000 0.001000 0.001000 0.001000 0.000100 0.000100 0.000100 0.000010 0.000010 0.000010 0.000001 0.000001 0.000001

[0332] The compound (Sodium-D-Xylose-2-Phosphate) was left on the cells for the entire duration of the experiment (48h), after which the inhibition of infection was measured by quantifying the percentage of infected cells using a test based on immunofluorescence.

[0333] In parallel, the cytotoxicity of the same concentrations of compounds was determined under the same test conditions but in the absence of viral infection using the MTT test.

[0334] Objective

[0335] The aim of this study is to test the antiviral and cytotoxic properties of 8 concentrations of Sodium-D-Xylose-2-Phosphate alone against HCMV.

[0336] Test samples

[0337] - Identity: D Sodium D-Xylose-2-phosphate (Molar mass 274.07 g / mol). Batch Used: Batch 2 (APEX-000122-5-1, 947mg) received from APEX Molecular

[0338] - Received: March 28, 2023

[0339] - Stored at: Room temperature

[0340] Controls

[0341] - Ganciclovir (HCMV).

[0342] Test system

[0343] Human foreskin fibroblasts (HFFs)

[0344] - HCMC, Merlin, VRS stock P2 June 2022 (IxlO6 TCID50 / ml).

[0345] - Reading: IF (Immunofluorescence) for the antiviral test & MTT assay for the test cytotoxicity

[0346] Reagents

[0347] - full media: HFF - DMEM (Gibco 10566016) + 10% FBS (Gibco 10500064) + Ix p / s (Gibco 15070063)

[0348] - infection media: HFF - DMEM low glucose pyruvate (Gibco 11885084) + 5% FBS + Ix p / s.

[0349] - Control Drug stock:

[0350] Ganciclovir 50mM in DMSO (G2536-100MG Lot 0000132914 Source 000091795).

[0351] Experimental procedure

[0352] Cell plating

[0353] The day before the experiment, plate 5,000 HFF cells / well into 2 plates of 96 wells, one black Perkin Elmer plate for the antiviral test and one clear Sarstedt plate for the cytotoxicity study.

[0354] Preparation of the compound

[0355] Alternatively, prepare 400 mM sodium D-Xylose-2-phosphate (molar mass = 274.07 g / mol). Dissolve 947 mg of D-Xylose-2-phosphate in infection medium to a final volume of 8.64 mL. Warm to 37°C and vortex.

[0356] Filter and sterilize through a 0.22 pM filter. After use, store the remainder at -20°C.

[0357] Prepare 20 mM of sodium D-Xylose-2-phosphate (=2x final maximum concentration of 10 mM) in 1000 µL:

[0358] • 50 µl of 400 mM Sodium D-Xylose-2-phosphate + 950 µl of infection medium (vol = 1000 pl).

[0359] The ganciclovir stock is 50 mM in DMSO.

[0360] Prepare 200 pM of Ganciclovir (= 2x final maximum concentration of 100 pM):

[0361] • 4pl of Ganciclovir 50mM + 996pl of infection medium.

[0362] As this is the control and it contains a diluent different from that of the compounds tested, and the final concentration of the diluent is 0.2% at the higher concentration of ganciclovir, the diluent is not taken into account.

[0363] To wells 4 to 6 of row A, add 170 µl of 20 mM sodium D-Xylose-2-phosphate.

[0364] To wells 4 to 6 of rows B to H, add 153 µl of infection medium.

[0365] Serially dilute the test samples 10 times, going down 17 µl from row A (wells 4 to 6) up to H, mixing 10 times.

[0366] To wells 7 to 9 of row A, add 240 pl of control compound.

[0367] To wells 7 to 9 of rows B to H, add 160 µl of infection medium.

[0368] Serially dilute the test samples 3 times by moving down 80 pl from row A (wells 7 to 9) to H, mixing 10 times.

[0369] To columns 1 to 3 and 10 to 12, add 150 µl of infection medium

[0370] Cytotoxicity

[0371] Remove the media from the cells in the cytotoxicity plate.

[0372] Replace with 50 µl of compound dilutions from the round-bottom plate immediately followed by 50 µl of infection medium.

[0373] Incubate HFF for 5 days at 37°C and 5% CO2.

[0374] Infection

[0375] Calculate the required virus stock volume using the formula below:

[0376] [(Number of cells / wells*) x (number of wells + >10% excess number of wells) x MOI] / virus Ul / ml

[0377] * Double the number of cells spread out the day before

[0378] HCMV = (10,000 x 110 x 2) / lx 106 x 1,000 = 2,200 pl

[0379] Thaw an aliquot of virus and add 2200 µl of virus + 3.3 ml of medium of infection (total volume 110*50 μl = 5,500 μl).

