WO2006097120A1 - A process for the preparation of hypoallergenic alimentary proteins - Google Patents

A process for the preparation of hypoallergenic alimentary proteins Download PDF

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WO2006097120A1
WO2006097120A1 PCT/EP2005/002744 EP2005002744W WO2006097120A1 WO 2006097120 A1 WO2006097120 A1 WO 2006097120A1 EP 2005002744 W EP2005002744 W EP 2005002744W WO 2006097120 A1 WO2006097120 A1 WO 2006097120A1
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proteins
process according
carbamylation
carried out
alimentary
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PCT/EP2005/002744
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French (fr)
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Luigi Di Berardino
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Tred Srl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76—Albumins
    • C07K14/77—Ovalbumin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
    • A23J3/00—Working-up of proteins for foodstuffs
    • A23J3/04—Animal proteins
    • A23J3/08—Dairy proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4732—Casein
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention concerns a process for the preparation of hypoallergenic alimentary proteins by subjecting said proteins to carbamylation reaction.
  • Hypoallergenic formula are used to prevent cow milk related hypersensitivity reaction in atopic babies and to avoid clinical manifestation in allergic patients. They are prepared by extensive hydrolysis of the native proteins with proteases. These formulas are usually effective, but contain residual peptides that preserve immunoreactive epitopes and clinical intolerance has been observed. The low allergenicity of the extensively hydrolyzed formula supports its use in allergy prophylaxis but these have lost the IgG response (antigenicity). ⁇ -amino groups of lysine are exposed to the solvent, so they are surely involved in protein-protein interactions and this may be decisive in Ab-Ag reactions (Novotny J. et al., Immunology Today 1987; 8: 26), as the binding. may be influenced by changing this residue. Many paper reports how the substitution of only one amino acid in a linear epitope is sufficient to prevent 1 uitigen by the related antibody.
  • this amino acid is Lysine, as this amino acid results exposed toward the solvent and therefore easily available to interact with other proteins in solution.
  • the amino acid residues critical for IgE binding determined in the allergen LoI p5 are the residues Lys 57 in the peptide 49-60 and LyS 275 in the peptide 265-276.
  • EP 0421949Bl, 1994 leads to a slight change in the protein structure of the allergen since the epsilon amino group of the amino acid is modified into an ureidic derivative (carbamylation). While both the molecular weight and the dimension of the modified protein remain practically unchanged, its electrical charge results modified: for every reacted lysine, a cationic charge is lost.
  • the present invention provides a solution to the above problem, since it allows to modify the amino acid sequence of the main epitopes, which are thereby rendered immunogically different from the native ones.
  • the object of the invention has been reached by chemical modification of the lysine of the allergenic polypeptides into homocitrulline, previously disclosed but only for the preparation of allergoids for the immunotherapy of allergic diseases. (Falagiani P., Brenna O. and Mistrello G., 1993: "Chemically modified allergens and process for the preparation thereof, IT 1237475.
  • the modified products obtainable by the process of the invention can therefore be consumed also by subjects allergic to milk proteins or other food proteins without manifesting severe intolerance symptoms.
  • the foods of the invention are particularly indicated for atopic patients, since the reduced exposition to allergens can avoid or reduce the risk of sensitisation.
  • food proteins are reacted with an alkali cyanate or other reagents useful as a cyanate source, suck as carbamyl phosphate and the like.
  • Cyanate does not react with arginine whereas at acidic pH, the formation of intra/ inter pseudo-peptide bonds occurs.
  • Carbamylation may be carried out in apH range from about 6.5 to alkaline pH.
  • a stable ureido group is obtained when cyanate is reacts with the ⁇ -NH 2 of lysine, according to the following scheme: P-(CH 2 ) 4 - NH 2 ( ⁇ ) ⁇ P-(CH 2 ) 4 - NH-CO-NH 2 STABLE
  • reaction conditions are preferred, when an alkaline cyanate is used: pH 9.1 ⁇ 0.1 ; 40°C-50°C; 16-20 h, giving 90% ⁇ -amino group modification.
  • reaction temperature and time may anyhow range within wide limits, for instance from 15 to 150 0 C and from 30 s to 24 h, depending on the considered protein and the desired carbam
  • the percent carbamylation of the ⁇ -amino groups of the protein obtainable according to the invention is higher than 5%, preferably higher than 50% and more preferably higher than 90%.
  • the protein Molecular weight (MW) and 3D-structure practically are unchanged whereas pi is acidified, sensitivity to trypsin attack decreases and sensitivity to chymotrypsin attack increases.
  • proteins of dietetic interest may be treated according to the invention, for instance proteins from milk, egg, soy, cereal etc..
  • EXAMPLE 1 (carbamylated milk proteins) A mixture of 4 g of sodium caseinate and 6 g of milk serum protein is suspended in 400 ml of 0.1 M sodium tetraborate buffer, adjusting the pH to 9.1 ⁇ 0.1 with 1 M NaOH. 20 of re-crysta ind allowed to react under mild stirring at 45 0 C for 18 hrs. At the same time 1/10 of a similar mixture, wherein KCNO is replaced by an equivalent amount of KCl, is treated under the same conditions (blank).
  • Table 2 reports the substitution degree values of the e-amino groups as 5 a function of the reaction time at 40 0 C.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Toxicology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Mycology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

