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Use of colostrinin, constituent peptides thereof, and analogs thereof as modulators of intracellular signaling moleculesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Lymphokine, InterleukinUse of colostrinin, constituent peptides thereof, and analogs thereof as modulators of intracellular signaling molecules description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070065399, Use of colostrinin, constituent peptides thereof, and analogs thereof as modulators of intracellular signaling molecules. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority to U.S. Provisional Application Ser. No. 60/420,369, filed Oct. 22, 2002, and is a Continuation-In-Part of U.S. patent application Ser. No. 10/281,652, filed on Oct. 28, 2002, which is a Divisional of U.S. patent application Ser. No. 09/641,803, filed Aug. 17, 2000 (issued on Dec. 31, 2002 as U.S. Pat. No. 6,500,798), which claims the benefit of U.S. Provisional Application Ser. No. 60/149,310, filed Aug. 17, 1999, all of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] 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. [0003] Colostrum also includes or contains a proline-rich polypeptide aggregate or complex, which is referred to as colostrinin (CLN). 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. WO-A-98/14473. [0004] Although certain uses for colostrinin have been identified, it would represent an advancement in the art to discover and disclose other uses for colostrinin, or a component thereof, that are not readily ascertainable from the information currently known about colostrinin or its constituents. SUMMARY OF THE INVENTION [0005] 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 an N-terminal sequence equivalent to an N-terminal sequence of at least one of the colostrinin constituent peptides), and combinations thereof, as modulators of intracellular signaling mechanisms. The signaling molecules discovered to date that are modulated include 4HNE adduct formation, GSH, P53, and JNK. [0006] Furthermore, 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 an N-terminal sequence equivalent to an N-terminal sequence of at least one of the colostrinin constituent peptides), and combinations thereof, in the inhibition of apoptosis. Specifically, the apoptotic (cytotoxic) effect of B amyloid on SH-SY5Y neuronal cells and TNF-alpha. [0007] In one embodiment, the present invention provides a method of modulating an intracellular signaling molecule in a cell. The method includes contacting the cell with a modulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to accomplish at least one of the following: reduce 4HNE-protein adduct formation; inhibit 4HNE-mediated glutathione depletion; inhibit 4HNE-induced activation of p53 protein; or inhibit 4HNE-induced activation of c-Jun NH2-terminal kinases. [0008] In one embodiment, the present invention provides a method of down regulating 4HNE-mediated lipid peroxidation in a cell. The method includes contacting the cell with a modulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, wherein: the active analog is an active analog of a constituent peptide of colostrinin selected from the group of SEQ ID NO:1 through SEQ ID NO:34; the active analog comprises a peptide having an amino acid sequence with at least about 15 percent proline and having at least about 70 percent structural similarity to one or more constituent peptides of colostrinin; and the active analog does not interfere with cellular uptake of redox-sensitive 2',7'-dihydro-dichlorofluorescein-diacetate. [0009] In one embodiment, the present invention provides a method for inhibiting apoptosis in a cell (typically, due to DNA damage). The method includes contacting the cell with an effective amount of an apoptosis inhibitor selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof. [0010] In another embodiment of inhibiting apoptosis in a cell, a method is provided that includes contacting the cell with an effective amount of an apoptosis inhibitor selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, wherein; the active analog is an active analog of a constituent peptide of colostrinin selected from the group of SEQ ID NO:1 through SEQ ID NO:34; the active analog comprises a peptide having an amino acid sequence with at least about 15 percent proline and having at least about 70 percent structural similarity to one or more constituent peptides of colostrinin; and the active analog does not interfere with cellular uptake of redox-sensitive 2',7'-dihydro-dichlorofluorescein-diacetate. [0011] Other methods of the present invention include protecting against DNA damage in a cell, and reducing the toxic effect of .beta.