WO1999049727A1 - Composes de proteines antimicrobiens comme nouveaux agents hyperthermiques oraux de regulation du poids corporel et de l'hypertension - Google Patents

Composes de proteines antimicrobiens comme nouveaux agents hyperthermiques oraux de regulation du poids corporel et de l'hypertension Download PDF

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Publication number
WO1999049727A1
WO1999049727A1 PCT/US1999/006942 US9906942W WO9949727A1 WO 1999049727 A1 WO1999049727 A1 WO 1999049727A1 US 9906942 W US9906942 W US 9906942W WO 9949727 A1 WO9949727 A1 WO 9949727A1
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Prior art keywords
nisin
composition
body weight
active ingredient
individual
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PCT/US1999/006942
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English (en)
Inventor
Jennifer A. Nasser
Paul A. Lachance
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Rutgers, The State University Of New Jersey
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Priority to AU32171/99A priority Critical patent/AU3217199A/en
Publication of WO1999049727A1 publication Critical patent/WO1999049727A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • This invention relates to the field of weight loss therapy and hypertension treatment in mammals.
  • the invention relates to a class of peptides the ingestion of which in small amounts causes weight loss and is capable of alleviating hypertension.
  • Obesity the accumulation of excess body fat, occurs in approximately 34 percent of the adult U.S. population. It is the leading risk factor in chronic disease (e.g. hypertension, cardiovascular and cerebrovascular disease, and diabetes) pathogenesis ( achance, 1994, Food Tech. 48 . : 127-138 ; Van Itallie 1985, 1985, Ann. Internal Med. 103 :983-988) .
  • a sufficient supply of food and a genetic predisposition for converting food to body fat seem to be necessary for the development of obesity (Dulloo and Miller, 1989 ,Nutri . 5 . 5:7-9) .
  • Human obesity is a disease arising from the interaction of a number of genetic and environmental - 2 - factors (Foreyt and Poston, 1997, J. Biol . Chem. 256 : 7113-7114) . Identification of genetic factors that contribute to the predisposition of accumulating excess body fat is important to the development of effective treatment and prevention strategies.
  • weight gain or loss is not believed to be directly related to triiodothyronine levels. Variations in metabolic response to normal thyroid hormone levels at the cellular level however, may be a contributing factor to obesity.
  • Ca,Mg-ATPase an energy generating enzyme system responsible for maintaining intracellular calcium concentrations at 0.1 ⁇ M, accounts for 4-27% of ATP consumption in various tissues such as erythrocytes, cardiac muscle, liver, kidney, and pancreas; and is modulated by triiodothyronine (Buttgereit et al . , 1991, Biochem. International 2 ⁇ :59-67; Davis and Bias, 1981, Biochem. Biophys . Res. Comm. 11:1073-1080; Davis et al . , 1982, Life Sciences 3_0 : 675-682 ; Davis et al . , 1987, J. Clin. Endocrin.
  • Mg-ATPase another energy generating system is reported to be increased in obese monosodium glutamate fed rats (Remke et al . , 1992, Exper. Path. 4_3:67-73). In rats, the ratio of Ca,Mg-ATPase/Mg-ATPase is stimulated or inhibited by triiodothyronine depending upon the fat composition of the diet, which determines the lipid makeup of the plasma membrane (Galo et al . , J. Biol. Chem. 256: 7113-7114, 1981). Nasser (1998, Ph.D.
  • a substance that could increase Ca,Mg- ATPase activity and decrease Mg-ATPase activity would increase the Ca,Mg-ATPase/Mg-ATPase ratio and possibly have potential as an anti-obesity agent.
  • an ingestible composition for controlling obesity which comprises as an active ingredient an effective amount of at least one antimicrobial polypeptide selected from the group consisting of nisin, pediocin, subtilin, hemolysin, colicins, monicins, subticins, staphlocins, lactacins A - X, defensins, epidermin, gallidermin and any combination thereof, or fragments of the aforementioned polypeptides and combinations thereof.
  • the effective concentration of the active ingredient is about 1 ng to 1 mg per kg body weight, with concentrations greater than 1 ⁇ g/kg body weight particularly preferred.
  • Nisin, pediocin and subtilin are the preferred active ingredients, with nisin- being particularly preferred.
  • a method for controlling obesity in a patient in need of such treatment comprises administering one of the aforementioned antimicrobial peptides in an amount and for a time sufficient to effect the obesity control .
  • an ingestible composition for controlling hypertension comprises as an active ingredient an effective amount (e.g., 1 ng to 1 mg / kg body weight) of at least one antimicrobial peptide selected from the group listed above in connection with treatment of obesity.