A process for the preparation of hypoallergenic alimentary proteins by subjecting said proteins to carbamylation reaction.

Description

A PROCESS FOR THE PREPARATION OF HYPOALLERGENIC ALIMENTARY PROTEINS
The present invention concerns a process for the preparation of hypoallergenic alimentary proteins by subjecting said proteins to carbamylation reaction.
Background of the invention Allergic syndromes, in particular food intolerances, are continuously increasing. This is a remarkable problem, since food is nowadays the main cause of serious allergic reactions.
To date, the sole possibility for the sensitised patient to avoid such reactions is not to ingest the incriminated food, which is quite difficult to do with nutritionally important food, such as milk proteins. Moreover, the presence in these proteins of highly sensitising epitopes induces new sensitisation phenomena, with persistence or even worsening of the related clinical manifestations.
Hypoallergenic formula are used to prevent cow milk related hypersensitivity reaction in atopic babies and to avoid clinical manifestation in allergic patients. They are prepared by extensive hydrolysis of the native proteins with proteases. These formulas are usually effective, but contain residual peptides that preserve immunoreactive epitopes and clinical intolerance has been observed. The low allergenicity of the extensively hydrolyzed formula supports its use in allergy prophylaxis but these have lost the IgG response (antigenicity). ε-amino groups of lysine are exposed to the solvent, so they are surely involved in protein-protein interactions and this may be decisive in Ab-Ag reactions (Novotny J. et al., Immunology Today 1987; 8: 26), as the binding. may be influenced by changing this residue. Many paper reports how the substitution of only one amino acid in a linear epitope is sufficient to prevent 1 uitigen by the related antibody.
In many cases this amino acid is Lysine, as this amino acid results exposed toward the solvent and therefore easily available to interact with other proteins in solution. For example, the amino acid residues critical for IgE binding determined in the allergen LoI p5 are the residues Lys57 in the peptide 49-60 and LyS275 in the peptide 265-276. (Suphioglu C, et al.. MoI. Immunol. 1998 35:293; Swoboda I. et al.; Eur. J. Immunol. 2002;32:270. This chemical modification, already patented to prepare allergoids from aeroallergens (to be used in hyposensitizing therapies, Falagiani P. Brenna O. and Mistrello G. EP 0421949Bl, 1994) leads to a slight change in the protein structure of the allergen since the epsilon amino group of the amino acid is modified into an ureidic derivative (carbamylation). While both the molecular weight and the dimension of the modified protein remain practically unchanged, its electrical charge results modified: for every reacted lysine, a cationic charge is lost.
We can suppose therefore that, while the natural interaction is not prevented between the modified allergen and the specific antibody, the binding constant is surely modified.
Furthermore, since the digestion of a protein influences its absorption, the fact that the main point of attack for the trypsin (lysine) is modified, according to the patented process, surely different peptides are originated, with probable important differences in their absorption. The reactions between milk proteins and lactose, that lead to different derivatives in which lysine is involved (lactulosyl-lysine, advanced Maillard compounds, carboxymethyl lysine: Finot P. et al., Progress in Food and Nutrition Science, vol 5: Maillard reaction in foods. Ed. C Erikson Pergamon Press, Oxford: 1981 ; Evangelisti F. et al.; J. Dairy Res. 1999;66:237) are well known. Through a derived amino acid (f :id hydrolysis of the proteins of milk, the thermal damage suffered by milk can be evaluated (Tirelli A., J. Food Prot. 1998;61 : 1400). These reactions could interfere with the allergenicity of the milk proteins, assuming that lysine is important for the activity of the epitopes. However some Japanese authors (Matsuda T. et., J. Food Sci. 1985: 50:618) reported that such modifications cause the appearance of new epitopes and therefore the aforesaid changes have not considered useful to decrease the allergenicity of milk proteins.
The reaction of carbamylation of the ε amino group of lysine is less drastic from a structural point of view; furthermore, the demonstration of the decrease of allergenic activity of carbamylated aeroallergens has been already acquired after 10 years of clinical trials and > 40,000 patients involved (sublingual route: lymphatic/digestive route).
The problem of allergic responses to some proteins present in food, particularly Cow Milk Allergy has not yet found a satisfactory solution, the partial hydrolysis of said proteins involving the drawbacks mentioned above.
Description of the invention The present invention provides a solution to the above problem, since it allows to modify the amino acid sequence of the main epitopes, which are thereby rendered immunogically different from the native ones.
