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3秒自动关闭窗口Trophic factor combinations for nervous system treatment
United States Patent Application
The present invention relates to a composition including an effective amount of at least one of an antimicrobial peptide and a substance having an antimicrobial peptide effect and an effective amount of a neurotrophin. The composition can also include an effective amount of at least one of a growth factor and a neuropeptide. The present invention also relates a method of treating an injury to a nervous system of an animal that includes the steps of identifying the injury to the nervous system and applying to the injury an effective amount of at least one of antimicrobial peptide and a substance having an antimicrobial peptide effect. The method can also include applying an effective amount of one or more trophic factors selected from the group consisting of a growth factor, a neurotrophin, and a neuropeptide to the injury.
Inventors:
Murphy, Christopher J. (Madison, WI, US)
Mcanulty, Jonathan F. (Oregon, WI, US)
Mitchell, Gordon S. (Madison, WI, US)
Golder, Francis J. (Stoughton, WI, US)
Application Number:
Publication Date:
09/06/2007
Filing Date:
08/29/2005
Export Citation:
Primary Class:
Other Classes:
International Classes:
A61K38/18; A61K9/14; A61K38/17
View Patent Images:
&&&&&&PDF help
Related US Applications:
March, 2009Kapel et al.April, 2010Gurtner et al.July, 2009NelsonDecember, 2006JensenJune, 2009Wakkach et al.July, 2008Schatten et al.April, 2003ThompsonNovember, 2004Leblanc et al.July, 2007LewisOctober, 2009Doi et al.October, 2007Thompson et al.
Primary Examiner:
MACFARLANE, STACEY NEE
Attorney, Agent or Firm:
Whyte, Hirschboeck Dudek S. C. (555 EAST WELLS STREET, SUITE 1900, MILWAUKEE, WI, 53202, US)
What is claimed is:
1. A composition comprising: A. an effective amount of at least one of an antimicrobial peptide and a substance having an antimicr and B. an effective amount of a neurotrophin.
2. The composition of claim 1, further comprising an effective amount of at least one of a growth factor and a neuropeptide.
3. The composition of claim 1, further comprising an effective amount of a growth factor.
4. The composition of claim 3, wherein the antimicrobial peptide is BNP-1, the neurotrophin is BDNF, and the growth factor is IGF-1.
5. The composition of claim 1, further comprising an effective amount of a neuropeptide.
6. The composition of claim 5, wherein the antimicrobial peptide is BNP-1, the neurotrophin is BDNF, and the neuropeptide is Substance P.
7. The composition of claim 1, further comprising an effective amount of a growth factor and an effective amount of a neuropeptide.
8. The composition of claim 7, wherein the antimicrobial peptide is BNP-1, the neurotrophin is BDNF, the growth factor is IGF-1, and the neuropeptide is Substance P.
9. The composition of claim 1, wherein the antimicrobial peptide is BNP-1 and the neurotrophin is BDNF.
10. The composition of claim 9, further comprising an effective amount of IGF-1 and an effective amount of Substance P.
11. The composition of claim 1, further comprising a viscous substance.
12. The composition of claim 1, further comprising a matrix.
13. The composition of claim 10, wherein the matrix comprises a hydrogel.
14. A method of treating an injury to a nervous system of an animal, the method comprising: A. identifying the injury t and B. applying to the injury an effective amount of at least one of antimicrobial peptide and a substance having an antimicrobial peptide effect.
15. The method of claim 14, wherein the at least one of an antimicrobial peptide and a substance having an antimicrobial peptide effect is combined with an effective amount of one or more trophic factors selected from the group consisting of a growth factor, a neurotrophin, and a neuropeptide.
16. The method of claim 14, wherein the injury to the nervous system comprises a spinal cord injury.
17. The method of claim 14, wherein the applying step produces an effect on the animal, the effect selected from the group consisting of reduced pain, neuronal plasticity, a neuroprotective effect, reduced body weight loss, increased motor recovery, increased evoked potential amplitudes, and lowered threshold current.
18. A kit comprising: A. at least one of an antimicrobial peptide and a substance having an antimicr and B. a neurotrophin.
19. The kit of claim 18, further comprising a viscous substance.
20. The kit of claim 18, further comprising at least one of a growth factor and a neuropeptide.
Description:
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 60/604,912, filed Aug. 27, 2004, the entirety of which is incorporated by reference herein.REFERENCE TO GOVERNMENT GRANT This invention was made with United States government support awarded by the National Institutes of Health, Grant # HL069064. The United States has certain rights in this invention.FIELD OF THE INVENTION The invention relates to combinations of neurochemically active agents for treating a nervous system and the methods of treating a nervous system with the combinatorial treatments. BACKGROUND OF THE INVENTION The nervous system is comprised of two divisions: the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS includes the brain and the spinal cord and controls most functions of the body and mind. The remainder of the nervous system is the PNS. Nerves of the PNS connect the CNS to sensory organs (such as the eyes and ears), other organs of the body, muscles, blood vessels, and glands. The peripheral nerves include the cranial nerves, the spinal nerves, and roots. The CNS controls all voluntary movement, such as movement of the legs during walking, and all involuntary movement, such as beating of the heart. The spinal cord connects the body and the brain by transmitting information to and from the body and the brain. The nervous system can be injured in numerous ways, and injuries can be traumatic. For instance, sudden physical assault on a portion of the nervous system results in a traumatic injury. In the case of a traumatic brain injury, the injury can be focal, i.e., confined to a specific area of the brain, or diffuse, i.e., involving more than one area of the brain. Injuries to the nervous system include contusions, which are bruises of the nervous system, and blood clots. Blood clots can form in or around the nervous system. For example, when bleeding occurs between the skull and the brain, the blood forms a clot. This puts pressure on the brain, which can lead to changes in brain function. Spinal cord injuries (SCI) are a particular type of injury to the nervous system. As of the year 2000, approximately 450,000 people in the United States have sustained SCI, with more than 10,000 new cases reported in the United States every year. Motor vehicle accidents are the leading cause of SCI (44 percent), followed by acts of violence (24 percent), falls (22 percent), sports injuries (8 percent), and other causes (2 percent). Of the 10,000 new cases of SCI in the United States each year, 51.7% have tetraplegia, i.e., injuries to one of the eight cervical segments of the spinal cord, and 56.7% have paraplegia, i.e., lesions in the thoracic, lumbar, or sacral regions of the spinal cord. Since 1990, the most frequent neurologic category is incomplete tetraplegia (29.5%), followed by complete paraplegia (27.9%), incomplete paraplegia (21.3%), and complete tetraplegia (18.5%). With spinal cord injuries in the neck, significant impairment of breathing may result. The most frequent site of spinal injury is the neck or cervical