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WO2002013850A1 - Utilisation de la colostrinine, de ses peptides constitutifs, et de ses analogues comme regulateurs du stress oxydatif - Google Patents

Utilisation de la colostrinine, de ses peptides constitutifs, et de ses analogues comme regulateurs du stress oxydatif Download PDF

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Publication number
WO2002013850A1
WO2002013850A1 PCT/US2000/022776 US0022776W WO0213850A1 WO 2002013850 A1 WO2002013850 A1 WO 2002013850A1 US 0022776 W US0022776 W US 0022776W WO 0213850 A1 WO0213850 A1 WO 0213850A1
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WIPO (PCT)
Prior art keywords
seq
oxidative stress
group
colostrinin
combinations
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PCT/US2000/022776
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English (en)
Inventor
G. John Stanton
Jr. Thomas K. Hughes
Istvan Boldogh
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The University Of Texas System
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Publication date
Application filed by The University Of Texas System filed Critical The University Of Texas System
Priority to AU2000269178A priority Critical patent/AU2000269178A1/en
Priority to PCT/US2000/022776 priority patent/WO2002013850A1/fr
Publication of WO2002013850A1 publication Critical patent/WO2002013850A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • Colostrum is a component of the milk of mammals during the first few days after birth. Colostrum is a thick yellowish fluid and is the first lacteal secretion post parturition and contains a high concentration of immunogloblins (IgG, IgM, and IgA) and a variety of non-specific proteins. Colostrum also contains various cells such as granular and stromal cells, neutrophils, monocyte/macrophages, and lymphocytes. Colostrum also includes growth factors, hormones, and cytokines. Unlike mature breast milk, colostrum contains low sugar, low iron, but is rich is lipids, proteins, mineral salts, vitamins, and immunoglobins.
  • Colostrum also includes or contains a proline-rich polypeptide aggregate or complex, which is referred to as colostrinin.
  • colostrinin One peptide fragment of colostrinin is Val-Glu-Ser-Tyr-Val-Pro-Leu-Phe-Pro (SEQ ID NO:31), which is disclosed in International Publication No. WO-A-98/14473.
  • Colostrinin and this fragment have been identified as useful in the treatment of disorders of the central nervous system, neurological disorders, mental disorders, dementia, neurodegenerative diseases, Alzheimer's disease, motor neurone disease, psychosis, neurosis, chronic disorders of the immune system, diseases with a bacterial and viral aetiology, and acquired immunological deficiencies, as set forth in International Publication No.
  • the present invention relates to the use of colostrinin, at least one constituent (i.e., component) peptide thereof, at least one active analog thereof (e.g., peptide having anN-terminal sequence equivalent to an N-terminal sequence of at least one of the colostrinin constituent peptides), and combinations thereof, as an oxidative stress regulator.
  • oxidative stress regulators can be used in vitro or in vivo, including internal and external use in animals including mammals such as humans. They can be used for preventative (i.e., prophylactic) treatments or for therapeutic treatments.
  • the present invention provides a method for modulating (e.g., regulating or adjusting) the oxidative stress level in a cell.
  • the method includes contacting the cell with an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to change (decrease or increase, but preferably, decrease) or prevent an increase in the level of an oxidizing species in the cell.
  • an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to change (decrease or increase, but preferably, decrease) or prevent an increase in the level of an oxidizing species in the cell.
  • an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to change (decrease or increase, but preferably, decrease) or prevent an increase in the level of an oxidizing species in the cell.
  • no increase or any amount of change (preferably, a decrease) in the level of one or more oxidizing species are within the scope of the invention,
  • the present invention provides a method for modulating the oxidative stress level in a patient.
  • the method includes administering to the patient an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to decrease or prevent an increase in the level of an oxidizing species in the patient.
  • an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to decrease or prevent an increase in the level of an oxidizing species in the patient.
  • Yet another method of the invention is a method of modulating the oxidative stress level of the skin of a patient, and preferably, treating (prophylactically or therapeutically) oxidative damage to the skin of a patient.
  • the method includes applying to skin a topical formulation (e.g., sun screen) that includes an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to change (increase or decrease, but preferably, decrease) or prevent an increase in the level of damage to a biomolecule of the patient.
  • a topical formulation e.g., sun screen
  • an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to change (increase or decrease, but preferably, decrease) or prevent an increase in the level of damage to a biomolecule of the patient.
  • biomolecules may be selected from the group of a DNA, a protein, a lipid, or combinations thereof.
  • the invention provides the use of an oxidative stress regulator in the manufacture of a medicament for use in the methods described herein.
  • a further embodiment of the invention is a cosmetic formulation that includes an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof.
  • an oxidative stress regulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof.
  • a or “an” means one or more (or at least one), such that combinations of active agents (i.e., active oxidative stress regulators), for example, can be used in the compositions and methods of the invention.
  • a composition that includes "a" polypeptide refers to a composition that includes one or more polypeptides.
  • amino acid is used herein to refer to a chemical compound with the general formula: NH 2 — CRH — COOH, where R, the side chain, is H or an organic group. Where R is organic, R can vary and is either polar or nonpolar (i.e., hydrophobic). The amino acids of this invention can be naturally occurring or synthetic (often referred to as nonproteinogenic).
  • an organic group is a hydrocarbon group that is classified as an aliphatic group, a cyclic group or combination of aliphatic and cyclic groups.
  • aliphatic group means a saturated or unsaturated linear or branched hydrocarbon group.