  • a method for controlling hypertension in a patient in need of such treatment is also provided, which comprises administering the aforementioned antimicrobial peptide in an amount and for a time sufficient to effect the hypertension control .
  • FIG. 1 The effect of nisin on Ca,Mg- ATPase activity, expressed as ⁇ mole phosphate per mg of erythrocyte membrane protein per hour, revealing a relationship with nisin concentration.
  • Working solutions of nisin were prepared in 10 ml of 20 mM TRIS-HCl, pH 7.4 - 7.6 (contains 250 ⁇ g nisin/ml) . Varying amounts of the working solution were added to assay tubes to give indicated concentrations of nisin. Assays were incubated at 37°C for 1 hr 20 min. Assays were initiated by addition of 0.1 ml Na 2 ATP to each assay tube.
  • Figure 2 The effect of nisin on Mg-ATPase activity, expressed in ⁇ M phosphate initially decreasing with increasing concentrations of nisin.
  • Figure 3 The effect of placebo or nisin on weight loss in women. A comparison of the effect of a placebo or nisin on weight loss in fifteen women is depicted. Each woman ingested the placebo daily for two weeks, followed by 570 ⁇ g nisin daily for two weeks.
  • Weight loss (lbs/week) was calculated by subtracting the weight on day 14 from the weight on day 1 and dividing by 2.
  • the present invention is drawn to a class of protein compounds, naturally occurring in certain food class microorganisms, which as the organism or active agent, can be used as food ingredients.
  • the active agent acts to decrease the efficiency of the eventual metabolic conversion of the macronutrients, carbohydrates, fats and excess protein, into usable molecular energy (ATP) by increasing the conversion of the available energy substrate to heat production.
  • ATP usable molecular energy
  • the active agent of this invention additionally acts to increase cellular Ca,Mg-ATPase activity and lower intracellular calcium concentrations. Lowering the intracellular calcium of vascular smooth muscle cells is known to result in vasodilation. These protein compounds can therefore also be described as vasodilative or hypotensive .
  • nisin a food grade ingredient
  • GRAS generally recognized as safe
  • the various hyperthermic/vasodilative proteins, of which nisin is an example, are natural - 7 - products of cells, including but limited to, .lactococci, lactobacilli , pediococci, streptococci, mammalian leukocytes and reptilian skin tissue. These proteins are not antibiotic and do not lyse the cells that produce them.
  • the amino acid composition of the hyperthermic/ vasodilative proteins is characterized by the presence of unusual amino acids such as: dehyro-alanine, dehyro- butyrine and sulfur (thio bridge) containing structures such as lanthionine and methyl lanthionine.
  • These protein are generally small (3 to 10 kDa) with a high isoelectric point (e.g., the pi of nisin is 10.5) and containing both hydrophilic and hydrophobic domains.
  • the protein is described by the suffix "in” appended to the originating microbial species name.
  • the proteins of the invention include, but are not limited to, nisin, pediocin, subtilin, hemolysin, colicins, monicins, subticins, staphlocins, lactacins A - X, defensins, epidermin, gallidermin and combinations of one or more of these polypeptides . Fragments of these polypeptides or the entire peptide may be suitable for use in the invention. The use of polypeptide fragments is particularly suitable for the larger members of the group, such as colicins (-25-90 kDa) . Members of this peptide class are commonly referred to as "bacteriocins" . Most bacteriocins with known sequences are amphiphilic cationic peptides showing alpha-helix, beta sheet, or in the case of lantibiotics, screw-like secondary structures .
  • nisin (which is a preferred compound for use in the present invention) is a polypeptide antimicrobial produced by Streptococcus lactis .
  • Nisin contains 34 amino acid residues, eight of which are rarely found in nature, including lanthionine (two alanines bonded to sulfur at the ⁇ -carbons) and ⁇ - methyllanthionine (Merck Index) .
  • the bacteriocins of the present invention facilitate reduction of obesity and are expected to be useful for treating hypertension.
  • nisin 1_12 a chymotrypsin derived fragment of nisin, competes with nisin for binding to membranes (Moll et al . , 1997, J. Bact. 179:135-140) .
  • This nisin fragment has a reduced capacity to collapse the ⁇ pH and ⁇ of the membrane, however, for an in vivo usage, increased membrane permeability not cell lysis is the goal.
  • small amounts of the whole molecule or the twelve amino acid fragment could be absorbed into the blood and carried throughout the body to the main thermogenic tissue.
  • Nisin functioning as a protonophore, stimulates oxygen consumption in gram-negative bacteria (deMelo et al . , 1996, Appl. Envir. Micro. 62 . : 1831-1834) . Increasing oxygen consumption in humans would promote weight loss. Nisin and similar antimicrobial peptides may function in a similar fashion to UCP3 , a mitochondrial uncoupling protein, which mediates triiodothyronine regulated thermogenesis in mammalian muscle and white adipose tissue (WAT) (Gong et al . , 1997, J.