region and, of these, the major cause of death arises from respiratory complications. For patients that survive a major spinal cord injury in the neck, they may spend the rest of their lives depending on an artificial ventilator or phrenic nerve pacemaker to sustain their lives. For others with less severe respiratory impairment, they may be able to breathe normally, but are unable to sigh or breathe deeply and maintain the integrity of the lung. As a consequence, regions of the lung will collapse in these patients, causing pneumonia and allowing other respiratory infections to become established. Clearly, restoration of normal breathing ability, including deep breaths and sighs, is a major goal in the treatment of spinal cord injury patients. Injury to the spinal cord and other parts of the nervous system may be particularly devastating to life and the quality of life. In addition, injury to the nervous system can engender serious economic losses to the individual and to society. Currently, there are few effective treatment options available for patients with spinal cord injuries, although there are a few promising indications that physical therapy or chronic intermittent hypoxia (CIH), may have beneficial effects. Exposure to intermittent hypoxic episodes has been shown to initiate spinal protein synthesis. However, studies have also shown that chronic intermittent hypoxia has other drawbacks as a treatment for spinal cord injuries. For example, certain CIH treatment methods can cause systemic hypertension, altered sympathetic chemoreflexes, and hippocampal cell death by the process of apoptosis. Physical training and preconditioning have been used to treat SCI. Almost all patients with spinal cord injuries can now achieve a partial return of function with proper physical therapy that maintains flexibility and function of the muscles and joints, and strengthens the neural pathways that underlie movement. Physical therapy can also help reduce the risk of blood clots and boost the patient's morale. Physical training currently being investigated includes body weight-supported treadmill training, in which patients with partial spinal cord injury “walk” on a treadmill while they are partially supported through the use of a specially designed harness attached to an overhead lift. Unfortunately, this type of therapy is very expensive, and efficacy is far from complete. SUMMARY OF THE INVENTION The invention, which is defined by the claims set out at the end of this disclosure, is intended to solve at least some of the problems noted above. A composition is provided that includes an effective amount of at least one of an antimicrobial peptide and a substance having an antimicrobial peptide effect. The composition also includes an effective amount of a neurotrophin. In another embodiment, the composition also includes an effective amount of at least one of a growth factor and a neuropeptide. Also provided is a method of treating an injury to a nervous system of an animal. In one embodiment, the method includes the steps of identifying the injury to the nervous system and applying to the injury an effective amount of at least one of antimicrobial peptide and a substance having an antimicrobial peptide effect. In another embodiment, an injury to the nervous system is identified. An effective amount of at least one of an antimicrobial peptide and a substance having an antimicrobial peptide effect is combined with an effective amount of one or more trophic factors selected from the group consisting of a growth factor, a neurotrophin, and a neuropeptide. The combination is applied to the injury. A kit is also provided. In an embodiment, the kit includes at least one of an antimicrobial peptide and a substance having an antimicrobial peptide effect. The kit also includes a neurotrophin. In another embodiment, the kit also includes a viscous substance. In some embodiments, the kit also includes at least one of a growth factor and a neuropeptide.BRIEF DESCRIPTION OF THE DRAWINGS Preferred exemplary embodiments of the invention are illustrated in the accompanying drawings in which: FIG. 1 is a graph showing change in body weight at 2 weeks after spinal cord injury (Y-axis) in two strains of rats, Sprague Dawley and Lewis (X-axis). For each strain of rats, the body weight is shown for spinal injury alone (black bar) and for spinal injury and a trophic factor combination made in accordance with the invention (grey bar). In addition, corresponding data are shown for all rats combined. FIG. 2 is a graph showing peak neurogram voltages from the phrenic nerve during inspiration on the side of injury (Y-axis) at 2 weeks post-injury in two strains of rats, Sprague Dawley and Lewis (X-axis). For each strain of rats, neurogram voltages are shown for spinal injury alone (black bar) and for spinal injury and the trophic factor combination (grey bar). In addition, corresponding data are shown for all rats combined. FIG. 3 is a graph showing evoked potential voltage (in volts) from the phrenic neurogram on the side of injury at 2 weeks post-injury (Y-axis) in two strains of rats, Sprague Dawley and Lewis (X-axis). The stimulating current was 1000 uA. For each strain of rats, evoked potential voltages are shown for spinal injury alone (black bar) and for spinal injury and the trophic factor combination (grey bar). In addition, corresponding data are shown for all rats combined. FIG. 4 is a graph showing the stimulating current (in uAmps) required to evoke potentials in the phrenic nerve on the side of injury at 2 weeks post-injury (Y-axis) in two strains of rats, Sprague Dawley and Lewis (X-axis). For each strain of rats, stimulating currents are shown for spinal injury alone (black bar) and for spinal injury and the trophic factor combination (grey bar). In addition, corresponding data are shown for all rats combined. FIG. 5 is a graph showing the change in body mass in grams at 2 weeks post-injury (Y-axis) in different Lewis rats (X-axis). The body weight is shown for spinal injury alone (SCI) and for spinal injury and a trophic factor combination made in accordance with the invention (SCI+NTs). FIG. 5 also shows change in phrenic amplitude at 2 weeks post-injury (Y-axis) in the rats (X-axis) for spinal injury alone (SCI) and for spinal injury and a trophic factor combination made in accordance with the invention (SCI+NTs).Before explaining embodiments of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments or being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. DETAILED DESCRIPTION Definitions To facilitate understanding of the invention, a number of terms are defined below. As used herein, the term “antimicrobial polypeptide” refers to polypeptides that inhibit the growth of microbes (e.g., bacteria). Examples of antimicrobial polypeptides include, but are not limited to, the polypeptides described in Tables 1 and 2 below. Antimicrobial polypeptides include peptides synthesized from both L-amino and D-amino acids. As used herein, the term “pore forming agent” refers to any agent (e.g., peptide or other organic compound) that forms pores in a biological membrane. When the pore forming agent is a peptide, the peptide can be synthesized from both L-amino and D-amino acids. As used herein, the term “growth factor” refers to any compound that is involved in cell differentiation and growth. Growth factors can be proteins (e.g., IGF-1 (insulin-like growth factor 1), IGF-2 (insulin-like growth factor 2), NGF-β (nerve growth factor-β), EGF (epidermal growth factor), CSGF (colony-stimulating growth