The object of the invention has been reached by chemical modification of the lysine of the allergenic polypeptides into homocitrulline, previously disclosed but only for the preparation of allergoids for the immunotherapy of allergic diseases. (Falagiani P., Brenna O. and Mistrello G., 1993: "Chemically modified allergens and process for the preparation thereof, IT 1237475.
Therefore, for the first time this process is applied to food proteins. It is already known that homocitrulline, obtained from lysine through chemical modification, is not toxic or dangerous to s not undergo metabolisation. The daily intake of lysine from other unmodified proteins, to which the patient is not sensitised, is largely sufficient for maintaining a correct nutritional state.
The modified products obtainable by the process of the invention can therefore be consumed also by subjects allergic to milk proteins or other food proteins without manifesting severe intolerance symptoms. Moreover, the foods of the invention are particularly indicated for atopic patients, since the reduced exposition to allergens can avoid or reduce the risk of sensitisation.
According to the invention, food proteins are reacted with an alkali cyanate or other reagents useful as a cyanate source, suck as carbamyl phosphate and the like.
Cyanate reacts with functional side groups in proteins as follows: • P-NH2 (α) ► P-NH-CO-NH2 ► (hydantoin)
• P-SH ► P-S-HN-CO-NH2 ► (unstable)
• P-tyrosine-OH P-tyrosine-O-CO-NH2 (unstable, as for histidine)
• P-CONH2 ► unstable derivatives
Cyanate does not react with arginine whereas at acidic pH, the formation of intra/ inter pseudo-peptide bonds occurs.
Carbamylation may be carried out in apH range from about 6.5 to alkaline pH.
A stable ureido group is obtained when cyanate is reacts with the ε-NH 2 of lysine, according to the following scheme: P-(CH2)4 - NH2 (ε) ► P-(CH2)4 - NH-CO-NH2 STABLE
The following reaction conditions are preferred, when an alkaline cyanate is used: pH 9.1 ± 0.1 ; 40°C-50°C; 16-20 h, giving 90% ε-amino group modification.
The reaction temperature and time may anyhow range within wide limits, for instance from 15 to 1500C and from 30 s to 24 h, depending on the considered protein and the desired carbam
The percent carbamylation of the ε-amino groups of the protein obtainable according to the invention is higher than 5%, preferably higher than 50% and more preferably higher than 90%.
The protein Molecular weight (MW) and 3D-structure practically are unchanged whereas pi is acidified, sensitivity to trypsin attack decreases and sensitivity to chymotrypsin attack increases.
Any kind of proteins of dietetic interest may be treated according to the invention, for instance proteins from milk, egg, soy, cereal etc..
The problem is of course particularly critical in milk and dairy industries, since allergy to milk proteins is becoming more and more frequent and represents one of the most important component of an equilibrated diet, in view of its supply of proteins, sugars, fat, vitamins, calcium ions and other salts. Lysine is present in the linear epitopes of many of the milk allergens
(table 1) and carbamylation of these lysines abolishes the reactivity of IgE related to those linear epitopes.
Moreover, shifting the proteolytic susceptibility leads to different peptides that can trigger a different mechanism in the allergic response:
Table 1
Figure imgf000006_0001
The following Examples further illustrate the invention. EXAMPLE 1 (carbamylated milk proteins) A mixture of 4 g of sodium caseinate and 6 g of milk serum protein is suspended in 400 ml of 0.1 M sodium tetraborate buffer, adjusting the pH to 9.1 ± 0.1 with 1 M NaOH. 20 of re-crysta ind allowed to react under mild stirring at 450C for 18 hrs. At the same time 1/10 of a similar mixture, wherein KCNO is replaced by an equivalent amount of KCl, is treated under the same conditions (blank). To calculate the substitution degree of the lysine ε-groups, at the end of the reaction 10 ml of the two solutions are gel-filtered through a G25® Fine column (2.5 x 15 cm), eluting with 20 mM sodium phosphate buffer, pH 6.86. The initial protein peak from each eluate is collected and submitted first to the biuret test (Gornall A G et al., 0 J.Biol. Chem. 1949: 177: 751), to evaluate the protein content and then to the reaction with TNBS (Ηabeeb AF. Anal. Biochem. 1966: 14:328), to evaluate the amino groups concentration (reference curves obtained with BSA).
Mix 4/6 CNO A 540 nm = 0,264 mgP/mL = 5. ,4 a
Mix 4/6 Ref A 540 nm = 0,296 mgP/mL = 6. ,15 b 5 TNBS assay
Mix 4/6 CNO A 345 nm = 0,4 μM NH2AnL = 0,074 C
Mix 4/6 Ref A 345 nm = 1 ,3 μM NH2/mL = 8,67 d
% substitution = c/a/d/b x 100 = 95%
The rest of the derivative is gel-filtered though a column with suitable
>0 dimensions.
EXAMPLE 2
10 g of ovalbumin are treated under the conditions of example 1. Samples are takes at different times to follow the substitution reaction.
Table 2 reports the substitution degree values of the e-amino groups as 5 a function of the reaction time at 400C.
Figure imgf000007_0001