  • WAT white adipose tissue
  • UCP3 acts as a protonophore through translocation of fatty acids from the inner surface of the mitochondria membrane to the cytoplasm surface where they are protonated and diffuse back into the mitochondria. A proton is thus transported through the membrane uncoupled from ATP synthesis.
  • Nisin and the class of proteins of the invention may also promote weight loss through the creation of a futile calcium influx/efflux cycle.
  • the stimulation of Ca,Mg-ATPase taught in Example 1 can be accomplished by increasing the permeability of the plasma membrane to calcium, which would increase the concentration of calcium at the inner surface of the membrane (Vincenzi, 1989, Red Blood Cell Membranes, eds. Agre, P. and Parker, J.C., Marcel Dekker New York, pp.
  • a class of antimicrobial proteins is known to increase plasma membrane permeability to small ions, amino acids, adenine nucleotides and protons (Winkowski et al . , 1996, supra; Gao et al . , 1991, Appl. Envir. Microbiol. J57 . : 2164-2170) .
  • Bruno et al . (1992, Appl. Envirn. Micro. 5_8: 2255-2259) have shown that nisin destroys the ⁇ pH (chemical) component of the plasma membrane proton motive force in bacteria at low - 10 - concentrations and completely destroys the proton motive force at high concentrations. Roufogalis et al .
  • ⁇ G ( ATP ) m ⁇ (Ca2+) (m is equal to the stoichiometric ratio of moles of Ca 2+ translocated/mole ATP hydrolyzed) .
  • Roufogalis et al . (1989, supra) further state that destroying the Ca chemical gradient or preventing its formation will cause the ATP to work at maximum rate . It is possible that, by increasing the membrane permeability to calcium, nisin is modulating the chemical gradient. In in vi tro experiments with erythrocyte membranes, Nasser (1998, supra) showed that the concentration of nisin needed to increase Ca,Mg-ATPase activity was equivalent to the concentration Bruno et al . (1992, supra) reported as effective in collapsing the ⁇ pH component of the proton motive force of bacterial cell membranes .
  • Example 2 The stimulation of Ca,Mg-ATPase activity by nisin taught in Example 1 may also lead to weight loss taught in Example 2 through the reduction of intracellular calcium.
  • Kim et al . (1996, supra) reported that agouti gene-dependent obesity is partially regulated by an intracellular calcium mechanism that can be blocked by the use of an anti -hypertensive calcium channel - blocking drug. An 18% decrease in fat pad weight and an elevation of core body temperature were observed in mice treated with a calcium channel blocker. Tuck et al . - 11 -
  • Nisin and its family of proteins may promote weight loss not only by increasing energy expenditure but also by reducing energy intake.
  • Taste is the most important determinant of human food choice (Glanz et al . , 1998, JADA 98:1118-1126). Increases in intracellular calcium of the sweet-sensitive taste buds may be involved in signal transduction in rats (Bernhardt et al . , 1996, J. Physiol. (London) 490 :325-336) and humans (Fujiyama et al., 1998, FEBS Lett. 434 :47-50) .
  • the lingual taste buds in the golden hamster contain Ca,Mg-ATPase (Barry, 1992, 4.0:1919-1928) .
  • nisin By stimulating Ca,Mg-ATPase in the taste buds, nisin may decrease the increase intracellular calcium induced by sweet substances and block taste. Nisin may also act directly on the sweet receptor to block its stimulation.
  • Gurmarin a sweetness blocking peptide from Gymnema Sylvestre (Yoshie et al . , 1994 Arch. Histol . Cytol . 57:531-534; Ota et al . , 1998, Biopolymers 4J5: 231-238) , has some structural features which are similar to nisin.
  • Gurmarin contains 35 amino acid residues, including a number of amino acids with hydrophobic side chains that form a hydrophobic cluster, - 12 - sulfur containing amino acids and three intramolecular disulfide bonds.
  • the hydrophobic cluster of side chains of gurmarin interact with the sweet receptor.
  • Nisin likewise contains hydrophobic amino acids and thio bridges that substitute for disulfide bonds and therefore may also block the taste of sweetness.
  • nisin and its family of peptides may function similarly to known peptides that act in the gut to effect satiety.
  • peptides endogenous to the mammalian gastroinstestinal tract and released after food digestion are potent satiety agents (Thaw et al . , 1998, Physiol. Behav. 6_4:425-428) similar to the amphibian tetradecapeptide peptide bombesin. Bombesin increased that first postprandial intermeal interval by 177%.
  • GRP Gastrin-Releasing Peptide
  • GRP acts through a Ca-phosphoinositide mechanism and is responsible for the release of gastrin, which controls gastric acid and pepsin secretion.