[0380] Remove the media from the cells in the antiviral plate.

[0381] Replace with 50 µl of compound dilutions from the round-bottom plate, immediately followed by 50 µl of diluted virus or

[0382] infection media according to the arrangement of the plates above.

[0383] Incubate HCMV for 5 days at 37°C and 5% CO2.

[0384] Fixation and development

[0385] After 48 hours or 5 days of incubation, proceed with fixation (antiviral assay) or the MTT test (cytotoxicity assay). For the

[0386] MTT test, add Triton in column 11 (untreated cells + / - diluent) as a control.

[0387] Immunostaining

[0388] Stain the antiviral plaque using:

[0389] HCMV (mouse): Anti-gB, (The Native Antigen Company, catalog no. MAB12192); 1 mg / ml. Use at 2 pg / ml (1:500). Followed by Goat anti-mouse 488, (Invitrogen, catalog no. Al 1001); 2 mg / ml use at 2.5 pg / ml (1:800).

[0390] Test results.

[0391] Results for antiviral tests and analyses (performed by VRS)

[0392] % Infection [Tables 23] Sodiu mDX ylose-2-Phos phate (mM) Gancic lovir (p M). Empty Sodium-D-Xylo se-2-Phosphate (mM) Ganciclovir (p M). Infected + Diluent Non-infected + Diluent Empty 10,000,000 100,000 4.41 33.6 4 7.04 9.70 6.46 7.24 37.1 6 0.14 1.0000 00 33.333 5.95 5.76 8.13 11.2 0 11.1 5 8.74 40.3 5 0.42 0.1000 00 11.111 43.4 3 43.6 4 41.9 0 22.9 4 21.0 1 24.5 2 50.8 8 0.48 0.0100 00 3.704 41.4 9 49.9 3 47.6 0 37.6 7 26.9 3 32.4 6 36.4 9 0.15 0.0010 00 1.235 47.0 7 49.2 3 47.3 6 38.4 5 41.4 8 38.6 4 40.9 2 0.44 0.0001 00 0.412 44.9 9 38.0 7 41.4 8 48.8 2 44.5 1 48.5 4 39.6 1 0.08 0.0000 10 0.137 41.4 9 45.9 9 38.8 0 53.7 2 48.4 5 52.4 2 45.1 9 0.08 0.0000 01 0.046 39.9 0 45.3 1 42.3 7 45.4 9 47.1 2 39.3 1 42.4 9 0.15

[0393] Average for infected column + diluent: 41.64

[0394] Standard deviation for infected column + diluent: 4.65

[0395] Average for the uninfected column + diluent: 0.24

[0396] Standard deviation for uninfected column +diluent: 0.17

[0397] Viability Percentages [Tables24] Sodium mD-Xylos e-2-P hosph ate (m M) Ganci clovir (pM). Vide Sodium-D-Xy lose-2-Phosph ate (mM) Ganciclovir ( pM). Infected + Non-infected Diluent + Empty Diluent Number of lines 10.00 0000 100.000 0 89. 93 19. 31 83. 57 77. 15 84. 97 83. 10 18 10 15 A. A. 1,000,000 33,333 86. 21 86. 68 80. 95 73. 52 73. 65 79. 48 3.11 99.5 8 B 0.100 000 11.111 -4.3 3 -4.8 4.4.494. 84 41. 35 -22. 33 99.4 2 C 0.010 000 3.704 0.35 -20. 04 -14. 40 9.58 35. 52 22. 17 12. 43 100. 23 D 0.001 000 1.235 -13. 13 -18. 35 -13. 82 7.69 0.38 7.24 1.74 99.5 3 E 0.000 100 0.412 -8.1 0 8.61 0.38 -17. 35 -6.9 5 -16. 67 4.89 100. 39 F 0.000 010 0.137 0.35 -10. 51 6.86 -29. 19 -16. 47 -26. 06 -8.5 9 100. 39 G 0.000 001 0.046 4.19 -8.8 8 -1.7 8 -9.3 2 -13. 25 5.61 -2.0 6 100. 22 H No. 1 2 3 4 5 6 7 8 9 10 11 12 col wave euro

[0398] Interpretation of results

[0399] Previous tests of the antiviral activities of D-xylose (unmodified) against HCMV carried out by the same laboratory had revealed an IC50 = 86.4 mM

[0400] Such a concentration is very high (if converted into a dose)

[0401] The results obtained with Sodium D-xylose-2-Phosphate give an IC50 concentration of the unpurified product of 0.7722 mM.