  • cyclic group means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group.
  • alicyclic group means a cyclic hydrocarbon group having properties resembling those of aliphatic groups.
  • aromatic group refers to mono- or polycyclic aromatic hydrocarbon groups.
  • an organic group can be substituted or unsubstituted.
  • polypeptide and “peptide” are used interchangeably herein to refer to a polymer of amino acids. These terms do not connote a specific length of a polymer of amino acids. Thus, for example, the terms oligopeptide, protein, and enzyme are included within the definition of polypeptide or peptide, whether produced using recombinant techniques, chemical or enzymatic synthesis, or naturally occurring. This term also includes polypeptides that have been modified or derivatized, such as by glycosylation, acetylation, phosphorylation, and the like.
  • PC12 (A) and ECN304 (B) cell culture were harvested and prepared for cell cycle analysis. D ⁇ A content of cells was determined by flow cytometry. Each data points represent the mean fluorescence for 10,000 cells. Statistical analysis was carried out using ModFitLT N2.0 software.
  • FIG. 1 Change in DCF fluorescence intensity as function of time, after addition of H 2 O or TPA to PC 12 cells.
  • Cells (10 6 ) were loaded with H 2 DCF-DA (2.5 micromolar ( ⁇ M)) for 12 minutes (min) and increasing concentrations of H 2 O 2 (0, 12.5, 25 50 and 100 ⁇ M) or TPA (0, 50, 100, and 200 nanograms per milliliter (ng/ml)) was added. Fluorescence intensities were determined at 0, 5, 10 and 15 minutes after addition of H 2 O 2 or TPA addition. Each data point represents the mean fluorescence for 10,000 cells.
  • Figure 4 Effect of ⁇ -acetyl-L-cysteine. butylated hydroxyanisole. and catalase on H 2 O 2 -induced H 2 DCF oxidation.
  • Treated and non-treated cells, loaded with H 2 DCF-DA (2.5 ⁇ M) were exposed to 25 ⁇ M H 2 O 2 and changes in fluorescence intensities were determined at 0 and 15 min by flow cytometry. Each data points represent the mean fluorescence for 10,000 cells.
  • Figure 5 Effect of colostrum, colostrinin. and its constituent peptides.
  • Cells were H 2 DCF-DA loaded and treated with compounds as described in the Examples Section. Changes in fluorescence intensity of treated and mock- treated cell cultures were determined as a function time (0, 5, 10, 15 minutes) after addition of 25 ⁇ M H 2 O 2 .
  • the concentrations of colostrum colostrinin, and its constituent peptides were 10 micrograms per milliliter ( ⁇ g/ml). Each data points represent the mean fluorescence for 10,000 cells.
  • FIG. 6 Reduction in TPA-induced reactive oxidizing species (ROS) levels in the presence of colostrum, colostrinin. and its constituent peptides as a function of time.
  • Cells were H 2 DCF-DA loaded and treated with compounds as described in the Examples Section. Changes in fluorescence intensity of treated and mock-treated cell cultures were determined as a function time (0, 5, 10, 15 minutes) after addition of 100 nanograms (ng) TPA.
  • the concentrations of colostrum, colostrinin, and its constituent peptides were 10 ⁇ g/ml. Each data points represent the mean fluorescence for 10,000 cells.
  • FIG. 7 Reduction in ROS levels by colostrum, colostrinin. and its constituent peptides from three independent experiments.
  • H 2 DCF-DA-loaded cells were treated with compounds as described in the Examples Section. Changes in fluorescence intensity of treated and mock-treated cell cultures were determined as a function time (0, 5, 10, 15 minutes) after addition of 100 ng TPA. The concentrations of colostrum, colostrinin, and its constituent peptides were 10 ⁇ g/ml. Each data points represent the mean fluorescence for 10,000 cells.
  • colostrinin at least one constituent peptide thereof, and/or at least one active analog thereof (e.g., a peptide having an N- terminal sequence equivalent to anN-terminal sequence of at least one of the colostrinin constituent peptides) can be used as general purpose oxidative stress regulator for use in vitro and in vivo, including for internal and external use in animals including mammals such as humans.
  • active analog thereof e.g., a peptide having an N- terminal sequence equivalent to anN-terminal sequence of at least one of the colostrinin constituent peptides
  • Such oxidative stress regulators are referred to herein as "active agents.”
  • active agents can be administered alone or in various combinations to a patient (e.g., animals including humans) as a medication or dietary (e.g., nutrient) supplement in a dose sufficient to modulate the oxidative stress level throughout the patient's body, in a specific tissue site, or in a collection of tissues (organs).
  • a patient e.g., animals including humans
  • a medication or dietary (e.g., nutrient) supplement in a dose sufficient to modulate the oxidative stress level throughout the patient's body, in a specific tissue site, or in a collection of tissues (organs).
  • they can be administered topically to reduce the effects of environmental- and oxidative stress-induced aging of the skin and to improve dermal appearance and youthfubiess.
  • Reactive oxidizing species include superoxide, hydroxyl radicals, hydrogen peroxide, lipid peroxyl, oxoperoxinitrate, among others. Many of these are required for normal cell functions, but when present in excess, cells can become oxidatively stressed. Oxidative stress causes cellular damage, resulting in alteration of the redox state (e.g., depletion of nucleotide coenzymes and disturbance of sulfhydiyl-containing enzymes), and saturation and destruction of the antioxidant defense and DNA repair system.
