| Antimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormone -> Monitor Keywords |
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Antimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormoneRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 7 Or 8 Peptide Repeating Units In Known Peptide ChainAntimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormone description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060111300, Antimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormone. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to new pharmaceutical compositions useful as antimicrobial agents, including, for example, for use in reducing the viability of microbes, reducing the germination of yeasts, killing microbes without reducing the killing of microbes by human neutrophils, for treating inflammation in which there is microbial infection without reducing microbial killing, and for increasing the accumulation of cAMP in microbes. More particularly, this invention relates to antimicrobial agents including amino acid sequences derived from alpha-melanocyte-stimulating hormone (.alpha.-MSH) and biologically functional equivalents thereof. BACKGROUND OF THE INVENTION [0002] Mucosal secretions, phagocytes, and other components of the nonspecific (innate) host defense system initiate the response to microbial penetration before time-consuming adaptive immunity starts. Survival of plants and invertebrates, which lack adaptive immunity, illustrates effectiveness of host defense based on such innate mechanisms. [0003] Endogenous antimicrobial peptides are significant in epithelia, the barrier to environmental challenge that provides the first line of defense against pathogens. Production of natural antimicrobial peptides by phagocytes has been recognized for a long time. These natural antimicrobial peptides generally have a broad spectrum of activity against bacteria, fungi, and viruses. Martin, E., Ganz, T., Lehrer, R. I., Defensins and Other Endogenous Peptide Antibiotics of Vertebrates, J. Leukoc. Biol. 58, 128-136 (1995); Ganz, T., Weiss, J., Antimicrobial Peptides of Phagocytes and Eithelia, Sem. Hematol. 34, 343-354 (1997). [0004] The search for antimicrobial peptides, however, has been painfully difficult and slow. A rare and difficult find has been bactericidal/permeability-increasing protein ("BPI"), which has been used successfully to treat children with severe meningococcal sepsis. Giroir, B. P., Quint, P. A., Barton, P., Kirsh, E. A., Kitchen, L., Goldstein, B., Nelson, B. J., Wedel, N. I., Carrol, S. F., Scannon, P. J., Preliminary Evaluation of Recombinant Amino-terminal Fragment of Human Bactericidal/Permeability-increasing, Protein in Children with Severe Meningococcal Sepsis, Lancet 350,1439-1443 (1997). [0005] It would be an important advance in the science to identify the most active amino acid sequences responsible for broad spectrum antimicrobial activity, which would also be useful in new prophylactic and therapeutic antimicrobial treatments. SUMMARY OF INVENTION [0006] According to the approach of the invention, the existence of homologs of vertebrate antimicrobial peptides in invertebrates suggests that such peptides are ancestral components of the host defense system. Some of these peptides, or their synthetic homologs, might be suggested for use as therapeutic agents for controlling microbes. [0007] Alpha-melanocyte-stimulating hormone (".alpha.-MSH") is an ancient 13 amino acid peptide produced by post-translational processing of the larger precursor molecule proopiomelanocortin and shares the 1-13 amino acid sequence with adrenocorticotropic hormone ("ACTH"). Eberle, A. N., The Melanotropins, Karger, Basel, Switzerland (1988). .alpha.-MSH is known to be secreted by many cell types including pituitary cells, monocytes, melanocytes, and keratinocytes. Lipton, J. M., Catania, A., Anti-inflammatory Influence of the Neuroimmunomodulator .alpha.-MSH, Immunol. Today 18, 140-145 (1997) .alpha.-MSH occurs in the skin of rats and in the human epidermis. Thody, A. J., Ridley, K., penny, R. J., Chalmers, R., Fisher, C., Shuster, S., MSH Peptides Are Present in Mammalian Skin, Peptides 4, 813-816 (1983). .alpha.-MSH is also found in the mucosal barrier of the gastrointestinal tract in intact and hypophysectomized rats. Fox, J. A. E. T., Kraicer, J., Immunoreactive .alpha.-Melanocyte Stimulating Hormone, its Distribution in the Gastrointestinal Tract of Intact and Hypophysectomized Rats, Life. Sci. 28,2127-2132 (1981). We recently found that human duodenal cells produce .alpha.-MSH in culture. Catania et al., unpublished. The presence in barrier organs of this ancient peptide, relatively invariant in amino acid sequence over approximately 300 million years, suggests that it may have a role in the nonspecific (innate) host defense system. [0008] .alpha.-Melanocyte-stimulating hormone is known to have potent antipyretic and anti-inflammatory properties. Lipton, J. M., Antipyretic and Anti-inflammatory Lys Pro Val Compositions and Method of Use, U.S. Pat. No. 5,028,592, issued Jul. 2, 1991, which is incorporated herein by reference in its entirety; Lipton, J. M., Antipyretic and Anti-inflammatory Lys Pro Val Compositions and Method of Use, U.S. Pat. No. 5,157,023, Oct. 20, 1992, which is incorporated herein by reference in its entirety; Catania, A., Lipton, J. M., .alpha.-Melanocyte Stimulating Hormone in the Modulation of Host Reactions, Endocr. Rev; 14,564-576(1993); Lipton, J. M., Catania, A., Anti-inflammatory Influence of the Neuroimmunomodulator .alpha.-MSH, Immunol. Today 18, 140-145 (1997). .alpha.-MSH reduces production of proinflammatory mediators by host cells in vitro. Rajora, N., Ceriani, G., Catania, A., Star, R. A., Murphy, M. T., Lipton, J. M., .alpha.-MSH Production, Receptors, and Influence on Neopterin, in a Human Monocyte/macrophage Cell Line, J. Leukoc. Biol. 59, 248-253 (1996); Star, R. A., Rajora, p., Huang, J., Stock, R. C., Catania, A., Lipton, J. M., Evidence of Autocrine Modulation of Macrophage Nitric Oxide Synthase by .alpha.-MSH, Proc. Natl. Acad. Sci. (USA) 92, 8016-8020(1995). .alpha.