[0402] The purity of the product obtained from APEX molecular is 48%, i.e. IC50 = 0.371 mM (For Sodium D-xylose-2-Phosphate)

[0403] The antiviral properties of Sodium D-xylose-2-Phosphate against HCMV are therefore: IC50(D-xylose) / IC50(D-xylose-2-Phosphate) = 232.9 times more effective than those of D-xylose.

[0404] Example 3: Method for the synthesis and purification of Sodium D-Xylose-2-phosphate.

[0405] A schematic representation of this synthesis method is presented in [Fig.6].

[0406] Experimental procedure

[0407] [Chem.l] O H2N^''NH2 U. Na .5 H2O

[0408] Formula of sodium diamidophosphate pentahydrate (DAP pentahydrate)

[0409] Phenyl phosphorodiamidate (33.7 g, 196 mmol) was dissolved in hot 4 M aqueous sodium hydroxide (98 mL) and the mixture was heated to 110 °C and stirred at this temperature for 10 minutes. The mixture was allowed to cool to approximately 40 °C before adding IMS (490 mL) dropwise over a period of 20 minutes. The resulting mixture at this stage contained a dark gray oil and was cooled to -30 °C under stirring. The mixture was then seeded with some of the crystals from a previous batch, after which a large mass of solid formed in the mixture. The mass was mechanically broken up with a spatula, briefly sonicated, and stirred for 10 minutes at -5 °C. The resulting suspension was filtered and the collected solids were washed with ice-cold IMS (2 x 150 ml) and vacuum-dried on a sintered plate.

[0410]

[0411] for 4 h to give DAP pentahydrate (32.22 g, 155 mmol, yield of 79%) in the form of a pale grey, solid product. 31P NMR (202 MHz, D2O) δ 13.86. [Chem. 2]

[0412]

[0413]

[0414]

[0415] Formula of Sodium D-xylose-2-phosphate Prior to use, all commercial resins used in this synthesis were first washed sequentially with water / MeOH / water (2 CV each) to remove any residual color and impurities from the manufacturing process. A calibrated pH meter was used throughout this experiment to ensure accurate measurements. D-Xylose (1 g, 6.66 mmol) and DAP pentahydrate (832 mg, 4.00 mmol) were dissolved in water (8 mL) [initial pH ~9.4], then adjusted and maintained at a pH of ~7 throughout the reaction by the partial addition of Amberlite IR 120(H+) every few hours, with stirring at room temperature. The reaction was monitored by TLC [5:3:2 n-butanol / AcOH / water. Plates visualized in 5 w / v % ammonium molybdate tetrahydrate in IM H2SO4]. After 24 hours, a second portion of DAP pentahydrate (832 mg, 4.00 mmol) was added, and the mixture was stirred at room temperature for an additional 28 hours, after which TLC analysis showed that a minor amount of the starting material was still present. The mixture was acidified to a pH of 2.1 by the addition of concentrated HCl and stirred at room temperature for a further 17 hours, after which the pH increased to 4.5 and the mixture became cloudy.The pH was adjusted to 1.3 by the dropwise addition of concentrated HCl, which cleared the turbidity. The mixture was stirred at room temperature for a further 27 hours and neutralized by the dropwise addition of 2M aqueous NaOH. The resulting mixture was filtered to remove the resin, and the flask and stopper were washed with a 0.05M triethylammonium bicarbonate solution (TEAB, 20 mL). A 4 cm diameter glass column was packed with Dowex 1X8 200-400 mesh resin (Cl- form) to a depth of 9 cm, and the resin was pre-washed as described above. The column was eluted with a saturated aqueous solution of sodium bicarbonate (3 CV) to completely convert the resin to the bicarbonate form. The column was then washed with deionized water (3 CV) and finally The column was equilibrated by elution with a 0.05 M TEAB solution (100 mL; ~1 CV). The combined filtrates described above, containing the crude reaction mixture, were added to the prepared column, and the column was sequentially eluted with a 0.06 M to 0.4 M TEAB solution (in increasing 0.02 M increments of 50 mL [~0.5 CV] each) using very slight positive pressure to ensure an elution rate of 1–3 drops per second. Forty-seven 20 mL fractions were collected. The unreacted starting material was eluted in fractions 5–9. Fractions 24–41 containing the product were combined and then treated with 51 g of freshly washed Dowex 50WX8 resin (H+ form) (as previously described) until all effervescence had ceased and the pH was 2.5.