  • oxidizing species e.g., reactive oxygen species and reactive nitrogen species
  • reactive oxidizing species may serve as intracellular messengers in gene regulatory and signal transduction pahtways at cellular level.
  • alterations in oxidative metabolism have long been known to result in protein- protein and protein-DNA interactions, consequently reactive oxidizing species are important in the regulation of promoter activities (gene regulation), and more complex cellular processes.
  • the compositions described herein can be utilized to modulate oxidative stress that can occur in a wide variety of situations.
  • modulating oxidative stress can result in enhanced wound healing, as well as the reduction and/or elimination of side effects of cosmetic procedures.
  • Modulating oxidative stress can also result in enhanced repair, regeneration, and/or replacement, of cells, tissues, and/or organs (e.g., kidneys, liver, pancreas, skin, and other internal and external organs) either in vitro or in vivo, as well as enhanced preservation of such organs for transplantation, implantation, or scientific research.
  • organs e.g., kidneys, liver, pancreas, skin, and other internal and external organs
  • the present invention provides a method for modulating the oxidative stress level in a cell.
  • the method includes contacting the cell with an active agent under conditions effective to change (either to increase or decrease, but preferably, to decrease) or prevent an increase in the level of at least one oxidizing species in the cell (relative to the same cell under the same conditions without the oxidative stress regulator).
  • the cell can be in a cell culture, a tissue, an organ, or an organism. Hence, the method can be carried out in vitro or in vivo.
  • the cell can be a mammalian cell, and preferably a human cell.
  • the present invention provides a method for modulating the oxidative stress level in a patient. The method includes administering to the patient an active agent under conditions effective to change (increase or decrease, but preferably, decrease) or prevent an increase in the level of at least one oxidizing species in the patient (relative to the same conditions without the oxidative stress regulator).
  • the level of oxidative stress in a cell can be determined by the level of oxidizing species present, which can be determined by evaluating the abundance of oxidized molecules.
  • the level of at least one oxidizing species (and typically the level of all oxidizing species) in a cell or body fluid can be determined by the previously published method disclosed in R.B. Singh et al., Am. J. Cardiol.. 76, 1233-1238 (1995).
  • the level of increase or decrease in oxidizing activity is typically determined by comparison to a cell or other sample that has not been contacted with a composition described herein. Specific in vitro methods are described in the Examples Section.
  • Yet another method of the invention is a method of modulating the oxidative stress level of the skin of a patient, and preferably treating (prophylactically or therapeutically) oxidative damage to the skin of a patient.
  • the method includes applying to skin a topical formulation (e.g., sun screen) that includes an active agent under conditions effective to change (increase or decrease, but preferably decrease) or prevent an increase in the level of damage to a biomolecule of the patient, such as a DNA, a protein, and or a lipid.
  • the level of oxidative damage to the skin of a patient can be determined by the level of protein oxidation using western blot immunoassays according to the method of E. Shacter et al., Free Radic. Biol. Med..
  • Colostrinin is composed of peptides, the aggregate of which has a molecular weight range between about 5.8 to about 26 kiloDaltons (kDa) determined by polyacrylamide gel electrophoresis. It has a greater concentration of proline than any other amino acid.
  • Ovine colostrinin has been found to have a molecular weight of about 18 kDa and includes three non-covalently linked subunits having a molecular weight of about 6 kDa and has about 22 wt-% proline.
  • Ovine colostrinin has also been shown to contain the following number of residues per subunit: lysine - 2; histidine - 1; arginine - 0; aspartic acid - 2; threonine - 4; serine - 3; glutamic acid - 6; proline - 11; glycine - 2; alanine - 0; valine - 5; metWonine - 2; isoleucine - 2; leucine - 6; tyrosine - 1; phenylalanine - 3 ; and cysteine - 0.
  • Colostrinin has been found to include a number of peptides ranging from 3 amino acids to 22 amino acids or more. These can be obtained by various known techniques, including isolation and purification involving eletrophoresis and synthetic techniques. The specific method of obtaining colostrinin and SEQ ID NO:31 is described in International Publication No. WO-A-98/14473. Using HPLC and Edelman Degradation, over 30 constituent peptides of colostrinin have been identified, which can be classified into several groups: (A) those of unknown precursor; (B) those having a ⁇ -casein homologue precursor; (C) those having a ⁇ -casein precursor; and (D) those having an annexin precursor.
  • A those of unknown precursor
  • B those having a ⁇ -casein homologue precursor
  • C those having a ⁇ -casein precursor
  • D those having an annexin precursor.
  • These peptides are described in International Patent Application PCT/GBOO/02128, filed June 2, 2000, claiming priority to June 2, 1999, and can be synthesized according to the general method described in the Examples Section.