factor), FGF (fibroblast growth factor), PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor), TGF-β (transforming growth factor β, and bone morphogenetic proteins)), either purified from natural sources or genetically engineered, as well as fragments, mimetics, and derivatives or modifications thereof. Further examples of growth factors are provided in U.S. Pat. Nos. 5,183,805; 5,218,093; 5,130,298; 5,639,664; 5,457,034; 5,210,185; 5,470,828; 5,650,496; 5,998,376; and 5,410,019; all of which are incorporated herein by reference. The term “trophic factor” as used herein refers to a substance that stimulates growth and development or stimulates increased activity. The term “hyaluronic acid” includes hyaluronic acid and its derivatives, for instance, esters, salts such as the sodium, potassium, magnesium, calcium, alkaline, alkaline earth metals, and the like, and derivatives such as sulphated or polysulphated hyaluronates, or hyaluronates that have been otherwise modified in a manner way such that the function of hyaluronic acid is retained. The term “recombinant protein” or “recombinant polypeptide” as used herein refers to a protein molecule expressed from a recombinant DNA molecule. In contrast, the term “native protein” or “native polypeptide” is used herein to indicate a protein isolated from a naturally occurring (i.e., a nonrecombinant) source. Molecular biological techniques may be used to produce a recombinant form of a protein or polypeptide with similar or identical properties as compared to the native form of the protein. Where an amino acid sequence is recited herein to refer to an amino acid sequence of a naturally occurring protein molecule, amino acid sequence and like terms, such as polypeptide or protein are not meant to limit the amino acid sequence to the complete, native amino acid sequence associated with the recited protein molecule. As used herein in reference to an amino acid sequence or a protein, the term “portion” (as in “a portion of an amino acid sequence”) refers to fragments of that protein. The fragments may range in size from four amino acid residues to the entire amino acid sequence minus one amino acid (e.g., 5, 6, 7, 8, . . . x-1). As used herein, the term “variant,” when used in reference to a protein, refers to a protein encoded by partially homologous nucleic acids so that the amino acid sequence of the protein varies. As used herein, the term “variant” encompasses proteins encoded by homologous genes having both conservative and nonconservative amino acid substitutions that do not result in a change in protein function, as well as proteins encoded by homologous genes having amino acid substitutions that cause decreased protein function or increased protein function. As used herein, the term “fusion protein” refers to a chimeric protein containing the protein of interest (e.g., defensins and fragments thereof) joined to a heterologous protein fragment (e.g., the fusion partner which consists of a non-defensin protein). The fusion partner may enhance the solubility of a defensin as expressed in a host cell, may provide an affinity tag to allow purification of the recombinant fusion protein from the host cell or culture supernatant, or both. If desired, the fusion protein may be removed from the protein of interest (e.g., defensin or fragments thereof) by a variety of enzymatic or chemical processes known to the art. As used herein, the term “purified” refers to molecules, either nucleic or amino acid sequences, that are removed from their natural environment, isolated, or separated. The percent of a purified component is thereby increased in the sample. For example, an isolated defensin is therefore a purified defensin. Substantially purified molecules are at least 60% free, preferably at least 75% free, and more preferably at least 90% free from other components with which they are naturally associated. The term “gene” as used herein, refers to a DNA sequence that comprises control and coding sequences necessary for the production of a polypeptide or protein precursor. The polypeptide can be encoded by a full length coding sequence or by any portion of the coding sequence, as long as the desired protein activity is retained. The term “homology” refers to a degree of complementarity. There may be partial homology or complete homology (i.e., identity). A “partially complementary sequence” is one that at least partially inhibits a completely complementary sequence from hybridizing to a target nucleic acid. This situation is referred to using the functional term “substantially homologous.” The inhibition of hybridization of the completely complementary sequence to the target sequence may be examined using a hybridization assay (e.g., Southern or Northern blot, solution hybridization, and the like) under conditions of low stringency. A substantially homologous sequence or probe will compete for and inhibit the binding (i.e., the hybridization) of a completely homologous sequence or probe to a target under conditions of low stringency. This is not to say that conditions of low stringency are such that non-specific
low stringency conditions require that the binding of two sequences to one another be a specific (i.e., selective) interaction. The absence of non-specific binding may be tested by the use of a second target that lacks even a partial degree of complementarity (e.g., less than about 30% identity). In this case, in the absence of non-specific binding, the probe will not hybridize to the second non-complementary target. When used in reference to a double-stranded nucleic acid sequence such as a cDNA or a genomic clone, the term “substantially homologous” refers to any probe which can hybridize to either or both strands of the double-stranded nucleic acid sequence under conditions of low stringency as described herein. As used herein, the term “hybridization” is used in reference to the pairing of complementary nucleic acid strands. Hybridization and the strength of hybridization (i.e., the strength of the association between nucleic acid strands) is impacted by many factors well known in the art including the degree of complementarity between the nucleic acids, stringency of the conditions involved affected by such conditions as the concentration of salts, the Tm (melting temperature) of the formed hybrid, the presence of other components (e.g., the presence or absence of polyethylene glycol), the molarity of the hybridizing strands, and the G:C content of the nucleic acid strands. As used herein, the term “stringency” is used in reference to the conditions of temperature, ionic strength, and the presence of other compounds, under which nucleic acid hybridizations are conducted. With high stringency conditions, nucleic acid base pairing will occur only between nucleic acid fragments that have a high frequency of complementary base sequences. Thus, conditions of medium or low stringency are often required when it is desired that nucleic acids that are not completely complementary to one another be hybridized or annealed together. It is well known in the art that numerous equivalent conditions can be employed to comprise medium or low stringency conditions. The choice of hybridization conditions is generally evident to one skilled in the art and is normally guided by the purpose of the hybridization, the type of hybridization (DNA-DNA or DNA-RNA), and the level of desired relatedness between the sequences (e.g., Sambrook et al., 1989, Nucleic Acid Hybridization, A Practical Approach, IRL Press, Washington D.C., 1985, for a general