[0416] The mixture was stirred for an additional 10 minutes, filtered to remove the resin, and the pH of the filtrates was adjusted to 7.0 by the dropwise addition of aqueous NaOH IM. The resulting mixture was lyophilized overnight to obtain a white solid (1.7 g) containing 4 equivalents of triethylamine. The material was redissolved in water (50 mL) and treated with more Dowex 50WX8 (H+) resin (25 g), resulting in a pH of 1.1. The mixture was stirred for 30 minutes, then filtered, and the flask and resin bed were washed with water. The combined filtrates were neutralized to a pH of 7.0 by the careful addition of IM aqueous NaOH, then lyophilized overnight to obtain the compound of titer (1.20 g, 3.20 mmol, 48% yield, 73% purity), a white solid, in the form of a 1:1 mixture of alpha and beta anomers.

[0417] LC-MS-3 (method 2A): Rt 0.18 min; MS m / z 228.9 = [MH]- of the parent free acid [no UV chromophore]

[0418] 1H NMR (500 MHz, D2O) ô 5.28 (d, J = 3.5 Hz, 1H), 4.62 (d, J = 7.6 Hz, 1H), 3.96 - 3.91 (m, 2H), 3.81 (t, J = 8.6 Hz, 1H), 3.73 - 3.64 (m, 5H), 3.57 (t, J = 9.0 Hz, 1H), 3.37 - 3.32 (m, 1H).

[0419] 31P NMR (202 MHz, D2O) ô 4.18 (d, J = 7.5 Hz), 3.68 (d, J = 8.7 Hz).

[0420] Results

[0421] Sodium D-Xylose-2-phosphate containing some impurities was obtained with this method after ion-exchange chromatography and lyophilization.

[0422] The major impurity is excess DAP reagent (or a related hydrolysis derivative), which cannot be completely separated by ion-exchange chromatography.

[0423] Compounds obtained j. a. 1:1 mixture of alpha / beta anomers. Contains 0.12 equiv. triethylamine, 0.75 equiv. DAP, 0.05 equiv. presumed 3-phosphate isomer. Product purity by mole is 48.58%; Triethylamine HCl (18.14%); DAP by product (33.28%). b. 1:1 mixture of alpha / beta anomers. Contains 0.11 equiv. triethylamine, 0.75 equiv. DAP, 0.06 equiv. presumed 3-phosphate isomer. Product purity by mole is 46.33%; Triethylamine HCl (21.24%); DAP by product (32.43%). References

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Claims

Demands

1. Composition comprising at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate for use as a drug.

2. Composition for use according to the preceding claim, in the prevention or treatment of viral infection using syndecanes and / or glypicans as cell receptors, preferably said viral infection being selected from HSV-1, HSV-2, HPV-16, HPV-31, HVB, HCV, HIV-1, HTLV-1, SARS-CoV-2, HCMV, EBOLA, RSV, DENV-1, and DENV-2 infections.

3. Composition for use according to claim 1, in the treatment of type 2 diabetes.

4. Composition for use according to claim 1, in the treatment of cancer, preferably colon cancer, lung cancer, breast cancer, liver cancer, adult T-cell leukemia-lymphoma (ATLL), Burkett lymphoma in humans, nasopharyngeal cancer in humans, cervical cancer, oral cancer, hepatocellular carcinoma (HCC), Kaposi's sarcoma, breast cancer carcinogenesis, colorectal cancer, glioblastoma multiforme (GBM), lung carcinoma or nasopharyngeal carcinoma.

5. Composition for use according to claim 1, in the treatment of joint diseases, preferably osteoarthritis, arthritis, rheumatoid arthritis or gout.

6. Composition for use according to claim 1, as an anticoagulant.

7. Composition for use according to claim 1, in the treatment of dermatological diseases.

8. Composition for use according to any one of the preceding claims, in a form suitable for administration by oral, subcutaneous, intradermal, intravenous or intramuscular route.

9. Non-therapeutic topical cosmetic composition for the care of an area of ​​skin of a healthy subject comprising at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate.

10. Composition of a food supplement for oral or nasal administration for the healthy subject, comprising at least one compound selected from D-xylose-2-Phosphate, its esters, and / or oligosaccharides comprising D-xylose-2-Phosphate in a physiologically acceptable medium to stimulate the biosynthesis of glycosaminoglycans, preferably at least one selected from heparan sulfate, dermatan sulfate and chondroitin sulfate.