  • These peptides i.e., constituent peptides of colostrinin
  • MQPPPLP SEQ ID NO:l
  • LQTPQPLLQNMMEPQGD SEQ ID ⁇ O:2
  • DQPPDNEKPDLQPFQNQS SEQ ID ⁇ O:3
  • LFFFLPVVNNLP SEQ ID ⁇ O:4
  • DLEMPVLPVEPFPFV SEQ ID NO:5
  • MPQNFYKLPQM SEQ ID NO:6
  • VLEMKFPPPPQETVT SEQ ID NO:7
  • LKPFPKLKNENFPFP SEQ ID ⁇ O:8
  • NVMEV SEQ ID ⁇ O:9
  • TQTPVVVPPF (SEQ ID NO:20); LQPEIMGVPKVKETMVPK (SEQ ID NO:21); HKEMPFPKYPVEPFTESQ (SEQ ID NO:22); SLTLTDVEKLHLPLPLVQ (SEQ ID NO:23); SWMHQPP (SEQ ID NO:24); QPLPPTVMFP (SEQ ID NO:25); PQSVLS (SEQ ID NO:26); LSQPKNLPNPQKANPQRDMPIQ (SEQ ID ⁇ O:27); AFLLYQE (SEQ ID NO:28); RGPFPILN (SEQ ID ⁇ O:29); ATFNRYQDDHGEEILKSL (SEQ ID NO:30); NESYNPLFP (SEQ ID ⁇ O:31); FLLYQEPNLGPVR (SEQ ID ⁇ O:32); LNF (SEQ ID NO:33); and MHQPPQPLPPTVMFP (SEQ ID NO:34).
  • those of unknown precursor include SEQ ID NOs:2, 6, 7, 8, 10, 11, 14, and 33;
  • those having a ⁇ -casein homologue precursor include SEQ IDNOs:l, 3, 4, 5, 9, 12, 13, 15, 16, 17, and 31 ;
  • those having a ⁇ -casein precursor include SEQ ID NOs: 18 (casein amino acids 74-83), 19 (casein amino acids 84-92), 20 (casein amino acids 93-102), 21 (casein amino acids 103-120), 22 (casein amino acids 121-138), 23 (casein amino acids 139-156), 24 (casein amino acids 157-163), 25 (casein amino acids 164-173), 26 (casein amino acids 174-179), 27 (casein amino acids 180-201), 28 (casein amino acids 202-208), 29 (casein amino acids 214-222), 32 (casein amino acids 203-214), and 34 (casein amino acids 159-173); and (D) those having an annexin precursor include SEQ ID NOs: 18 (casein amino acids
  • a preferred group of such peptides includes: MQPPPLP (SEQ ID NO:l); LQTPQPLLQNMMEPQGD (SEQ ID ⁇ O:2); DQPPDNEKPDLQPFQNQS (SEQ ID ⁇ O:3); LFFFLPVVNVLP (SEQ ID NO:4); DLEMPVLPVEPFPFV (SEQ ID NO:5); MPQNFYKLPQM (SEQ ID NO:6); VLEMKFPPPPQETNT (SEQ ID ⁇ O:7); LKPFPKLKNENFPFP (SEQ ID ⁇ O:8); and combinations thereof.
  • polypeptides of SEQ ID NOs: 1 -34 can be in their free acid form or they can be amidated at the C-terminal carboxylate group.
  • the present invention also includes analogs of the polypeptides of SEQ ID NOs: 1-34, which includes polypeptides having structural similarity with SEQ ID NOs: 1-34. These peptides can also form a part of a larger peptide.
  • An "analog" of a polypeptide includes at least a portion of the polypeptide, wherein the portion contains deletions or additions of one or more contiguous or noncontiguous amino acids, or containing one or more amino acid substitutions. An “analog” can thus include additional amino acids at one or both of the terminii of the polypeptides listed above.
  • Substitutes for an amino acid in the polypeptides of the invention are preferably conservative substitutions, which are selected from other members of the class to which the amino acid belongs.
  • conservative substitutions which are selected from other members of the class to which the amino acid belongs.
  • an amino acid belonging to a grouping of amino acids having a particular size or characteristic can generally be substituted for another amino acid without substantially altering the structure of a polypeptide.
  • conservative amino acid substitutions are defined to result from exchange of amino acids residues from within one of the following classes of residues: Class I: Ala, Gly, Ser, Thr, and Pro (representing small aliphatic side chains and hydroxyl group side chains); Class II: Cys, Ser, Thr and Tyr (representing side chains including an -OH or -SH group); Class HI: Glu, Asp, Asn and Gin (carboxyl group containing side chains): Class IV: His, Arg and Lys (representing basic side chains); Class V: lie, Val, Leu, Phe and Met (representing hydrophobic side chains); and Class VI: Phe, Trp, Tyr and His (representing aromatic side chains).
  • the classes also include related amino acids such as 3Hyp and 4Hyp in Class I; homocysteine in Class II; 2-aminoadipic acid, 2-aminopimelic acid, ⁇ -carboxyglutamic acid, ⁇ - carboxyaspartic acid, and the corresponding amino acid amides in Class IE; o ithine, homoarginine, N-methyl lysine, dimethyl lysine, trimethyl lysine, 2,3- diaminopropionic acid, 2,4-diaminobutyric acid, homoarginine, sarcosine and hydroxylysine in Class IV; substituted phenylalanines, norleucine, norvalhie, 2- aminooctanoic acid, 2-aminoheptanoic acid, statine and ⁇ -valine in Class V; and naphthylalanines, substituted phenylalanines, tetrahydroisoquinoline-3- carboxylic acid, and hal
  • the active analogs of colostrinin and its constituent peptides include polypeptides having a relatively large number of proline residues.
  • a "large number" preferably means that a polypeptide includes at least about 15% proline (by number), and more preferably at least about 20% proline (by number).
  • active analogs include more proline residues than any other amino acid.
  • active analogs of colostrinin and its constituent peptides include polypeptides having structural similarity.