discussion of the state of the art). The stability of nucleic acid duplexes is known to decrease with an increased number of mismatched bases, and further to be decreased to a greater or lesser degree depending on the relative positions of mismatches in the hybrid duplexes. Thus, the stringency of hybridization can be used to maximize or minimize stability of such duplexes. Hybridization stringency can be altered, for example, by adjusting the temperat adjusting the percentage of helix destabilizing agents, such as formamide, in t and adjusting the temperature and/or salt concentration of the wash solutions. For filter hybridizations, the final stringency of hybridizations can be determined by the salt concentration and/or temperature used for the post-hybridization washes. “High stringency conditions” when used in reference to nucleic acid hybridization comprise conditions equivalent to binding or hybridization at 42° C. in a solution consisting of 5×SSPE (43.8 g/l NaCl, 6.9 g/l NaH2PO4.H2O and 1.85 g/l EDTA, pH adjusted to 7.4 with NaOH), 0.5% SDS, 5× Denhardt's reagent and 100 μg/ml denatured salmon sperm DNA followed by washing in a solution comprising 0.1×SSPE, 1.0% SDS at 42° C. when a probe of about 500 nucleotides in length is employed. “Medium stringency conditions” when used in reference to nucleic acid hybridization comprise conditions equivalent to binding or hybridization at 42° C. in a solution consisting of 5×SSPE (43.8 g/l NaCl, 6.9 g/l NaH2PO4.H2O and 1.85 g/l EDTA, pH adjusted to 7.4 with NaOH), 0.5% SDS, 5× Denhardt's reagent and 100 μg/ml denatured salmon sperm DNA followed by washing in a solution comprising 1.0×SSPE, 1.0% SDS at 42° C. when a probe of about 500 nucleotides in length is employed. “Low stringency conditions” comprise conditions equivalent to binding or hybridization at 42° C. in a solution consisting of 5×SSPE (43.8 g/l NaCl, 6.9 g/l NaH2PO4.H2O and 1.85 g/l EDTA, pH adjusted to 7.4 with NaOH), 0.1% SDS, 5× Denhardt's reagent [50× Denhardt's contains per 500 ml: 5 g Ficoll (Type 400, Pharamcia), 5 g BSA (Fraction V; Sigma)] and 100 μg/ml denatured salmon sperm DNA followed by washing in a solution comprising 5×SSPE, 0.1% SDS at 42° C. when a probe of about 500 nucleotides in length is employed. As used herein, the term “Tm” is used in reference to the melting temperature, which is the temperature at which 50% of a population of double-stranded nucleic acid molecules becomes dissociated into single strands. The equation for calculating the Tm of nucleic acids is well known in the art. The Tm of a hybrid nucleic acid can be estimated using a formula adopted from hybridization assays in 1 M salt, and commonly used for calculating Tm for PCR primers: [(number of A+T)×2° C.+(number of G+C)×4° C.]. (C. R. Newton et al., PCR, 2nd Ed., Springer-Verlag (New York, 1997), p. 24). This formula was found to be inaccurate for primers longer than 20 nucleotides. (Id.) Another simple estimate of the Tm value can be calculated by the equation: Tm=81.5+0.41(% G+C), when a nucleic acid is in aqueous solution at 1 M NaCl. (e.g., Anderson and Young, Quantitative Filter Hybridization, in Nucleic Acid Hybridization (1985). Other more sophisticated computations exist in the art which take structural as well as sequence characteristics into account for the calculation of Tm. A calculated Tm i the optimum temperature is commonly determined empirically. As used herein, the term “vector” is used in reference to nucleic acid molecules that transfer DNA segment(s) from one cell to another and capable of replication in a cell. Vectors may include plasmids, bacteriophages, viruses, cosmids, and the like. The terms “recombinant vector” and “expression vector” as used herein refer to DNA or RNA sequences containing a desired coding sequence and appropriate DNA or RNA sequences necessary for the expression of the operably linked coding sequence in a particular host organism. Prokaryotic expression vectors include a promoter, a ribosome binding site, an origin of replication for autonomous replication in host cells and can also include other sequences, e.g., an optional operator sequence. A “promoter” is defined as a DNA sequence that directs RNA polymerase to bind to DNA and to initiate RNA synthesis. Eukaryotic expression vectors include a promoter, polyadenylation signal and optionally an enhancer sequence. As used herein the term “coding region” when used in reference to structural gene refers to the nucleotide sequences which encode the amino acids found in the nascent polypeptide as a result of translation of a mRNA molecule. Typically, the coding region is bounded on the 5′ side by the nucleotide triplet ATG, which encodes the initiator methionine, and on the 3′ side by a stop codon (e.g., TAA, TAG, TGA). In some cases, the coding region is also known to initiate by a nucleotide triplet TTG. The terms “buffer” or “buffering agents” refer to materials that when added to a solution, cause the solution to resist changes in pH. The term “monovalent salt” refers to any salt in which the metal (e.g., Na, K, or Li) has a net 1+ charge in solution (i.e., one more proton than electron). The term “divalent salt” refers to any salt in which a metal (e.g., Mg, Ca, or Sr) has a net 2+ charge in solution. The term “solution” refers to an aqueous mixture. The term “buffering solution” refers to a solution containing a buffering reagent. The present invention relates to neurochemically active agents and combinations thereof. Neurochemically active agents include one or more antimicrobial peptide and/or a substance having an antimicrobial peptide effect. Antimicrobial peptides themselves are known to have trophic effects. As such, an antimicrobial peptide and/or a substance having an antimicrobial peptide effect can be used by itself in the methods of the invention. Neurochemically active agents also include one or more growth factor, neurotrophin, and neuropeptide. Combinations of neurochemically active agents are referred to herein as “trophic factor combinations.”According to the invention, neurochemically active agents can be used alone or in combination to treat injuries to the nervous system, i.e., the central nervous system and the peripheral nervous system. The one or more neurochemically active agents can be used to treat nervous system injuries, including trauma induced injuries, degenerative induced injuries, age induced injuries, and infection induced injuries. Injuries that can be treated include, but are not limited to, spinal cord injury, including