  • Another peptide, Gastric-Inhibitory Peptide (GIP) enhances insulin release and inhibits gastric acid secretion.
  • GIP Gastric-Inhibitory Peptide
  • Gurmarin depresses glucose-stimulated increase in GIP (Fushiki et al . , 1992, J. Nutri. 122 :2367-2373) .
  • Bacteriocins such as nisin may additionally lessen hypertension in patients.
  • High intracellular calcium concentrations in vascular smooth muscle are known to lead to increased vasoconstriction (Zemel, 1998, Mol . Cell. Biochem. 188 : 129-136) .
  • the higher Ca,Mg- ATPase found after nisin treatment as taught in Example 1 may lead to a decrease of intracelluar calcium concentrations in the vascular smooth muscle and therefore increased vasodilation.
  • the bacteriocins of the present invention may be obtained as isolated compounds and prepared for administration in a variety of formulations as described below.
  • microorganisms that produce a selected bacteriocin may be used.
  • Bacteria that produce bacteriocins and that are also either neutral or beneficial microflora of the mammalian gastrointestinal system are suitable for use in the present invention.
  • the mode of administration of microorganisms that produce bacteriocins is by oral or nasal injection, or by feeding (alone or incorporated into the subject's feed or food) .
  • nisin or the other bacteriocins suitable for use in the present invention may be obtained as purified compositions and formulated for administration in a variety of ways.
  • Nisin and the other bacteriocins listed above may be obtained from commercial sources (e.g., Sigma Chemical Co., Coulter Pharmaceutical, Rhodia, Inc.).
  • any carrier, solvent or excipient that is biologically compatible with the bacteriocin to be administered is considered suitable for use in the present invention for the preparation of pharmaceutical, nutraceutical or food additive formulations of the bacteriocin.
  • the formulations comprising the hyperthermic/hypotensive polypeptides of the invention are conveniently formulated for administration with a biologically acceptable medium such as water, buffered saline, ethanol, polyol (for example, glycerol , propylene glycol, liquid polyethylene glycol and the like), among others.
  • a biologically acceptable medium such as water, buffered saline, ethanol, polyol (for example, glycerol , propylene glycol, liquid polyethylene glycol and the like), among others.
  • These preparations may be formulated as tablets, capsules or liquids for oral or intranasal administration.
  • the active ingredient (s) may be mixed with a food product .
  • biologically acceptable medium includes any and all solvents, dispersion media and the like which may be appropriate for the desired route of administration of the pharmaceutical or nutraceutical preparation, as exemplified in the preceding paragraph.
  • the use of such media for is known in the art; moreover, nisin and many of the bacteriocins are routinely formulated for use by humans and animals.
  • any conventional media or agent is incompatible with the polypeptides to be administered, its use in the pharmaceutical, nutraceutical or food preparation is contemplated.
  • the present invention provides a method for treating obesity or hypertension in patients requiring such treatment.
  • the terms "patient,” “subject,” or “individual” all refer to humans or animals.
  • the method comprises administering to such patients a bacteriocin, such as nisin, at scheduled intervals appropriate to effect the reduction in obesity or hypertension.
  • a bacteriocin such as nisin
  • the bacteriocins are administered as dosage units.
  • dosage units refers to a physically discrete unit of the pharmaceutical preparation appropriate for the patient undergoing treatment .
  • Each dosage unit contains a quantity of active ingredient calculated to produce the desired effect in association with the selected pharmaceutical carrier.
  • a preferred single dose of bacteriocin effective for treating obesity ranges from 1 ng to 1 mg per kg body weight. Preferably, the dose ranges from 5 - 11 ⁇ g/kg body weight, and most preferably, a single dose is 5 - 7.5 ⁇ g/kg body weight. Similar preferred single doses of bacteriocin are effective for treating hypertension.
  • the dosage regimen for treating obesity or hypertension is determined according to standard methods known to medicinal chemists.
  • a dosage is administered once daily.
  • a dosage may be administered twice daily.
  • Example 1 Nisin Treatment Affects High Energy ATPase Enzymes
  • the titer of the activity of one of the distinct types of high energy ATP enzymes namely Ca ++ ,Mg ++ ,ATPase
  • the titer of activity of another ATP enzyme, namely Mg++, ATPase is changed (decreased) as the Ca,Mg-ATPase activity is elevated.
  • the phenomenon is one of unique protein (s) capable of "uncoupling" ATP metabolism and thus exerting a decrease in the efficiency in the energy that is derived during the catabolism of glucose from carbohydrate, fat and excess protein sources of energy.

