Use of low-molecular glycosidically bound terminal galactosides and fucosides for bonding to toxins that act as galectins in the treatment of intoxications, in particular ricin intoxications

Abstract

The invention relates to the use of low-molecular glycosidic compounds with terminal D-galactose and L-fucose in the treatment of intoxications with ricin. The identified compounds form a lectin bond with the B chain of the ricin and thereby prevent further endocytosis of the toxins. The compounds should be ingested as early as possible after incorporation of the toxin and can also be used preventively. The groups bonded to the D-galactose and L-fucose can be other saccharides (e.g. fructose), polyalcohols (e.g. sorbitol), diacyl-glycerides or flavonoids (e.g. quercetin).

Galactose-heteropolysaccharide hydrolysates such as guar gum flour can also be used. The identified compounds can be used for oral, pulmonary and systemic intoxications. They should be used in corresponding pharmaceutical forms of administration. The compounds are dosed in molar excess.

Claims

1. Use of chemical compounds with a. terminal pyranose-D-galactose (CAS No. 59-23-4) β-glycosidically bound at position 1 or b. terminal pyranose-L-fucose (CAS No. 2438-80-4) α-glycosidically bound at position 1 for bonding to galactoside detection regions of toxins that act as galectin in the treatment of intoxications.

2. Use according to claim 1, characterized in that the residues glycosidically bound to D-galactose or L-fucose in the manner described are selected from the group of saccharides, sugar alcohols and diacyl-glycerides that are formed from a. monosaccharides, in particular D-fructose and D-mannose bound to the respective carbon 4 b. disaccharides and oligosaccharides, especially lactose bound to carbon 2′ or 3 c. sugar alcohols, especially D(−)sorbitol d. diacylglycerides, in particular 1,2-diacyl-sn-glycerol bound to position 3.

3. Use according to claim 1, characterized in that the residues glycosidically bound to D-galactose or L-fucose in the manner described are selected from the group of flavonoids, which are formed from a. flavonols, especially quercetin, bound to carbon 3 b. anthocyanins, especially cyanidin, bound to carbon 3 c. flavanols, especially (−)epicatechin, bound to carbon 3.

4. Use according to claim 1, characterized in that hydrolysates of polysaccharides obtained by acid hydrolysis are selected from the group of galactose heteroglycans which is formed from arabinogalactans, guar, carubin and karaya.

5. Use according to claim 1 for inhibiting bonding to galactoside detection regions of a group of toxins which act as galectin and which, in particular, is formed from the toxins ricin (UniProt: P02879; CAS No. 9009-86-3), abrin (UniProtKB-P11140), modeccin (UniProtKB-Q6RUL6), the Shiga toxin subunit B (UniProtKB-Q7BQ98), the Shiga-like toxin 1 subunit B (UniProtKB-P69179) and diphtheria-toxin (UniProtKB-Q6KE85).

6. Use according to claim 1 to prevent the bonding of galactose-specific lectin of the toxins to terminal N-acetyl galactosamine residues or 1,4-bound galactose units of glycoproteins and glycolipids of the cell surface and the endocytosis triggered thereby in the cell. This endocytosis is a prerequisite for the further toxic effect of the toxins as inhibitors of the ribosomal peptide biosynthesis.

7. Use according to claim 1 for the inhibition of the specific detection regions of the toxins up to 12 hours, preferably up to 30 minutes after an ingestion of the toxins to prevent endocytosis and prophylactic use by people at risk.

8. Use of compounds according to claim 1 in orally administrable pharmaceutical preparations for bonding the toxins in the gastrointestinal tract after an oral ingestion of the toxins.

9. Use of compounds according to claim 1 in pharmaceutical preparations for pulmonary administration for bonding the toxins after a pulmonary ingestion of the toxins.

10. Use of compounds according to claim 1 which are absorbed enterally after oral administration but not or only partially metabolized in orally administrable pharmaceutical preparations and of compounds according to claim 1 in parenterally administrable pharmaceutical preparations for bonding the toxins in the vascular system.

Description

[0026] Embodiment of an oral pharmaceutical preparation according to para. [0015]:

[0027] 100 g guar gum flour is heated with 900 ml of 5% phosphoric acid for 30 minutes at 80° C. and then neutralized with a sodium hydroxide solution (pH 7.2).

[0028] Dosage: Take 200 ml after ingestion of the toxin. Take 50 ml 3 times a day for oral intoxication prophylaxis.

[0029] Embodiment of a pharmaceutical preparation to be inhaled according to para. [0016]:

[0030] 5% solution of lactulose in purified water, sterile filtered, filled into a pulmonary application form (pressure spray container).