peripheral nerve damage, brain injuries, e.g., blood clots, tumors, strokes, and is and Parkinson's disease, Alzheimer disease, muscular dystrophy, amyotrophic lateral sclerosis, multiple sclerosis, Pick's disease, prion diseases, Huntington disease, and related disorders. When applied to a the nervous system, trophic factor combinations of the invention result in at least one of the following: lower loss in body weight after the injury when compared to controls not receiving the trophic factor combinations, strengthened motor recovery in injured animals treated with the trophic factor combination when compared to animals not treated with the trophic factor combination, larger evoked potentials in nerves when compared to controls not receiving the trophic factor combination, and a lower current required to evoke a response (threshold current) when compared to controls not receiving the trophic factor combination. It is contemplated that the trophic factor combinations of the present invention used to treat injuries of the nervous system result in reduced inflammation, growth of new cells, increased plasticity, among other beneficial effects. I. Trophic Factor Combinations The present invention contemplates the use of trophic factor combinations and their individual components for treatment of injuries to the nervous system. Trophic factor combinations according to the invention can include one or more of the following elements: antimicrobial polypeptides (e.g., defensins), a substance having an effect of an antimicrobial peptide, a growth factor, a neurotrophin, and a neuropeptide. Additional components can also be included and are discussed below. A. Antimicrobial Peptides In some embodiments, one or more antimicrobial polypeptides and/or one or more substances having an antimicrobial peptide effect are used as a trophic factor to treat an injury to a nervous system. For additional information on antimicrobial peptides, see, for example, Antimicrobial Peptide Protocols, ed. W. M. Shafer, Humana Press, Totowa, N.J., 1997; and databases including http://aps.unmc.edu/AP/main.php (discussed in Wang Z, Wang G., APD: the Antimicrobial Peptide Database, Nucleic Acids Res. 2004 Jan. 1; 32(Database issue):D590-2), http://sdmc.lit.org.sg/Templar/DB/Antimic/, and http://www.bbcm.units.it/~zelezetsky/hdpdb.html (database of defense peptides) and Table 1 below. In some embodiments, the antimicrobial peptide is a compound or peptide selected from the following: bovine defensin peptide (BNP-1, Romeo et al., J. Biol. Chem. 263(15): [1988]), magainin (e.g., magainin I, magainin II, xenopsin, xenopsin precursor fragment, caerulein precursor fragment), magainin I and II analogs (PGLa, magainin A, magainin G, pexiganin, Z-12, pexigainin acetate, D35, MSI-78A, MG0 [K10E, K11E, F12W-magainin 2], MG2+ [K10E, F12W-magainin-2], MG4+ [F12W-magainin 2], MG6+ [f12W, E19Q-magainin 2 amide], MSI-238, reversed magainin II analogs [e.g., 53D, 87-ISM, and A87-ISM], Ala-magainin II amide, magainin II amide), cecropin P1, cecropin A, cecropin B, indolicidin, nisin, ranalexin, lactoferricin B, poly-L-lysine, cecropin A (1-8)-magainin II (1-12), cecropin A (1-8)-melittin (1-12), CA(1-13)-MA(1-13), CA(1-13)-ME(1-13), gramicidin, gramicidin A, gramicidin D, gramicidin S, alamethicin, protegrin, histatin, dermaseptin, lentivirus amphipathic peptide or analog, parasin I, lycotoxin I or II, globomycin, gramicidin S, surfactin, ralinomycin, valinomycin, polymyxin B, PM2 [(+/-) 1-(4-aminobutyl)-6-benzylindane], PM2c [(+/-)-6-benzyl-1-(3-carboxypropyl)indane], PM3 [(+/-) 1-benzyl-6-(4-aminobutyl)indane], tachyplesin, buforin I or II, misgurin, melittin, PR-39, PR-26, 9-phenylnonylamine, (KLAKKLA)n, (KLAKLAK)n, where n=1, 2, or 3, (KALKALK)3, KLGKKLG)n, and KAAKKAA)n, wherein N=1, 2, or 3, paradaxin, Bac 5, Bac 7, ceratoxin, mdelin 1 and 5, bombin-like peptides, PGQ, cathelicidin, HD-5, Oabac5alpha, ChBac5, SMAP-29, Bac7.5, lactoferrin, granulysin, thionin, hevein and knottin-like peptides, MPG1, 1bAMP, snakin, lipid transfer proteins, and plant defensins. Exemplary sequences for the above listed compounds are provided in Table 1. In some embodiments, the antimicrobial peptides or substances having an antimicrobial peptide effect (where they are peptides) are synthesized from L-amino acids, while in other embodiments, the peptides are synthesized from or comprise D-amino acids. The compounds listed above can be isolated and purified from natural sources as appropriate. The compounds can also be produced recombinantly or synthetically, as described below. In preferred embodiments, the trophic factor combinations of the present invention comprise one or more antimicrobial polypeptides and/or one or more substance having an antimicrobial peptide effect at a concentration of about 0.01 to about 1000 mg/L. In preferred embodiments, the trophic factor combinations comprise a solution comprising one or more antimicrobial polypeptides at a concentration of about 0.1 to about 5 mg/L. In some embodiments of the present invention, the antimicrobial polypeptide is a defensin. In preferred embodiments, the trophic factor combinations of the present invention comprise one or more defensins. In further preferred embodiments, the trophic factor combination comprises a solution comprising purified defensins at a concentration of about 0.01 to 1000 mg/L. In particularly preferred embodiments, the trophic factor combinations comprise a solution comprising defensins at a concentration of about 0.1 to 5 mg/L. In still further preferred embodiments, the antimicrobial polypeptide is BNP1 (also known as bactanecin and bovine dodecapeptide). In certain embodiments, the defensin comprises the following consensus sequence: X1CN1CRN2CN3ERN4CN5GN6CCX2, wherein N and X represent conservatively or nonconservatively substituted amino acids and N1=1, N2=3 or 4, N3=3 or 4, N4=1, 2, or 3, N6=5-9, X1 and X2 may be present, absent, or equal from 1-2. The present invention is not limited to any particular defensin. Indeed, trophic factor combinations comprising a variety of defensins are contemplated. Representative defensins are provided in Tables 1 and 2 below. In general, defensins are a family of highly cross-linked, structurally homologous antimicrobial peptides that can be found in the azurophil granules of polymorphonuclear leukocytes (PMNs) with homologous peptides being present in macrophages (e.g., Selsted et al., Infect. Immun. 45:150-154 [1984]). Originally described as “Lysosomal Cationic Peptides” in rabbit and guinea pig PMN (Zeya et al., Science 154: [1966]; Zeya et al., J. Exp. Med. 127:927-941 [1968]; Zeya et al., Lab. Invest. 24:229-236 [1971]; Selsted et al., [1984], supra.), this mixture was found to account for most of the microbicidal activity of the crude rabbit PMN extract against various microorganisms (Zeya et al., [1966], Lehrer et al., J. Infect. Dis. 136:96-99 [1977]; Lehrer et al., Infect. Immun. 11: [1975]). Six rabbit neutrophil defensins have been individually purified and are designated NP-1, NP-2, NP-3A, NP-3B, NP-4, and NP-5. Their amino acid sequences were determined, and their broad spectra of activity were demonstrated against a number of bacteria (Selsted et al., Infect. Immun. 45:150-154 [1984]), viruses (Lehrer et al., J. Virol. 54:467 [1985]), and fungi (Selsted et al., Infect. Immun. 49:202-206 [1985]; Segal et al., 151:890-894 [1985]). Defensins have also been shown to possess mitogenic activity (e.g., Murphy et al., J. Cell. Physiol. 155:408-13 [1993]). Four peptides of the defensin family have been isolated from human PMN's and are designated HNP-1, HNP-2, HNP-3, and HNP-4 (Ganz et al., J. Clin. Invest. 76: [1985]; Wilde et al., J. Biol. Chem. 264: [1989]). The amino acid sequences of HNP-1, HNP-2, and HNP-3 differ from each other only in their amino terminal residues, while each of the human defensins are identical to the six rabbit peptides in 10 or 11 of their 29 to 30 residues. These are the same 10 or 11 residues that are shared by all six rabbit peptides. Human defensin peptides have been shown to share with the rabbit defensins a broad spectrum of antimicrobial activity against bacteria, fungi, and enveloped viruses (Ganz et al., [1985], supra). Three defensins designated RatNP-1, RatNP-2, and RatNP-4, have been isolated from rat (Eisenhauer et al., Infection and Immunity 57: [1989]). A guinea pig defensin (GPNP) has also been isolated, purified, sequenced and its broad spectrum antimicrobial properties verified (Selsted et al., Infect. Immun. 