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View U.S. Patent Application Publication No. US-2020-0199185 in PDF Format 1111111111111111 IIIIII IIIII 1111111111 11111 111111111111111 1111111111 11111 1111111111 11111111 US 20200199185Al c19) United States c12) Patent Application Publication c10) Pub. No.: US 2020/0199185 Al Reed et al. (43) Pub. Date: Jun. 25, 2020 (54) METHODS OF PURIFYING MUCIN Publication Classification (51) Int. Cl. (71) Applicant: Wisconsin Alumni Research C07K 14147 (2006.01) Foundation, Madison, WI (US) C07K 1114 (2006.01) C07K 1130 (2006.01) (72) Inventors: Jess Dreher Reed, Verona, WI (US); C07K 1136 (2006.01) Sergio Madrigal-Carballo, Ontario, (52) U.S. Cl. CA (US); Michael Allen Polewski, CPC ............ C07K 1414727 (2013.01); C07K 1136 Madison, WI (US); Christian Gerald (2013.01); C07K 1130 (2013.01); C07K 11145 Krueger, Cambridge, WI (US); Emilia (2013.01) Alfaro-Viquez, Madison, WI (US) (57) ABSTRACT (73) Assignee: Wisconsin Alumni Research Methods of purifying mucin, purified mucin, and products Foundation, Madison, WI (US) comprising the purified mucin. The methods include com­ bining a mucin-containing substance with water and one or more purification agents to form a purification mixture, (21) Appl. No.: 16/723,551 incubating the purification mixture for a time sufficient to form a mucin precipitate in a liquid phase, and separating the (22) Filed: Dec. 20, 2019 mucin precipitate from the liquid phase. The purification agents include one or more of a surfactant, a chelating agent, and a protic solvent. The mucin purified from the methods Related U.S. Application Data can be used alone or in combination with a biopolymer such (60) Provisional application No. 62/783,894, filed on Dec. as a tannin and chitosan and can be used to generate 21, 2018. materials in the form of a gel, a foam, a film, or a powder. small Intestine- Sections ~sso mg sm:aU Intestine Mucus (s.lM) Ory MUC-2 Patent Application Publication Jun. 25, 2020 Sheet 1 of 9 US 2020/0199185 Al ~·X :+ ·~ .;: .❖ * Filtration ·X ·❖ ·X C❖ * * *~ •* • * * ~ : ...............................................................................................• ~ ·······························································································································································································~ ~ :."••xun«H Collection of muCin pellet and washing : ................................................................................................................................................................................................• ~-~; •·~- 5:. FIG. 1 Patent Application Publication Jun. 25, 2020 Sheet 2 of 9 US 2020/0199185 Al ·~ 00 ·W"1 ·'4 & N ■ (!) u. bD M ·C'l· ·~ ({ Patent Application Publication Jun. 25, 2020 Sheet 3 of 9 US 2020/0199185 Al FIG. 3 FIG. 4 Patent Application Publication Jun. 25, 2020 Sheet 4 of 9 US 2020/0199185 Al LO. (!) -LL Patent Application Publication Jun. 25, 2020 Sheet 5 of 9 US 2020/0199185 Al 100 so 60 40 20 --Mudn isolate 0 -+----....---.............................................,. ........ .___....,...... ........ -,- .................., ................... ..,....... ........ ......,... ................... 0 100 200 300 400 500 Temperature (°C) FIG. 6 Patent Application Publication Jun. 25, 2020 Sheet 6 of 9 US 2020/0199185 Al f ◄--···· .. ., .,E! (./) 0 c) 2 ---·0ff ±. :i;.: .s;; .., ______ ~ ¥ ~~ 0 0 ---,10 ....... (!) -LL. .~.,_, <:) r,~ -::::,:;:. (•:') ,~-.J Patent Application Publication Jun. 25, 2020 Sheet 7 of 9 US 2020/0199185 Al A ( 2: ~+ 2~ FIG. 8 Patent Application Publication Jun. 25, 2020 Sheet 8 of 9 US 2020/0199185 Al FIG. 9 C '<3 C C ::::J 'D 'D E ::, ::, .c. E E 0 ..c ..c m Q Q ,--.. ro ro ('S E <'"' 0 ro C E 0 0 .::,;; m 0 .._. -....,..· - ~ .e ¢ m m C ·n..., - 0 0. FIG. 10 Patent Application Publication Jun. 25, 2020 Sheet 9 of 9 US 2020/0199185 Al FIG. 11 FIG. 12 US 2020/0199185 Al Jun.25,2020 1 METHODS OF PURIFYING MUCIN the preferred embodiment of the invention made in conjunc­ tion with the accompanying drawings. BACKGROUND BRIEF DESCRIPTION OF THE DRAWINGS [0001] Mucins are a family of high molecular weight, heavily glycosylated proteins (glycoproteins) produced by [0009] FIG. 1. Schematic representation of an exemplary epithelial or other tissues in most animals. Mucins make up method of the invention for purifying mucin from small 80-90% of the mucus that coats the surfaces of cells lining intestine mucus. the respiratory, digestive, and urogenital tracts. Much of the [0010] FIG. 2. Schematic illustration of mucin extraction rest of mucus is water, although mucus also contains small yield per pig small intestine using an exemplary method of amounts of non-mucin protein (-1-2% w/w) and inorganic the invention. salts (-1 % w/w). Mucins protect epithelial cells from infec­ [0011] FIG. 