Claims

I . A process for the preparation of hypoallergenic alimentary proteins by subjecting said proteins to carbamylation reaction.
2. A process according to claim 1 wherein the carbamylation is carried out by reacting the protein with a cyanate or a cyanate source.
3. A process according to claim 1 or 2 wherein the carbamylation is carried out at a pH value from 6.5 to alkaline.
4. A process according to claim 1 to 3 wherein the carbamylation is carried out at temperature range from 15 to 1500C.
5 A process according to claim 1 to 4 wherein the carbamylation is carried out under the mentioned conditions for times spanning from 30 sec to 24 h.
6. A process according to claim 1 or 2, wherein the reaction is carried out at with an alkaline cyanate at a pH of 9.1 ± 0.1, a temperature range of
40°C-50°C for 16-2O h.
7. A process according to claim 3 wherein the percent carbamylation of the ε-amino groups of the protein is higher than 5%, preferably higher than 50% and more preferably higher than 90%.
8. A process according to anyone of claims from 1 to 7 wherein the proteins are milk, egg, cereal and soy proteins.
9. A process according to claim 8 wherein the proteins are cow milk proteins.
10. Alimentary proteins obtainable by the process of the processes of claims 1-9.
I I . Food products and compositions comprising the proteins of claim 10.
PCT/EP2005/002744 2005-03-15 2005-03-15 A process for the preparation of hypoallergenic alimentary proteins WO2006097120A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103141739A (en) * 2013-03-26 2013-06-12 呼伦贝尔双娃乳业有限公司 Hypo-allergenic lactoprotein powder based on complex carbohydrate modification and preparation method
WO2017158202A1 (en) * 2016-03-18 2017-09-21 Genclis Molecular origin of allergy

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0421949A1 (en) * 1989-10-06 1991-04-10 LABORATORIO FARMACEUTICO LOFARMA s.r.l. Chemically modified allergens and process for the preparation thereof
US20040209312A1 (en) * 2001-11-13 2004-10-21 Harding Fiona A Identifying and reducing the allergenicity of food proteins

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0421949A1 (en) * 1989-10-06 1991-04-10 LABORATORIO FARMACEUTICO LOFARMA s.r.l. Chemically modified allergens and process for the preparation thereof
US20040209312A1 (en) * 2001-11-13 2004-10-21 Harding Fiona A Identifying and reducing the allergenicity of food proteins

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MANSON W ET AL: "PRODUCTS OF THE HEAT-PROMOTED REACTION BETWEEN UREA AND THE PROTEIN FRACTION OF BOVINE MILK", JOURNAL OF DAIRY RESEARCH, vol. 52, no. 3, 1985, pages 401 - 408, XP009053229, ISSN: 0022-0299 *
SWEETSUR A W M ET AL: "ROLE OF CYANATE IONS IN THE UREA INDUCED STABILIZATION OF THE CASEINATE COMPLEX IN SKIM MILK", JOURNAL OF DAIRY RESEARCH, vol. 48, no. 1, 1981, pages 163 - 166, XP009053243, ISSN: 0022-0299 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103141739A (en) * 2013-03-26 2013-06-12 呼伦贝尔双娃乳业有限公司 Hypo-allergenic lactoprotein powder based on complex carbohydrate modification and preparation method
WO2017158202A1 (en) * 2016-03-18 2017-09-21 Genclis Molecular origin of allergy
CN109564204A (en) * 2016-03-18 2019-04-02 真克里斯公司 The Molecular Origin of allergy
US11234445B2 (en) 2016-03-18 2022-02-01 Genclis Molecular origin of allergy
EP4148427A1 (en) * 2016-03-18 2023-03-15 Genclis Molecular origin of allergy

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