55: [1987]). Eight of its 31 residues were among those invariant in six rabbit and three human defensin peptides. The sequence of GPNP also included three nonconservative substitutions in positions otherwise invariant in the human and rabbit peptides. Of the defensins tested in a quantitative assay HNP-1, RatNP-1, and rabbit NP-1 possess the most potent antimicrobial properties, while NP-5 possesses the least amount of antimicrobial activity when tested against a panel of organisms in stationary growth phase (Selsted et al., Infect. Immun. 45:150-154 [1984]; Ganz et al., J. Clin. Invest. 76: [1985]). Defensin peptides are further described in U.S. Pat. Nos. 4,543,252; 4,659,692; and 4,705,777 (each of which is incorporated herein by reference). Defensin peptides suitable for use alone in the methods and/or in trophic factor combinations of the present invention include natural defensin peptides isolated from known cellular sources, synthetic peptides produced by solid phase or recombinant DNA techniques, and defensin analogs which may be smaller peptides or other molecules having similar binding and biological activity as the natural defensin peptides (e.g., peptide mimetics). Methods for the purification of defensin peptides are described in U.S. Pat. Nos. 4,543,252; 4,659,692; and 4,705,777, the disclosures of which are incorporated herein by reference. In preferred embodiments, suitable synthetic peptides will comprise all or part of the amino acid sequence of a known peptide, more preferably incorporating at least some of the conserved regions identified in Table 2. In particularly preferred embodiments, the synthetic peptides incorporate at least one of the conserved regions, more typically incorporating two of the conserved regions, preferably conserving at least three of the conserved regions, and more preferably conserving four or more of the conserved regions. In preferred embodiments, the synthetic peptides comprise fifty amino acids or fewer, although there may be advantages in increasing the size of the peptide above that of the natural peptides in certain instances. In certain embodiments, the peptides have a length in the range from about 10 to 50 amino acids, preferably being in the range from about 10 to 40 amino acids, and most preferably being in the range from about 30 to 35 amino acids which corresponds generally to the length of the natural defensin peptides. In some cases, it may be desirable to incorporate one or more non-natural amino acids in the synthetic defensin peptides of the present invention. In preferred embodiments, non-natural amino acids comprise at least an N-terminus and a C-terminus of the peptide and have side chains that are either identical to or chemically modified or substituted from a natural amino acid counterpart. An example of a non-natural amino acid is an optical isomer of a naturally-occurring L-amino acid, such as a peptide containing all D-amino acids. Examples of the synthesis of peptides containing all D-amino acids include Merrifield et al., Ciba Found Symp. 186:5-26 (1994); Wade et al., Proc. Natl. Acad. Sci. USA 87(12):90); and U.S. Pat. No. 5,792,831, which is herein incorporated by reference. Examples of chemical modifications or substitutions include hydroxylation or fluorination of C—H bonds within natural amino acids. Such techniques are used in the manufacture of drug analogs of biological compounds and are known to one of ordinary skill in the art. Synthetic peptides having biological and binding activity the same or similar to that of natural defensin peptides can be produced by either of two exemplary approaches. First, the polypeptides can be produced by the well-known Merrifield solid-phase chemical synthesis method wherein amino acids are sequentially added to a growing chain (Merrifield, J. Am. Chem. Soc. 85: [1963]). Automatic peptide synthesis equipment is available from several commercial suppliers, including PE Biosystems, Inc., Foster City, Calif.; Beckman Instruments, Inc., Waldwick, N.J.; and Biosearch, Inc., San Raphael, Calif. Using such automatic synthesizers according to manufacturer's instructions, peptides can be produced in gram quantities for use in the present invention. Second, the synthetic defensin peptides of the present invention can be synthesized by recombinant techniques involving the expression in cultured cells of recombinant DNA molecules encoding a gene for a desired portion of a natural or analog defensin molecule. The gene encoding the defensin peptide can itself be natural or synthetic. Conveniently, polynucleotides can be synthesized by well-known techniques based on the desired amino acid sequence. For example, short single-stranded DNA fragments can be prepared by the phosphoramidite method (Beaucage et al., Tetra. Lett. 22: [1981]). A double-stranded fragment can then be obtained either by synthesizing the complementary strand and annealing the strands together under appropriate conditions, or by adding the complementary strand using DNA polymerase under appropriate conditions, or by adding the complementary strand using DNA polymerase with an appropriate primer sequence. The natural or synthetic DNA fragments coding for the desired defensin peptide can then be incorporated in a suitable DNA construct capable of introduction to and expression in an in vitro cell culture. The DNA fragments can be portions or variants of wild-type nucleic acids encoding defensins. Suitable variants include those both with conservative and nonconservative amino acid substitutions. The methods, compositions, and trophic factor combinations of the present invention can also employ synthetic non-peptide compositions that have biological activity functionally comparable to that of known defensin peptides. By functionally comparable, it is meant that the shape, size, flexibility, and electronic configuration of the non-peptide molecule is such that the biological activity of the molecule is similar to defensin peptides. In particular, the non-peptide molecules should display comparable mitogenic activity and/or antimicrobial activity or pore forming ability, preferably possessing both activities. Such non-peptide molecules will typically be small molecules having a molecular weight in the range from about 100 to about 1000 daltons. The use of such small molecules is frequently advantageous in the preparation of trophic factor combinations. Candidate mimetics can be screened in large numbers to identify those having the desired activity. The identification of such nonpeptide analog molecules can be performed using techniques known in the art of drug design. Such techniques include, but are not limited to, self-consistent field (SCF) analysis, configuration interaction (CI) analysis, and normal mode dynamics computer analysis, all of which are well described in the scientific literature (e.g., Rein et al., Computer-Assisted Modeling of Receptor-Ligand Interactions, Alan Liss, N.Y., [1989]). Preparation of the identified compounds will depend on the desired characteristics of the compounds and will involve standard chemical synthetic techniques (e.g., Cary et al., Advanced Organic Chemistry, part B, Plenum Press, New York [1983]). In some embodiments of the present invention, one or more substances having an effect that an antimicrobial peptide has can be used. Effects that antimicrobial peptides have include, but are not limited to, the following: form pores