-MSH also reduces production of local and systemic reactions in animal models of inflammation. Lipton, J. M., Ceriani, G., Macaluso, A., McCoy, D., Carnes, K., Biltz, J., Catania, A., Anti-inflammatory Effects of the Neuropeptide .alpha.-MSH in Acute, Chronic, and Systemic Inflammation, Ann. N.Y. Acad. Sci. 741, 137-148 (1994); Rajora, N., Boccoli, G., Burns, D., Sharma, S., Catania, A., Lipton, J. M., .alpha.-MSH Modulates Local and Circulating Tumor Necrosis Factor A in Experimental Brain Inflammation, J. Neurosci. 17, 2181-2186 (1997). The "core" .alpha.-MSH sequence (4-10) has learning and memory behavioral effects but little antipyretic and anti-inflammatory activity. Lipton, J. M., Catania, A., Anti-inflammatory Influence of the Neuroimmunomodulator .alpha.-MSH, Immunol. Today 18, 140-145 (1997). The active message sequence for these antipyretic and anti-inflammatory activities resides in the C-terminal amino acid sequence of .alpha.-MSH, that is, lysine-proline-valine ("Lys-Pro-Val" or "KPV"), which has activities in vitro and in vivo that parallel those of the parent molecule. Richards, D. B., Lipton, J. M., Effect of .alpha.-MSH (11-13) (Lysine-proline-valine) on Fever in the Rabbit, Peptides 5, 815-817 (1984); Hiltz, M. E., Lipton, J. M., Anti-inflammatory Activity of a COOH-terminal Fragment of the Neuropeptide .alpha.-MSH, FASEB J. 3, 2282-2284 (1989). These peptides are known to have extremely low toxicity. Lipton, J. M., Catania, A., Anti-inflammatory Influence of the Neuroimmunomodulator .alpha.-MSH, Immunol. Today 18, 140-145 (1997). [0009] Melanocortin peptides, including .alpha.-MSH, ACTH, and other amino acid sequences derived from .alpha.-MSH or ACTH, have heretofore not been studied for potential antimicrobial activity, and there has been no suggestion that melanocortin peptides would have such activity. [0010] According to the invention, it has been determined that .alpha.-MSH and certain other amino acid sequences derived from .alpha.-MSH have significant antimicrobial uses, including for example, for use in reducing the viability of microbes, reducing the germination of yeasts, killing microbes without reducing the killing of microbes by human neutrophils, for treating inflammation in which there is microbial infection without reducing microbial killing, and increasing the accumulation of cAMP in microbes. [0011] According to a broad aspect of the invention, the antimicrobial agent is selected from the group consisting of one or more peptides including the C-terminal amino acid sequence of .alpha.-MSH, that is, KPV, one or more peptides including the amino acid sequence MEHFRWG, or a biologically functional equivalent of any of the foregoing. [0012] According to one aspect of the invention, the antimicrobial agent is selected from the group consisting of one or more peptides including the C-terminal amino acid sequence of .alpha.-MSH, that is, KPV, or a biologically functional equivalent of any of the foregoing. The KPV sequence is the amino acid sequence .alpha.-MSH (11-13). This type of antimicrobial agent includes a dimer of the amino acid sequence KPV, such as VPKCCKPV. [0013] According to a further aspect of the invention, the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence HFRWGKPV or a biologically functional equivalent of any of the foregoing. The HFRWGKPV sequence is the amino acid sequence a .alpha.-MSH (6-13). [0014] According to a still further aspect of the invention, the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence SYSMEHFRWGKPV or a biologically functional equivalent of any of the foregoing. The SYSMEHFRWGKPV sequence is the entire amino acid sequence of .alpha.-MSH (1-13). [0015] According to yet another aspect of the invention, the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence MEHFRWG or a biologically functional equivalent of any of the foregoing. The MEHFRWG sequence is sometimes referred to as the "core" amino acid sequence of .alpha.-MSH, that is, .alpha.-MSH (4-10). [0016] With these aspects of the invention, it is believed that the shorter amino acid sequences tend to be more effective. Preferably, the antimicrobial agent is further selected from the group consisting of one or more peptides having an amino acid chain length of up to thirteen. Still more preferably, the antimicrobial agent is further selected from the group consisting of one or more peptides having an amino acid chain length of up to eight. Based on the experimental results obtained thus far, the tripeptide KPV is the most effective. [0017] According to the invention, an effective concentration of the antimicrobial agent is at least 10.sup.-12 molar, and more preferably the concentration of the antimicrobial agent is at least 10.sup.-6 molar. [0018] It is fully expected that these peptides, which have extremely low toxicity, will be effective in animal and human subjects without adverse effect. [0019] These and other aspects of the invention will be apparent to those persons skilled in the art upon reading the following description of the experimental evidences and discussion. BRIEF DESCRIPTION OF THE DRAWING [0020] The accompanying figures of the drawing are incorporated into and form a part of the specification to provide illustrative examples of the present invention and to explain the principles of the invention. The figures of the drawing are only for purposes of illustrating preferred and alternate embodiments of how the invention can be made and used. It is to be understood, of course, that the drawing is intended to represent and illustrate the concepts of the invention. The figures of the drawing are not to be construed as limiting the invention to only the illustrated and described examples. Various advantages and features of the present invention will be apparent from a consideration of the written specification and the accompanying figures of the drawing wherein: Continue reading about Antimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormone... Full patent description for Antimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormone Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Antimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormone patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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