[0031] Dosage: Apply 10 to 20 sprays after a pulmonary ingestion of the toxin. Apply 2 sprays every hour for prophylaxis.

[0032] Embodiment of an oral pharmaceutical preparation according to para. [0017]:

[0033] Tablets with 500 mg quercetin galactoside/tablet

[0034] Dosage: Take up to 10 tablets. Take 2 tablets 3 times a day for prophylaxis.

[0035] Embodiment of a parenteral pharmaceutical preparation according to para. [0017]:

[0036] A 5% lactulose solution in purified water is sterilized and filled as an infusion.

[0037] Dosage: Infuse 500 ml of the infusion solution within 30 minutes. Infuse 100 ml several times a day for prophylaxis.

Patent Citations

[0038]

TABLE-US-00001 Publication Priority Publication number date date Assignee Title U.S. Pat. No. 9,133,253B2 2010 Apr. 22 2013 Nov. 7 US Secretary Ricin vaccine of Army and methods of making thereof U.S. Pat. No. 5,626,844A 1991 Nov. 4 1997 May 6 US Secretary Monoclonal of Army antibody against ric A chain US20080089959A1 2003 Apr. 7 2008 Apr. 17 La Jolla Composition and Pharmaceutical uses of galecti Co antagonists GlycoGenesys Inc SE0100172D0 2001 Jan. 22 2001 Jan. 22 Worldwide New inhibitors applications against galectins CA2520647A1 2003 Mar. 28 2004 Nov. 4 Bristol Myers Compositions Squibb Co containing lactulose for treating rotavirus infections U.S. Pat. No. 9,974,802B2 2011 Dec. 28 2017 Jul. 20 Galectin Composition of Therapeutics Inc novel carbohydrate drug for treatment of human diseases

Non-Patent Literature Cited

[0039] (1) R. Rasooly, X. He, M. Friedman, Milk inhibits the biological activity of ricin, J. Biol. Chem. 287 (33) (2011) 27924-27929, http://dx.doi.org/10.1074/jbc.M112.362988 (http://www.ncbi.nlm.nih.gov/pubmed/22733821). [0040] (2) P. D. R. Dyer, et al., An in vitro evaluation of epigallocatechin gallate (eGCG) as a biocompatible inhibitor of ricin toxin, [0041] (3) Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbagen.2016.03.024 [0042] (4) Lambert J M, McIntyre G, Gauthier M N, Zullo D, Rao V, Steeves R M, Goldmacher V S, Blattler W A., The galactose-bonding sites of the cytotoxic lectin ricin can be chemically blocked in high yield with reactive ligands prepared by chemical modification of glycopeptides containing triantennary N-linked oligosaccharides. Biochemistry.

[0043] 1991 Apr. 2; 30 (13): 3234-47. [0044] (5) GL Nicolson, J. Blaustein, The interaction of Ricinus communis agglutinin with normal and tumor cell surfaces, Biochim. Biophys. Acta 226 (1972) 543-547 (http://www.ncbi.nlm.nih.gov/pubmed/4338881). [0045] (6) Klyosov A A, Platt D, Zomer E. (2003) Preclinical Studies of

[0046] Anticancer Efficacy of 5-Fluorouracil when Co-Administered with the 1,4-β-D-Galactomannan. PRECLINICA, 1,175-186 [0047] (7) Glinsky G V, Price J E, Glinsky V V, Mossine V V, Kiriakova G, Metcalf J B (1996), Inhibition of human breast cancer metastasis in nude mice by synthetic glycoamines. Cancer Res. 1; 56 (23): 5319-24 [0048] (8) Streetly M J, Maharaj L, Joel S, Schey S A, Gribben J G, Cotter F E (2010) GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death, Blood vol. 115 no. 19 3939-3948 [0049] (9) Téllez-Sanz R, Garcia-Fuentes L, Vargas-Berenguel A, (2013) Human Galectin-3 Selective and High Affinity Inhibitors. Present State and Future Perspectives. Current Medicinal Chemistry 20: 2979-2990 [0050] (10) Dawson, R M, Alderton M R, Wells D, Hartley P G, (2006) Monovalent and polyvalent carbohydrate inhibitors of ricin bonding to a model of the cell-surface receptor. J. Appl. Toxicol. 26: 247-252 [0051] (11) Pauly D, Worbs S, Kirchner S, Shatohina O, Dorner M B, et al. (2012) Real-Time Cytotoxicity Assay for Rapid and Sensitive Detection of Ricin from Complex Matrices. PLoS ONE 7 (4): e35360