3. Photographs depicting the extraction and tion, dehydration, and physical or chemical injury, as well as purification of MUC2 from pig small intestine at various aid the passage of materials through a tract. Mucin 2 stages in an exemplary method of the invention. (MUC2, encoded by the MUC2 gene) is the most abundant [0012] FIG. 4. Images depicting the normal physical mucin in the small intestine of mice, rats, swine, and appearance of mucin: (A) Reagent grade porcine stomach humans. mucin obtained from Sigma-Aldrich (St. Louis, Mo.; Cat. [0002] Commercially available mucins are generally No. M1778-10G, Batch No. 064K7005); (B) Porcine small highly processed, which compromises their structure and intestine mucin isolated from the small intestine. properties. Mucin purification methods that preserve the [0013] FIG. 5. Identification of mucin domains in com­ structure and properties of mucins is needed. mercial porcine stomach mucin (Ref-Mucin) and porcine small intestine mucin isolated from the duodenum (Duo­ FIELD OF THE INVENTION Mucin) and jejunum (Jej-Mucin) using an exemplary method of the invention. Coomassie Blue Assay stains [0003] The invention is directed to methods of purifying turquoise the protein domains in mucin. PAS/Schiff assay mucin, purified mucin, and products comprising purified stains purple the polysaccharide domains in mucin. The mucm. reactions with Coomassie blue and PAS demonstrate that mucins isolated from swine intestines using an exemplary SUMMARY OF THE INVENTION method of the invention is very similar to reagent grade porcine stomach mucin obtained from Sigma-Aldrich (St. [0004] The present invention relates to rapid and inexpen­ Louis, Mo.; Cat. No. M1778-10G, Batch No. 064K7005). sive methods for purifying mucin from mucus. In an exem­ [0014] FIG. 6. Thermal gravimetric analysis (TGA) ther­ plary method, mucus is treated with a purification solution mogram of commercial porcine stomach mucin (Ref-Mucin) to solubilize non-mucin components of mucus and precipi­ and porcine small intestine mucin isolated (Mucin Isolate) tate mucin. The mucin is then separated from the solubilized using an exemplary method of the invention. components by centrifugation or other methods. An exem­ [0015] FIG. 7. Fourier transform infrared (FT-IR) spec­ plary purification solution comprises water and one or more troscopy analysis showing the chemical characterization of purification agents selected from a surfactant, a chelating commercial porcine stomach mucin (Ref-Mucin) and por­ agent, and a protic solvent. In certain versions, the surfactant cine small intestine mucin isolated from the duodenum comprises sodium laurel sulfate, the chelating agent com­ (Mucin-Duo) and jejunum (Mucin-Jej) using an exemplary prises ethylenediaminetetraacetic acid (EDTA), and the pro­ method of the invention. Principal peaks associated with tic solvent comprises ethylene glycol monoethyl ether. mucin chemical bonds are marked with arrows. Spectro­ [0005] The methods of the invention are inexpensive and scopic data was adjusted on the Y-axis so the data does not rapid and are suitable for the largescale commercial produc­ overlap to facilitate comparative analysis. tion of purified mucin, such as MUC2. The present method [0016] FIG. 8 shows a PAS glycoprotein stain (panel A), preserves mucin structure, including the disulfide bonds and Simply Blue protein stain (panel B), and Western Blot analy­ oligosaccharides, which provide the high molecular weight sis (panel C) of MUC2 isolates run on gels. The numbers and useful physical properties of mucin such as lubricity, above each lane in panel A refer to the samples as identified gel-forming ability, and biological activity. This is in con­ in Table 6 and are the same for each of panels A, B, and C. trast to conventional mucin purification methods, which The numbers to the left of panels B and C refer to molecular reduce the disulfide bonds that crosslink mucin, hydrolyze weights in kDa. the mucin peptide bonds and oligosaccharides, and break [0017] FIG. 9 shows a Western Blot analysis of MUC2 down the mucin to peptides or small polysaccharide com­ isolates prepared with varying room temperature extraction ponents, thus affecting overall bioactivity of mucin. The times. The numbers above each lane refer to the samples as mucin purified with the methods of the invention maintain identified in Table 6. the ability to form hydrogels, which commercial mucin [0018] FIG. 10 shows a PAS glycoprotein stain (left), preparations cannot do. The mucin purified with the methods SimplyB!ue protein stain (middle), and Western Blot analy­ of the invention can be used in nutritional and biomedical sis (right) of raw mucus, MUC2 isolated from mucus, and applications. porcine stomach mucin. [0006] The invention also relates to purified
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