  • Structural similarity is generally determined by aligning the residues of the two amino acid sequences to optimize the number of identical amino acids along the lengths of their sequences; gaps in either or both sequences are permitted in making the alignment in order to optimize the number of identical amino acids, although the amino acids in each sequence must nonetheless remain in their proper order.
  • two amino acid sequences are compared using the Blastp program, version 2.0.9, of the BLAST 2 search algorithm, available at http://www.ncbi.nlm.nih.gov/gorf'bl2.html.
  • an active analog of colostrinin or its constituent peptides has a structural similarity to colostrinin or one or more of its constituent peptides (preferably, one of SEQ ID NOs: 1-34) of at least about 70% identity, more preferably, at least about 80% identity, and most preferably, at least about 90% identity.
  • Colostrinin or any combination of its peptide components or active analogs thereof can be derived (preferably, isolated and purified) naturally such as by extraction from colostrum or can be synthetically constructed using known peptide polymerization techniques.
  • the peptides of the invention may be synthesized by the solid phase method using standard methods based on either t-butyloxycarbonyl (BOC) or 9-fluorenylmethoxy-carbonyl (FMOC) protecting groups. This methodology is described by G.B. Fields et al. in Synthetic Peptides: A User's Guide, W.M. Freeman & Company, New York, NY, pp. 77-183 (1992).
  • gene sequence encoding the colostrinin peptides or analogs thereof can be constructed by known techniques such as expression vectors or plasmids and transfected into suitable microorganisms that will express the DNA sequences thus preparing the peptide for later extraction from the medium in which the microorganism are grown.
  • U.S. Patent No. 5,595,887 describes methods of forming a variety of relatively small peptides through expression of a recombinant gene construct coding for a fusion protein which includes a binding protein and one or more copies of the desired target peptide. After expression, the fusion protein is isolated and cleaved using chemical and/or enzymatic methods to produce the desired target peptide.
  • the peptides used in the methods of the present invention may be employed in a monovalent state (i.e., free peptide or a single peptide fragment coupled to a carrier molecule).
  • the peptides may also be employed as conjugates having more than one (same or different) peptide fragment bound to a single carrier molecule.
  • the carrier may be a biological carrier molecule (e.g., a glycosaminoglycan, a proteoglycan, albumin or the like) or a synthetic polymer (e.g., a polyalkyleneglycol or a synthetic chromatography support).
  • a synthetic polymer e.g., a polyalkyleneglycol or a synthetic chromatography support
  • ovalbumin, human serum albumin, other proteins, polyethylene glycol, or the like are employed as the carrier.
  • Such modifications may increase the apparent affinity and/or change the stability of a peptide.
  • peptide/carrier molecule conjugates may be prepared by treating a mixture of peptides and carrier molecules with a coupling agent, such as a carbodiimide.
  • the coupling agent may activate a carboxyl group on either the peptide or the carrier molecule so that the carboxyl group can react with a nucleophile (e.g., an amino or hydroxyl group) on the other member of the peptide/carrier molecule, resulting in the covalent linkage of the peptide and the carrier molecule.
  • conjugates of a peptide coupled to ovalbumin may be prepared by dissolving equal amounts of lyophilized peptide and ovalbumin in a small volume of water.
  • l-ethyl-3-(3- dime ylamino-propyl)-carboiimide hydrochloride (EDC; ten times the amount of peptide) is dissolved in a small amount of water.
  • EDC l-ethyl-3-(3- dime ylamino-propyl)-carboiimide hydrochloride
  • the EDC solution was added to the peptide/ovalbumin mixture and allowed to react for a number of hours.
  • the mixture may then dialyzed (e.g., into phosphate buffered saline) to obtain a purified solution of peptide/ovalbumin conjugate.
  • Peptide/carrier molecule conjugates prepared by this method typically contain about 4 to 5 peptides per ovalbumin molecule.
  • the present invention also provides a composition that includes one or more active agents (i.e., colostrinin, at least one constituent peptide thereof, or active analog thereof) of the invention and one or more carriers, preferably a pharmaceutically acceptable carrier.
  • the methods of the invention include administering to, or applying to the skin of, a patient, preferably a mammal, and more preferably a human, a composition of the invention in an amount effective to produce the desired effect.
  • the active agents of the present invention are formulated for enteral administration (oral, rectal, etc) or parenteral administration (injection, internal pump, etc.).
  • the administration can be via direct injection into tissue, interarterial injection, intervenous injection, or other internal administration procedures, such as through the use of an implanted pump, or via contacting the composition with a mucus membrane in a carrier designed to facilitate transmission of the composition across the mucus membrane such as a suppository, eye drops, inhaler, or other similar administration method or via oral administration in the form of a syrup, a liquid, a pill, capsule, gel coated tablet, or other similar oral administration method.
  • the active agents can be incorporated into an adhesive plaster, a patch, a gum, and the like, or it can be encapsulated or incorporated into a bio-erodible matrix for controlled release.
  • the carriers for internal administration can be any carriers commonly used to facilitate the internal administration of compositions such as plasma, sterile saline solution, IV solutions or the like.
  • Carriers for administration through mucus membranes can be any well-known in the art.
  • Carriers for administration oral can be any carrier well-known in the art.
  • the formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulations.
  • Formulations suitable for parenteral administration conveniently include a sterile aqueous preparation of the active agent, or dispersions of sterile powders of the active agent, which are preferably isotonic with the blood of the recipient.
  • Isotonic agents that can be included in the liquid preparation include sugars, buffers, and sodium chloride.