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  • Health & Medical Sciences (AREA)
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  • Gastroenterology & Hepatology (AREA)
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Abstract

L'invention concerne des compositions de régulation de l'obésité et de l'hypertension. L'ingrédient actif est une bactériocine, telle qu'une nisine, dont on a découvert qu'elle réduisait le poids corporel grâce à un mécanisme qu'on pense également hypotenseur. L'invention concerne également des méthodes de réduction du poids corporel et de l'hypertension par ingestion des compositions de la présente invention.
PCT/US1999/006942 1998-03-30 1999-03-30 Composes de proteines antimicrobiens comme nouveaux agents hyperthermiques oraux de regulation du poids corporel et de l'hypertension WO1999049727A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32171/99A AU3217199A (en) 1998-03-30 1999-03-30 Antimicrobial protein compounds as novel oral hyperthermic agents for control ofbody weight and hypertension

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7994398P 1998-03-30 1998-03-30
US60/079,943 1998-03-30

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WO1999049727A1 true WO1999049727A1 (fr) 1999-10-07

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4156718A (en) * 1976-11-19 1979-05-29 The New England Institute, Inc. Control and reversal of the immunological senescence
US4537776A (en) * 1983-06-21 1985-08-27 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl) pyrrolidone
US4557934A (en) * 1983-06-21 1985-12-10 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one
US5688767A (en) * 1992-08-21 1997-11-18 University Of British Columbia Treatment of endotoxin-associated disorders with cationic peptides
US5728705A (en) * 1993-10-04 1998-03-17 The Trustees Of Columbia University In The City Of New York Method of inducing vasorelaxation to treat pulmonary hypertension

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4156718A (en) * 1976-11-19 1979-05-29 The New England Institute, Inc. Control and reversal of the immunological senescence
US4537776A (en) * 1983-06-21 1985-08-27 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl) pyrrolidone
US4557934A (en) * 1983-06-21 1985-12-10 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one
US5688767A (en) * 1992-08-21 1997-11-18 University Of British Columbia Treatment of endotoxin-associated disorders with cationic peptides
US5728705A (en) * 1993-10-04 1998-03-17 The Trustees Of Columbia University In The City Of New York Method of inducing vasorelaxation to treat pulmonary hypertension

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