enter cells without membrane lysis and, once in the cytoplasm, bind to, and inhibit the activity of specific molecular targets essential to bacterial growth, thereb induce expression of syndecan, an integral membrane proteoglycan associated largely with epithelial cells, in mesenchymal cells and inhibit the NADPH oxidase activity of neutrophils, suggesting a role of this peptide in wound rep exert a protective effect in various animal models of ischemia-reperfusion injury, preventing the post-ischemi induce angiogenesis both
inhibit membra inhibit DNA stimulat interfere
chemoattract stimulate stimulate adhesion and chloride secretion.
TABLE 1Human Antimicrobial PeptidesOrganismProtein NameNameLengthSequenceAntibacterial170MKTQRDGHSLGRWSLVLLLLGLVMPLAIIAQVpeptide LL-37LSYKEAVLRAIDGINQRSSDANLYRLLDLDPRprecursorPTMDGDPDTPKPVSFTVKETVCPRTTQQSPEDCDFKKDGLVKRCMGTVNLNQARGSFDISCDKDNKRFALLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES AntibacterialHomo170MKTQRDGHSLGRWSLVLLLLGLVMPLAIIAQVprotein FALL-sapiensLSYKEAVLRAIDGINQRSSDANLYRLLDLDPR39 precursorPTMDGDPDTPKPVSFTVKETVCPRTTQQSPEDCDFKKDGLVKRCMGTVTLNQARGSFDISCDKDNKRFALLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES AntimicrobialHomo476MQPVMLALWSLLLLWGLATPCQELLETVGTLpeptide RYA3sapiensARIDKDELGKAIQNSLVGEPILQNVLGSVTAVNRGLLGSGGLLGGGGLLGHGGVFGVVEELSGLKIEELTLPKVLLKLLPGFGVQLSLHTKVGMHCSGPLGGLLQLAAEVNVTSRVALAVSSRGTPILILKRCSTLLGHISLFSGLLPTPLFGVVEQMLFKVLPGLLCPVVDSVLGVVNELLGAVLGLVSLGALGSVEFSLATLPLISNQYIELDINPIVKSVAGDIIDFPKSRAPAKVPPKKDHTSQVMVPLYLFNTTFGLLQTNGALDMDITPELVPSDVPLTTTDLAALLPEALGKLPLHQQLLLFLRVREAPTVTLHNKKALVSLPANIHVLFYVPKGTPESLFELNSVMTVRAQLAPSATKLHISLSLERLSVKVASSFTHAFDGSRLEEWLSHVVGAVYAPKLNVALDVGIPLPKVLNINFSNSVLEIVENAVVLTVAS AzurocidinHomo251MTRLTVLALLAGLLASSRAGSSPLLDIVGGRKprecursorsapiensARPRQFPFLASIQNQGRHFCGGALIHARFVMTAASCFQSQNPGVSTVVLGAYDLRRRERQSRQTFSISSMSENGYDPQQNLNDLMLLQLDREANLTSSVTILPLPLQNATVEAGTRCQVAGWGSQRSGGRLSRFPRFVNVTVTPEDQCRPNNVCTGVLTRRGGICNGDGGTPLVCEGLAHGVASFSLGPCGRGPDFFTRVALFRDWIDGVLNNPGPGPA BactericidalHomo483MARGPCNAPRWVSLMVLVAIGTAVTAAVNPpermeability-sapiensGVVVRISQKGLDYASQQGTAALQKELKRIKIPincreasingDYSDSFKIKHLGKGHYSFYSMDIREFQLPSSproteinQISMVPNVGLKFSISNANIKISGKWKAQKRFLprecursor (BPI)KMSGNFDLSIEGMSISADLKLGSNPTSGKPTI(CAP 57)TCSSCSSHINSVHVHISKSKVGWLIQLFHKKIESALRNKMNSQVCEKVTNSVSSKLQPYFQTLPVMTKIDSVAGINYGLVAPPATTAETLDVQMKGEFYSENHHNPPPFAPPVMEFPAAHDRMVYLGLSDYFFNTAGLVYQEAGVLKMTLRDDMIPKESKFRLTTKFFGTFLPEVAKKFPNMKIQIHVSASTPPHLSVQPTGLTFYPAVDVQAFAVLPNSSLASLFLIGMHTTGSMEVSAESNRLVGELKLDRLLLELKHSNIGPFPVELLQDIMNYIVPILVLPRVNEKLQKGFPLPTPARVQLYNVVLQPHQNFLLFGADVVYK bactericidal/per-Homo487MRENMARGPCNAPRWVSLMVLVAIGTAVTAmeability-sapiensAVNPGVVVRISQKGLDYASQQGTAALQKELKincreasingRIKIPDYSDSFKIKHLGKGHYSFYSMDIREFQLproteinPSSQISMVPNVGLKFSISNANIKISGKWKAQKprecursorRFLKMSGNFDLSIEGMSISADLKLGSNPTSGKPTITCSSCSSHINSVHVHISKSKVGWLIQLFHKKIESALRNKMNSQVCEKVTNSVSSKLQPYFQTLPVMTKIDSVAGINYGLVAPPATTAETLDVQMKGEFYSENHHNPPPFAPPVMEFPAAHDRMVYLGLSDYFFNTAGLVYQEAGVLKMTLRDDMIPKESKFRLTTKFFGTFLPEVAKKFPNMKIQIHVSASTPPHLSVQPTGLTFYPAVDVQAFAVLPNSSLASLFLIGMHTTGSMEVSAESNRLVGELKLDRLLLELKHSNIGPFPVELLQDIMNYIVPILVLPRVNEKLQKGFPLPTPARVQLYNVVLQPHQNFLLFGADVVYK beta defensinHomo111MKSLLFTLAVFMLLAQLVSGNWYVKKCLNDV126sapiensGICKKKCKPEEMHVKNGWAMCGKQRDCCVPADRRANYPVFCVQTKTTRISTVTATTATTTLepididymalMMTTASMSSMAPTPVSPTGsecretoryproteinESP13.2; betadefensin 26;chromosome20 openreading frame8 beta-defensinHomo65MRTFLFLFAVLFFLTPAKNAFFDEKCNKLKGTsapiensCKNNCGKNEELIALCQKFLKCCRTIQPCGSIID Beta-defensinHomo67MRIHYLLFALLFLFLVPVPGHGGIINTLQKYYC103 precursorsapiensRVRGGRCAVLSCLPKEEQIGKCSTRGRKCC(Beta-defensinRRKK3) (DEFB-3)(BD-3) (hBD-3)(HBD3)(Defensin likeprotein) Beta-defensinHomo72MQRLVLLLAVSLLLYQDLPVRSEFELDRICGY104 precursorsapiensGTARCRKKCRSQEYRIGRCPNTYACCLRKW(Beta-defensinDESLLNRTKP4) (DEFB-4)(BD-4) (hBD-4) beta-defensinHomo77MALIRKTFYFLFAMFFILVQLPSGCQAGLDFS105sapiensQPFPSGEFAVCESCKLGRGKCRKECLENEKPDGNCRLNFLCCRQR Beta-defensinHomo78MALIRKTFYFLFAMFFILVQLPSGCQAGLDFS105 precursorsapiensQPFPSGEFAVCESCKLGRGKCRKECLENEK(Beta-defensinPDGNCRLNFLCCRQRI5) (DEFB-5)(BD-5) beta-defensinHomo57MRTFLFLFAVLFFLTPAKNAFFDEKCNKLKGT106sapiensCKNNCGKNEELIALCQKSLKCCRTI Beta-defensinHomo65MRTFLFLFAVLFFLTPAKNAFFDEKCNKLKGT106 precursorsapiensCKNNCGKNEELIALCQKSLKCCRTIQPCGSII(Beta-defensinD6) (DEFB-6)(BD-6) Beta-defensinHomo63MKIFVFILAALILLAQIFQARTAIHRALISKRME107 precursorsapiensGHCEAECLTFEVKIGGCRAELAPFCCKNR(Beta-defensin7) (DEFB-7)(Fragment) beta-defensinHomo59MRIAVLFFTIFFFMSQVLPAKGKFKEICERPN108sapiensGSCRDFCLETEIHVGRCLNSRPCCLPL Beta-defensinHomo73MRIAVLLFAIFFFMSQVLPARGKFKEICERPN108 precursorsapiensGSCRDFCLETEIHVGRCLNSQPCCLPLGHQP(Beta-defensinRIESTTPKKD8) (DEFB-8) Beta-defensinHomo123MKLLLLALPMLVLLPQVIPAYSGEKKCWNRS118 precursorsapiensGHCRKQCKDGEAVKDTCKNLRACCIPSNED(Beta-defensinHRRVPATSPTPLSDSTPGIIDDILTVRFTTDYF18) (DEFB-18)EVSSKKDMVEESEAGRGTETSLPNVHHSS(Epididymalsecretoryprotein 13.6)(ESP13.6) Beta-defensinHomo84MKLLYLFLAILLAIEEPXISGKRHILRCMGNSGI119 precursorsapiensCRASCKKNEQPYLYCRNCQSCCLQSYMRISI(Beta-defensinSGKEENTDWSYEKQWPRLP19) (DEFB-19) Beta-defensinHomo88MKLLYLFLAILLAIEEPVISVECWMDGHCRLLC120 precursorsapiensKDGEDSIIRCRNRKRCCVPSRYLTIQPVTIHGI(Beta-defensinLGWTTPQMSTTAPKMKTNITNR20) (DEFB-20) Beta-defensinHomo67MKLLLLTLTVLLLLSQLTPGGTQRCWNLYGK123 precursorsapiensCRYRCSKKERVYVYCINNKMCCVKPKYQPK(Beta-defensinERWWPF23) (DEFB-23) Beta-defensinHomo43EFKRCWKGQGACQTYCTRQETYMHLCPDA124 (Beta-sapiensSLCCLSYALKPPPVdefensin 24)(DEFB-24)(Fragment) Beta-defensinHomo152MLTFIICGLLTRVTKGSFEPQKCWKNNVGHC125 precursorsapiensRRRCLDTERYILLCRNKLSCCISIISHEYTRRP(Beta-defensinAFPVIHLEDITLDYSDVDSFTGSPVSMLNDLIT25) (DEFB-25)FDTTKFGETMTPETNTPETTMPPSEATTPETTMPPSETATSETMPPPSQTALTHN Beta-defensinHomo111MKFLLFTLAVFMLLAQLVSGNWYVKKCLNDV126 precursorsapiensGICKKKCKPEEMHVKNGWAMCGKQRDCCV(Beta-defensinPADRRANYPVFCVQTKTTRISTVTATTATTTL26) (DEFB-26)MMTTASMSSMAPTPVSPTG(Epididymalsecretoryprotein 13.2)(ESP13.2) Beta-defensinHomo99MGLFMIIAILLFQKPTVTEQLKKCWNNYVQGH127 precursorsapiensCRKICRVNEVPEALCENGRYCCLNIKELEACK(Beta-defensinKITKPPRPKPATLALTLQDYVTIIENFPSLKTQ27) (DEFB-27)ST Beta-defensinHomo183MKLLFPIFASLMLQYQVNTEFIGLRRCLMGLG129 precursorsapiensRCRDHCNVDEKEIQKCKMKKCCVGPKVVKLI(Beta-defensinKNYLQYGTPNVLNEDVQEMLKPAKNSSAVIQ29) (DEFB-29)RKHILSVLPQIKSTSFFANTNFVIIPNATPMNSATISTMTPGQITYTATSTKSNTKESRDSATASPPPAPPPPNILPTPSLELEEAEEQ Beta-defensinHomo70MRVLFFVFGVLSLMFTVPPGRSFISNDECPS131 precursorsapiensEYYHCRLKCNADEHAIRYCADFSICCKLKIIEI(Beta-defensinDGQKKW31) (DEFB-31) Beta-DefensinHomo37PVTCLKSGAICHPVFCPRRYKQIGTCGLPGT2sapiensKCCKKP Beta-defensinHomo64MRVLYLLFSFLFIFLMPLPGVFGGIGDPVTCL2 precursorsapiensKSGAICHPVFCPRRYKQIGTCGLPGTKCCKK(BD-2) (hBD-2)P(Skin-antimicrobialpeptide 1)(SAP1) beta-defensinHomo156MNILMLTFIICGLLTRVTKGSFEPQKCWKNNV25 precursorsapiensGHCRRRCLDTERYILLCRNKLSCCISIISHEYTRRPAFPVIHLEDITLDYSDVDSFTGSPVSMLNDLITFDTTKFGETMTPETNTPETTMPPSEATTPETTMPPSETATSETMPPPSQTALTHN beta-defensinHomo93MKLFLVLIILLFEVLTDGARLKKCFNKVTGYCR28 precursorsapiensKKCKVGERYEIGCLSGKLCCANDEEEKKHVSFKKPHQHSGEKLSVLQDYIILPTITIFTV Beta-DefensinHomo45GIINTLQKYYCRVRGGRCAVLSCLPKEEQIGK3sapiensCSTRGRKCCRRKK beta-defensinHomo95MKFLLLVLAALGFLTQVIPASAGGSKCVSNTP32 precursorsapiensGYCRTCCHWGETALFMCNASRKCCISYSFLPKPDLPQLIGNHWQSRRRNTQRKDKKQQTTVTS Beta-defensin-Homo47GNFLTGLGHRSDHYNCISSGGQCLYSACPIF1 (Fragment)sapiensTKIQGTCYRGKAKCCK Beta-Defensin-Homo41GIGDPVTCLKSGAICHPVFCPRRYKQIGTCGL2sapiensPGTKCCKKP Beta-defensin-Homo67MRIHYLLFALLFLFLVPVPGHGGIINTLQKYYC3sapiensRVRGGRCAVLSRLPKEEQIGKCSTRGRKCCRRKK Calgranulin AHomo93MLTELEKALNSIIDVYHKYSLIKGNFHAVYRDD(MigrationsapiensLKKLLETECPQYIRKKGADVWFKELDINTDGAinhibitoryVNFQEFLILVIKMGVAAHKKSHEESHKEfactor-relatedprotein 8)(MRP-8)(Cystic fibrosisantigen)(CFAG) (P8)(Leukocyte L1complex lightchain) (S100calcium-bindingprotein A8)(CalprotectinL1L subun Calgranulin BHomo114MTCKMSQLERNIETIINTFHQYSVKLGHPDTL(MigrationsapiensNQGEFKELVRKDLQNFLKKENKNEKVIEHIMEinhibitoryDLDTNADKQLSFEEFIMLMARLTWASHEKMHfactor-relatedEGDEGPGHHHKPGLGEGTPprotein 