  • Solutions of the active agent can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions of the active agent can be prepared in water, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, glycerol esters, and mixtures thereof.
  • the ultimate dosage form is sterile, fluid, and stable under the conditions of manufacture and storage. The necessary fluidity can be achieved, for example, by using liposomes, by employing the appropriate particle size in the case of dispersions, or by using surfactants.
  • Sterilization of a liquid preparation can be achieved by any convenient method that preserves the bioactivity of the active agent, preferably by filter sterilization.
  • Preferred methods for preparing powders include vacuum drying and freeze drying of the sterile injectible solutions.
  • Subsequent microbial contamination can be prevented using various antimicrobial agents, for example, antibacterial, antiviral and antifungal agents including parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Absorption of the active agents over a prolonged period can be achieved by including agents for delaying, for example, aluminum monostearate and gelatin.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as tablets, troches, capsules, lozenges, wafers, or cachets, each containing a predetermined amount of the active agent as a powder or granules, as liposomes containing the active agent, or as a solution or suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, an emulsion, or a draught.
  • the amount of active agent is such that the dosage level will be effective to produce the desired result in the subject.
  • Nasal spray formulations include purified aqueous solutions of the active agent with preservative agents and isotonic agents.
  • Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes.
  • Formulations for rectal or vaginal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids.
  • Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye.
  • Topical formulations include the active agent dissolved or suspended in one or more media such as mineral oil, DMSO, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
  • Useful dosages of the active agents can be determined by comparing their in vitro activity and the in vivo activity in animal models. Methods for extrapolation of effective dosages in mice, and other animals, to humans are known in the art; for example, see U.S. Patent No. 4,938,949.
  • the tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, fructose, lactose or aspartame; and a natural or artificial flavoring agent.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, fructose, lactose or aspartame
  • a natural or artificial flavoring agent such
  • Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form.
  • tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar and the like.
  • a syrup or elixir may contain one or more of a sweetening agent, a preservative such as methyl- or propylparaben, an agent to retard crystallization of the sugar, an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol, a dye, and flavoring agent.
  • the material used in preparing any unit dosage form is substantially nontoxic in the amounts employed.
  • the active agent may be incorporated into sustained-release preparations and devices.
  • the active agents of the present invention can be used in cosmetic formulations (e.g., skincare cream, sunscreen, decorative make-up products, and other dermatological compositions) in various pharmaceutical dosage forms, and especially in the form of oil-in- water or water-in-oil emulsions, solutions, gels, or vesicular dispersions.
  • cosmetic formulations may take the form of a cream which can be applied either to the face or to the scalp and hair, as well as to the human body. They can also serve as a base for a lipstick.
  • Particularly preferred cosmetic formulations can also include additives such as are usually used in such formulations, for example preservatives, bactericides, perfumes, antifoams, dyes, pigments which have a coloring action, surfactants, thickeners, suspending agents, fillers, moisturizers and/or humectants, fats, oils, waxes or other customary constituents of a cosmetic formulation, such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents, or silicone derivatives.
  • Cosmetic formulations typically include a lipid phase and often an aqueous phase.
  • the lipid phase can advantageously be chosen from the following group of substances: mineral oils, mineral waxes oils, such as triglycerides of capric or of caprylic acid, but preferably castor oil; fats, waxes and other natural and synthetic fatty substances, preferably esters of fatty acids with alcohols of low C number, for example with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids of low C number or with fatty acids; alkyl benzoates; silicone oils, such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof.
  • mineral oils mineral waxes oils, such as triglycerides of capric or of caprylic acid, but preferably castor oil
  • fats, waxes and other natural and synthetic fatty substances preferably esters of fatty acids with alcohols of low C number, for example with isopropanol, prop
  • the aqueous phase of the formulations according to the invention advantageously includes alcohols, diols or polyols of low C number and ethers thereof, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products, furthermore alcohols of low C number, for example ethanol, isopropanol, 1,2-propanediol and glycerol, and, in particular, one or more thickeners, which can advantageously be chosen from the group consisting of silicon dioxide, aluminium silicates, polysaccharides and derivatives thereof, for example hyaluronic acid, xanthan gum and hydroxypropyhnethylcellulose, particularly advantageously from the group consisting of poly-acrylates, preferably a polyacrylate
  • a preferred cosmetic formulation is a sunscreen composition.
  • a sunscreen can advantageously additionally include at least one further UVA filter and/or at least one further UVB filter and/or at least one inorganic pigment, preferably an inorganic micropigment.
  • Ther UVB filters can be oil-soluble or water-soluble.
  • Advantageous oil-soluble UVB filter substances are, for example: 3-benzylidenecamphor derivatives, preferably 3-(4-methylbenzylidene)camphor and 3-benzylidenecamphor; 4-aminobenzoic acid derivatives, preferably 2- ethylhexyl 4-(dimethylamino)benzoate and amyl 4-(dm ⁇ ethylamino)benzoate; esters of cinnamic acid, preferably 2-ethylhexyl 4-methoxycinnamate and isopentyl 4-methoxycinnamate; derivatives of benzophenone, preferably 2- hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'- methylbenzophenone and 2,2'-dihydroxy-4-methoxybenzophenone; esters of benzalmalonic acid, preferably di(2-ethylhexyl) 4-methoxybenzalmalonate.