-amyloid or retinoic acid on a cell. These methods involve contacting the cell with an effective amount of a compound selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof. [0012] The cell can be present in a cell culture, a tissue, an organ, or an organism. For certain embodiments, the cell is a mammalian cell. For certain embodiments, the cell is a human cell. [0013] For certain embodiments, the compound (e.g. modulator such as an apoptosis inhibitor) is a constituent peptide of colostrinin. Preferably, the modulator is selected from the group of MQPPPLP (SEQ ID NO:1), LQTPQPLLQVMMEPQGD (SEQ ID NO:2), DQPPDVEKPDLQPFQVQS (SEQ ID NO:3), LFFFLPVVNVLP (SEQ ID NO:4), DLEMPVLPVEPFPFV (SEQ ID NO:5), MPQNFYKLPQM (SEQ ID NO:6), VLEMKFPPPPQETVT (SEQ ID NO:7), LKPFPKLKVEVFPFP (SEQ ID NO:8), VVMEV (SEQ ID NO:9), SEQP (SEQ ID NO:10), DKE (SEQ ID NO:11), FPPPK (SEQ ID NO:12), DSQPPV (SEQ ID NO:13), DPPPPQS (SEQ ID NO:14), SEEMP (SEQ ID NO:15), KYKLQPE (SEQ ID NO:16), VLPPNVG (SEQ ID NO:17), VYPFTGPIPN (SEQ ID NO:18), SLPQNILPL (SEQ ID NO:19), 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), LSQPKVLPVPQKAVPQRDMPIQ (SEQ ID NO:27), AFLLYQE (SEQ ID NO:28), RGPFPILV (SEQ ID NO:29), ATFNRYQDDHGEEILKSL (SEQ ID NO:30), VESYVPLFP (SEQ ID NO:31), FLLYQEPVLGPVR (SEQ ID NO:32), LNF (SEQ ID NO:33), and MHQPPQPLPPTVMFP (SEQ ID NO:34), and combinations thereof. [0014] As used herein, "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. Thus, a composition that includes "a" polypeptide refers to a composition that includes one or more polypeptides. [0015] "Amino acid" is used herein to refer to a chemical compound with the general formula: NH.sub.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). As used herein, an organic group is a hydrocarbon group that is classified as an aliphatic group, a cyclic group or combination of aliphatic and cyclic groups. The term "aliphatic group" means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example. The term "cyclic group" means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group. The term "alicyclic group" means a cyclic hydrocarbon group having properties resembling those of aliphatic groups. The term "aromatic group" refers to mono- or polycyclic aromatic hydrocarbon groups. As used herein, an organic group can be substituted or unsubstituted. [0016] The terms "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. [0017] The following abbreviations are used throughout the application: TABLE-US-00001 A = Ala = Alanine T = Thr = Threonine V = Val = Valine C = Cys = Cysteine L = Leu = Leucine Y = Tyr = Tyrosine I = Ile = Isoleucine N = Asn = Asparagine P = Pro = Proline Q = Gln = Glutamine F = Phe = Phenylalanine D = Asp = Aspartic Acid W = Trp = Tryptophan E = Glu = Glutamic Acid M = Met = Methionine K = Lys = Lysine G = Gly = Glycine R = Arg = Arginine S = Ser = Serine H = His = Histidine BRIEF DESCRIPTION OF THE DRAWINGS [0018] The invention can be better understood with reference to the following detailed description together with the appended illustrative drawings in which like elements are numbered the same: [0019] FIG. 1. Colostrinin inhibits formation of protein-HNE (i.e., 4-HNE protein) adducts. (A): 4HNE (25 nM); (B): H.sub.2O.sub.2 (100 .mu.M); (C): CLN(10 .mu.g/ml) pre-treatment followed by 4HNE (25 nM) exposure; (D): LAH (10 .mu.g/ml) pre-treatment followed by 4HNE (25 nM) exposure; (E): HNE-protein adducts detected by Western blot analysis. Lane 1, 25 nM; lane 2, 12.5 nM; lane 3, 6.2 nM of 4HNE alone; lanes 4-6, CLN (10 .mu.g/ml) plus 4HNE, 25, 12.5 and 6.2 nM, respectively. [0020] FIG. 2. Colostrinin inhibits 4HNE-induced oxidative stress. (A): 1, control; 2, colostrinin (10 .mu.g/ml); 3, 4HNE (25 nM); 4, 4HNE (25 nM) plus colostrinin (10 .mu.g/ml); 5, lactalbumin hydrolysate (10 .mu.g/ml); 6, lactalbumin hydrolysate (10 .mu.g/ml) plus 4HNE (25 nM). (B): A representative FACS histogram of fluorescence of cells treated with 4HNE (25 nM) and CLN (10 .mu.g/ml) plus 4HNE. [0021] FIG. 3. Effect of CLN on 4HNE-induced loss of intracellular GSH levels. Cells were mock-treated or treated with CLN (or LAH) and/or 4HNE for 30 min, and o-phthalaldehyde-mediated fluorescence was determined as described in Materials and Methods. Open columns: 1, mock-treated; 2, CLN (10 .mu.g/ml)-; 3, LAH (10 .mu.g/ml)-; 4, 4HNE (25 nM)-treated. Filled solid columns: 5, CLN (10 .mu.g/ml) pre- and 4HNE (25 nM)-treated for 30 min; 6, LAH (10 .mu.g/ml) pre- and 4HNE (25 nM)-treated for 30 min. Continue reading about Use of colostrinin, constituent peptides thereof, and analogs thereof as modulators of intracellular signaling molecules... 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