  • 4-aminobenzoic acid derivatives
  • Advantageous water-soluble UVB filter substances are, for example: salts of 2- phenylbenzimidazole-5-sulphonic acid, such as its sodium, potassium or its triethanolammonium salt, and the sulphonic acid itself; sulphonic acid derivatives of benzophenones, preferably 2-hydroxy-4-methoxybenzophenone- 5-sulphonic acid and salts thereof; sulphonic acid derivatives of 3- benzylidenecamphor, such as, for example, 4-(2-oxo-3-bornylidenemethyl) benzenesulphonic acid, 2-methyl-5-(2-oxo-3-bornylidenemethyl) benzenesulphonic acid and salts thereof.
  • the list of further UVB filters mentioned which can be used in combination with the active agent(s) according to the invention is not of course intended to be limiting.
  • the coupling step was carried out as follows: a. Prepare the following solution: 1 mmole Fmoc (i.e. fluorenyhnethyloxycarbonyl) amino acid 2.1 ml of 0.45 M HBTU HOBT (1 mmol) (2-( 1 H-benzotriazol- 1 -yl)- 1,1,3,3 -tetramethyluronium hexafluorophosphate/N-hydroxybenzotriazole-H 2 O) 348 ⁇ l of DIEA (2 mmol) (diisopropylethylamine); and b. Add the solution to the resin and shake for a minimum of 30 minutes.
  • Fmoc i.e. fluorenyhnethyloxycarbonyl
  • the molecular weight of the synthesised peptides was checked by Matrix- Assisted Laser Desorption Time-of-Flight Mass Spectroscopy (LDMS), and the purity was checked by HPLC using a C- 18, 300 Angstrom, 5 ⁇ m column.
  • LDMS Matrix- Assisted Laser Desorption Time-of-Flight Mass Spectroscopy
  • PC 12 cell line derived from medullary pheochromocytoma cells and immortalized human endothelial cells (ECN304: developed from the umbilical vein; K. Takashashi et al., In Vitro Cell Dev. Biol..25, 265-274, 1990) were used to undertake studies described bellow.
  • PC 12 cells were obtained from the American Type Culture Collection.
  • ECV304 cells were kindly provided by Dr. Goto (Patology Division, National Cancer Institute, Tokyo, Japan).
  • PC12 and ECV304 cells were cultured in
  • RPMI-1640 and M199 medium were supplemented with 10% fetal bovine serum (Hyclone Laboratories Inc., Logan, UT), penicillin (100 U/ml) and streptomycin (100 ⁇ g/ml).
  • fetal bovine serum Hyclone Laboratories Inc., Logan, UT
  • penicillin 100 U/ml
  • streptomycin 100 ⁇ g/ml
  • Oxidation may be achieved by reaction with H 2 O 2 in the presence of peroxidase, cytochrome c, or Fe 2+ .
  • H 2 DCF may also be oxidized by peroxynitrite, superoxide and nitric oxide (M. Tsuchiya et al., Methods EnzymoL.233. 128-140 (1994); C.P. LeBel et al., Chem. Res. Toxicol. 5, 227-231 (1992); G. Rothe et al., J. Leukoc. Biol., 47, 440-448 (1990); J.A. Royall et al., Arch. Biochem. Biophys.. 302. 348-355 (1993); and N.W. Kooy et al., Free Radic. Res..27, 245-254 (1997).
  • H 2 DCF-DA final concentration of 2.5 ⁇ M
  • H 2 O 2 25 ⁇ M
  • a change in fluorescence intensity were determined as a function of time by flow cytometry.
  • H 2 DCF-DA-loaded cells in parallel were treated with H 2 O 2 (12.5, 25, 50 ⁇ M) alone.
  • a typical histogram is shown in Figure 1C.
  • antioxidants N-acetyl-L-cysteine and butylated hydroxyanisole were used. All assays were carried out in phenol red-free media, containing 1% fetal bovine serum and 10 mM HEPES (pH: 7.4).
  • Flow cytometry was performed on a FACScan flow cytometer (Becton Dickinson).
  • the excitation and emission wavelength were 485 nanometers (nm) and 530 nm, respectively.
  • Instrument calibration was performed daily using Calibrate Beads (BDIS) according to the recommendation of the manufacturer (Becton Dickinson). Each sample was run in the setup mode until a cell acquisition gate was established, at which point only events in this gate were acquired. 10,000 events were collected in all studies.
  • Cell viability assay Cell viability was determined by flow cytometry after staining cells (10 6 ) with 1 ⁇ M propidium iodine. Cell suspensions with a viability of more than 95%, were used. Cell cycle stage distribution was determined by DNA content measurement. A typical histogram is shown in Figure 2.
  • N-acetyl-L-cysteine, catalase, butylated hydroxyanisole and H 2 O 2 were purchased from Sigma Chemicals Co. (St. Louis, MO).
  • DCF, 2'-7'- dichlorofluorescin diacetate, and propidium iodine were purchased from Molecular Probes (Eugene, OR).
  • Catalase from beef liver, 65,000 U/mg crystalline suspension in water) was obtained from Boehringer-Mannheim (Indianapolis, IN). Stock solutions were prepared according to manufacturers' recommendations.
  • RPMI- 1640 and Ml 99 and other medium supplements were purchased from Gibco-BRL, and fetal bovine serum was obtained from Hyclone, Inc.
  • SEQ ID NO:l The oxidative stress regulating activity of SEQ ID NO:l, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:3, SEQ ID NO:2, SEQ ID NO:4, and SEQ ID NO:5, SEQ ID NO:31, cholostrinin, and colostrum was similar in both PC 12 (medullary pheochromocytoma) and ECV304 (immortalized human endothelial cells developed from the umbilical vein) cells indicating that their effect is not cell type specific (in this report data generated using PC 12 cells are shown).
  • PC 12 medullary pheochromocytoma
  • ECV304 immortalized human endothelial cells developed from the umbilical vein

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Abstract

L'invention concerne des procédés utilisant des compositions renfermant la colostrinine, un peptide constitutif de celle-ci, un analogue actif de celle-ci, ainsi que des combinaisons de ceux-ci, comme régulateurs du stress oxydatif.
PCT/US2000/022776 2000-08-17 2000-08-17 Utilisation de la colostrinine, de ses peptides constitutifs, et de ses analogues comme regulateurs du stress oxydatif WO2002013850A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037851A3 (fr) * 2002-10-22 2004-12-09 Univ Texas Utilisation de colostrinine, peptides constitutifs de celle-ci, et analogues de celle-ci utilises en tant que modulateurs de molecules de signalisation intracellulaire et inhibiteurs de l'apoptose
US6903068B1 (en) 1999-08-17 2005-06-07 Board Of Regents, The University Of Texas System Use of colostrinin, constituent peptides thereof, and analogs thereof for inducing cytokines
US6939847B2 (en) 1999-08-17 2005-09-06 Board Of Regents, The University Of Texas System Use of colostrinin, constituent peptides thereof, and analogs thereof, as oxidative stress regulators
US7119064B2 (en) 1999-08-17 2006-10-10 Board Of Regents, The University Of Texas System Use of colostrinin, constituent peptides thereof, and analogs thereof as modulators of intracellular signaling molecules
WO2006068480A3 (fr) * 2004-12-23 2007-01-04 Campina Nederland Holding Bv Hydrolysat de proteines enrichi en peptides inhibant dpp-iv et utilisation de ce dernier
US8431531B2 (en) 2005-11-30 2013-04-30 Campina Nederland Holding B.V. Methods for stimulating glucagon-like peptide-1(GLP-1) secretion and treatments comprising same

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JPH0641191A (ja) * 1992-03-04 1994-02-15 Calpis Food Ind Co Ltd:The ペプチド及びこれを含む生理活性剤
WO1998014473A1 (fr) * 1996-10-03 1998-04-09 Ludwick Hirszfeld Institute Of Immunology And Experimental Therapy Polish Academy Of Sciences Colostrinine et utilisations de celle-ci
WO2000075173A2 (fr) * 1999-06-02 2000-12-14 Regen Therapeutics Plc Peptides
WO2001012650A2 (fr) * 1999-08-17 2001-02-22 The University Of Texas System Utilisation de la colostrinine, de ses peptides constitutifs, et de ses analogues comme regulateurs du stress oxydatif

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Publication number Priority date Publication date Assignee Title
JPH0641191A (ja) * 1992-03-04 1994-02-15 Calpis Food Ind Co Ltd:The ペプチド及びこれを含む生理活性剤
WO1998014473A1 (fr) * 1996-10-03 1998-04-09 Ludwick Hirszfeld Institute Of Immunology And Experimental Therapy Polish Academy Of Sciences Colostrinine et utilisations de celle-ci
WO2000075173A2 (fr) * 1999-06-02 2000-12-14 Regen Therapeutics Plc Peptides
WO2001012650A2 (fr) * 1999-08-17 2001-02-22 The University Of Texas System Utilisation de la colostrinine, de ses peptides constitutifs, et de ses analogues comme regulateurs du stress oxydatif

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DATABASE WPI Section Ch Week 199411, Derwent World Patents Index; Class B04, AN 1994-089332, XP002155477 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6903068B1 (en) 1999-08-17 2005-06-07 Board Of Regents, The University Of Texas System Use of colostrinin, constituent peptides thereof, and analogs thereof for inducing cytokines
US6939847B2 (en) 1999-08-17 2005-09-06 Board Of Regents, The University Of Texas System Use of colostrinin, constituent peptides thereof, and analogs thereof, as oxidative stress regulators
US7119064B2 (en) 1999-08-17 2006-10-10 Board Of Regents, The University Of Texas System Use of colostrinin, constituent peptides thereof, and analogs thereof as modulators of intracellular signaling molecules
WO2004037851A3 (fr) * 2002-10-22 2004-12-09 Univ Texas Utilisation de colostrinine, peptides constitutifs de celle-ci, et analogues de celle-ci utilises en tant que modulateurs de molecules de signalisation intracellulaire et inhibiteurs de l'apoptose
WO2006068480A3 (fr) * 2004-12-23 2007-01-04 Campina Nederland Holding Bv Hydrolysat de proteines enrichi en peptides inhibant dpp-iv et utilisation de ce dernier
JP2008525430A (ja) * 2004-12-23 2008-07-17 カンピナ ネーデルランド ホールディング ビー．ブイ． Ｄｐｐ−ｉｖを阻害するペプチド中に濃縮されたタンパク質の加水分解物及びその使用
US8273710B2 (en) 2004-12-23 2012-09-25 Campina Nederland Holding B.V. Protein hydrolysate enriched in peptides inhibiting DPP-IV and their use
US8431531B2 (en) 2005-11-30 2013-04-30 Campina Nederland Holding B.V. Methods for stimulating glucagon-like peptide-1(GLP-1) secretion and treatments comprising same

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