14)(MRP-14)(P14)(Leukocyte L1complex heavychain) (S100calcium-binding proteinA9)(CalprotectinL1H subunit) Calgranulin CHomo92MTKLEEHLEGIVNIFHQYSVRKGHFDTLSKGE(CAGC)sapiensLKQLLTKELANTIKNIKDKAVIDEIFQGLDANQ(CGRP)DEQVDFQEFISLVAIALKAAHYHTHKE(NeutrophilS100 protein)(Calcium-binding proteinin amniotic fluid1) (CAAF1)(p6) [Contains:Calcitermin] cathelicidinHomo170MKTQRNGHSLGRWSLVLLLLGLVMPLAIIAQVantimicrobialsapiensLSYKEAVLRAIDGINQRSSDANLYRLLDLDPRpeptidePTMDGDPDTPKPVSFTVKETVCPRTTQQSPEDCDFKKDGLVKRCMGTVTLNQARGSFDISCDKDNKRFALLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES Cathepsin GHomo255MQPLLLLLAFLLPTGAEAGEIIGGRESRPHSRprecursor (ECsapiensPYMAYLQIQSPAGQSRCGGFLVREDFVLTAA3.4.21.20) (CG)HCWGSNINVTLGAHNIQRRENTQQHITARRAIRHPQYNQRTIQNDIMLLQLSRRVRRNRNVNPVALPRAQEGLRPGTLCTVAGWGRVSMRRGTDTLREVQLRVQRDRQCLRIFGSYDPRRQICVGDRRERKAAFKGDSGGPLLCNNVAHGIVSYGKSSGVPPEVFTRVSSFLPWIRTTMRSFKLLDQMETPL chromograninHomo457MRSAAVLALLLCAGQVTALPVNSPMNKGDTEA; parathyroidsapiensVMKCIVEVISDTLSKPSPMPVSQECFETLRGDsecretoryERILSILRHQNLLKELQDLALQGAKERAHQQKprotein 1KHSGFEDELSEVLENQSSQAELKEAVEEPSSKDVMEKREDSKEAEKSGEATDGARPQALPEPMQESKAEGNNQAPGEEEEEEEEATNTHPPASLPSQKYPGPQAEGDSEGLSQGLVDREKGLSAEPGWQAKREEEEEEEEEAEAGEEAVPEEEGPTVVLNPHPSLGYKEIRKGESRSEALAVDGAGKPGAEEAQDPEGKGEQEHSQQKEEEEEMAVVPQGLFRGGKSGELEQEEERLSKEWEDSKRWSKMDQLAKELTAEKRLEGQEEEEDNRDSSMKLSFRARAYGFRGPGPQLRRGWRPSSREDSLEAGLPLQVRGYPEEKKEEEGSANRRPEDQELESLSAIEAELEKVAHQLQALRRG Defensin 5Homo94MRTIAILAAILLVALQAQAESLQERADEATTQKprecursorsapiensQSGEDNQDLAISFAGNGLSALRTSGSQARAT(Defensin,CYCRTGRCATRESLSGVCEISGRLYRLCCRalpha 5) Defensin 6Homo101MRTLTILTAVLLVALQAKAEPLQAEDDPLQAKsapiensAYEADAQEQRGANDQDFAVSFAEDASSSLRALGGSTRAFTCHCRRSCYSTEYSYGTCTVMGINHRFCCL Defensin 6Homo100MRTLTILTAVLLVALQAKAEPLQAEDDPLQAKprecursorsapiensAYEADAQEQRGANDQDFAVSFAEDASSSLR(Defensin,ALGSTRAFTCHCRRSCYSTEYSYGTCTVMGIalpha 6)NHRFCCL defensin alpha-Homo65CCSPGADCSGHPRSGCFPCMGRKLGSKAS3 precursorsapiensRLKEKHGLLLQNTSVHCRRTSLWNLHLPGKT(mistranslated)LGILL defensin betaHomo60MKIFFFILAALILLAQIFQARTAIHRALISKRME107sapiensGHCEAECLTFEVKIGGCRAELAPFCC defensin betaHomo52GKFKEICERPNGSCRDFCLETEIHVGRCLNS108sapiensQPCCLPLGHQPRIESTTPKKD Defensin betaHomo21SCTAIGGRCKNQCDDSEFRIS112 (Fragment)sapiens Defensin betaHomo39KRYGRCKRDCLESEKQIDICSLPGKICCTEKL114 (Fragment)sapiensYEEDDMF defensin betaHomo101GEKKCWNRSGXCRKQCKDGEAVKDTCKNX118sapiensRACCIPSNEDHRRVPATSPTPLSDSTPGIIDDILTVRFTTDYFEVSSKKDMVEESEAGRGTETSLPNVHHSS defensin betaHomo94SLLFTLAVFMLLAQLVSGNWYVKKCLNDVGI126sapiensCKKKCKPEEMHVKNGWAMCGKQRDCCVPADRRANYPVFCVQTKTTRISTVTATTATTTLMMTT defensin betaHomo59EQLKKCWNNYVQRHCRKICRVNEVPEALCE127sapiensNGRYCCLNIKELEACKKITKPPSPKQHLH defensin betaHomo155MKLLFPIFASLMLQYQVNTEFIGLRRCLMGLG129sapiensRCRDHCNVDEKEIQKCKMKKCCVGPKVVKLIKNYLQYGTPNVLNEDVQEMLKPAKNSSAVIQRKHILSVLPQIKSTSFFANTNFVIIPNATPMNSATISTMTPGQITYTATSTKSNTKESRDS defensin beta-1Homo36DHYNCVSSGGQCLYSACPIFTKIQGTCYRGKsapiensAKCCK Defensin HNP-Homo30DCYCRIPACIAGERRYGTCIYQGRLWAFCC3 - Chain Bsapiens EP2EHomo80MKVFFLFAVLFCLVQTNSGDVPPGIRNTICRMsapiensQQGICRLFFCHSGEKKRDICSDPWNRCCVSNTDEEGKEKPEMDGRSGI gene TAP1Homo33GYDTEVGEAGSQLSGGQRQAVALARALIRKPproteinsapiensCV HepcidinHomo84MALSSQIWAACLLLLLLLASLTSGSVFPQQTGprecursorsapiensQLAELQPQDRAGARASWMPMFQRRRRRDT(Liver-HFPICIFCCGCCHRSKCGMCCKTexpressedantimicrobialpeptide)(LEAP-1)(Putative livertumorregressor)(PLTR)[Contains:Hepcidin 25(Hepc25);Hepcidin 20(Hepc20)] High mobilityHomo215MGKGDPKKPRGKMSSYAFFVQTCREEHKKKgroup protein 1sapiensHPDASVNFSEFSKKCSERWKTMSAKEKGKF(HMG-1)EDMAKADKARYEREMKTYIPPKGETKKKFKDPNAPKRPPSAFFLFCSEYRPKIKGEHPGLSIGDVAKKLGEMWNNTAADDKQPYEKKAAKLKEKYEKDIAAYRAKGKPDAAKKGVVKAEKSKKKKEEEEDEEDEEDEEEEEDEEDEDEEEDDDDE liver-expressedHomo81MWHLKLCAVLMIFLLLLGQIDGSPIPEVSSAKantimicrobialsapiensRRPRRMTPFWRGVSLRPIGASCRDDSECITRpeptide 2LCRKGQQSPPTMLRSMEYisoform Liver-Homo77MWHLKLCAVLMIFLLLLGQIDGSPIPEVSSAKexpressedsapiensRRPRRMTPFWRGVSLRPIGASCRDDSECITRantimicrobialLCRKRRCSLSVAQEpeptide 2precursor(LEAP-2) Lysozyme CHomo148MKALIVLGLVLLSVTVQGKVFERCELARTLKRprecursor (ECsapiensLGMDGYRGISLANWMCLAKWESGYNTRATN3.2.1.17) (1,4-YNAGDRSTDYGIFQINSRYWCNDGKTPGAVbeta-N-NACHLSCSALLQDNIADAVACAKRVVRDPQGacetylmurami-IRAWVAWRNRCQNRDVRQYVQGCGVdase C) NeutrophilHomo94MRTLAILAAILLVALQAQAEPLQARADEVAAAdefensin 1sapiensPEQIAADIPEVVVSLAWDESLAPKHPGSRKNprecursorMACYCRIPACIAGERRYGTCIYQGRLWAFCC(HNP-1) (HP-1)(HP1)(Defensin,alpha 1)[Contains: HP1-56;Neutrophildefensin 2(HNP-2) (HP-2)(HP2)] NeutrophilHomo94MRTLAILAAILLVALQAQAEPLQARADEVAAAdefensin 3sapiensPEQIAADIPEVVVSLAWDESLAPKHPGSRKNprecursorMDCYCRIPACIAGERRYGTCIYQGRLWAFCC(HNP-3) (HP-3)(HP3)(Defensin,alpha 3)[Contains: HP3-56;Neutrophildefensin 2(HNP-2) (HP-2)(HP2)] NeutrophilHomo97MRIIALLAAILLVALQVRAGPLQARGDEAPGQdefensin 4sapiensEQRGPEDQDISISFAWDKSSALQVSGSTRGprecursorMVCSCRLVFCRRTELRVGNCLIGGVSFTYCC(HNP-4) (HP-4)TRVD(Defensin,alpha 4) RetrocyclinHomo56MPCFSWWPCRLRRSHFRQELMKLQPRSSLEsapiensQMIRKWLMPLHGMKVPLFRFQTQREA Ribonuclease 7Homo156MAPARAGFCPLLLLLLLGLWVAEIPVSAKPKGprecursor (ECsapiensMTSSQWFKIQHMQPSPQACNSAMKNINKHT3.1.27.-)KRCKDLNTFLHEPFSSVAATCQTPKIACKNG(RNase 7)DKNCHQSHGPVSLTMCKLTSGKYPNCRYKE(Skin-derivedKRQNKSYVVACKPPQKKDSQQFHLVPVHLDantimicrobialRVLprotein 2)(SAP-2) Salivary glandHomo46MHDFWVLWVLLEYIYNSACSVLSATSSVSSRantimicrobialsapiensVLNRSLQVKVVKITNsalvic Secretogranin IHomo677MQPTLLLSLLGAVGLAAVNSMPVDNRNHNEprecursor (SgI)sapiensGMVTRCIIEVLSNALSKSSAPPITPECRQVLKT(ChromograninSRKDVKDKETTENENTKFEVRLLRDPADASEB) (CgB)AHESSSRGEAGAPGEEDIQGPTKADTEKWA[Contains:EGGGHSRERADEPQWSLYPSDSQVSEEVKTGAWKRHSEKSQREDEEEEEGENYQKGERGEDSSECCB peptide]EKHLEEPGETQNAFLNERKQASAIKKEELVARSETHAAGHSQEKTHSREKSSQESGEEAGSQENHPQESKGQPRSQEESEEGEEDATSEVDKRRTRPRHHHGRSRPDRSSQGGSLPSEEKGHPQEESEESNVSMASLGEKRDHHSTHYRASEEEPEYGEEIKGYPGVQAPEDLEWERYRGRGSEEYRAPRPQSEESWDEEDKRNYPSLELDKMAHGYGEESEEERGLEPGKGRHHRGRGGEPRAYFMSDTREEKRFLGEGHHRVQENQMDKARRHPQGAWKELDRNYLNYGEEGAPGKWQQQGDLQDTKENREEARFQDKQYSSHHTAEKRKRLGELFNPYYDPLQWKSSHFERRDNMNDNFLEGEEENELTLNEKNFFPEYNYDWWEKKPFSEDVNWGYEKRNLARVPKLDLKRQYDRVAQLDQLLHYRKKSAEFPDFYDSEEPVSTHQEAENEKDRADQTVLTEDEKKELENLAAMDLELQKIAEKFSQRG Similar toHomo226AEGKWGLAHGRAEAHVWPGQGGWRLGPPazurocidin 1sapiensQGRWTGSSPLLDIVGGRKARPRQFPFLASIQ(CationicNQGRHFCGGALIHARFVMTAASCFQSQNPGantimicrobialVSTVVLGAYDLRRRERQSRQTFSISSMSENGprotein 37)YDPQQNLNDLMLLQLDREANLTSSVTILPLPL(Fragment)QNATVEAGTRCQVAGWGSQRSGGRLSRFPRFVNVTVTPEDQCRPNNVCTGVLTRRGGICNVSAPCGGRRGPERY
Nonhuman AnimalAntimicrobial PeptidesOrganismProtein NameNameLengthSequence11.5 kDaCarcinus84NKDCKYWCKDNLGLNYCCGQPGVTYPPFTKantibacterialmaenasKHLGRCPAVRDTCTGVRTQLPTYCPHDGACproteinQFRSKCCYDTCLKHHVCKTAEYPY 27 kDaCyprinus19GIGGKPVQTAFVDNDGIYDantibacterialcarpioprotein(Fragment) 4 kDa defensinAndroctonus37GFGCPFNQGACHRHCRSIRRRGGYCAGLFKaustralisQTCTCYR 4 kDa defensinLeiurus38GFGCPLNQGACHRHCRSIRRRGGYCAGFFK(Antibacterial 4quinquestriatusQTCTCYRNkDa peptide) 7.5 kDaOvis aries164METQMASPSLGRCSLWLLLLGLLLPSASAQAbactinecinLSYREAVLRAVGQLNEKSSEVNLYRLLELDP(Fragment)PPKDAEDQGARKPVSFRVKETVCPRTSQQPPEQCDFKENGLVKQCVGTVSLDTSNDEFDLNCNELQSVRRLRPRRPRLPRPRPRPRPRPRSLPLPRPQPRRI AbaecinBombus39FVPYNPPRPGQSKPFPSFPGHGPFNPKIQWpascuorumPYPLPNPGH AbaecinApis mellifera53MKVVIFIFALLATICAAFAYVPLPNVPQPGRRPprecursorFPTFPGQGPFNPKIKWPQGY Acaloleptin A1Acalolepta71SLQPGAPNVNNKDQPWQVSPHISRDDSGNTluxuriosaRTDINVQRHGENNDFEAGWSKVVRGPNKAKPTWHIGGTHRW AchacinAchatina531MLLLNSALFILCLVCWLPGTSSSRVLTRREGPprecursorfulicaQCSRSVDVAVVGAGPSGTYSAYKLRNKGQTVELFEYSNRIGGRLFTTHLPNVPDLNLESGGMRYFKNHHKIFGVLVKELNLSNKEFTEGFGKPGRTRFFARGKSLTLEEMTSGDVPYNLSTEEKANQANLAGYYLKKLTGFDGEVLTIPQANKLEVDDGRKLYQLTVDEALDKVGTPEGKEFLKAFSTGNTEFIEGVSAVNYFLVELGEREEEILTLTDGMSALPQALADAFLKSSTSHALTLNRKLQSLSKTDNGLYLLEFLETNTHEGYTEESNITDLVCARKVILAIPQSALIHLDWKPLRSETVNEAFNAVKFIPTSKVFLTFPTAWWLSDAVKNPAFVVKSTSPFNQMYDWKSSNVTGDAAMIASYADTSDTKFQENLNSKGELIPGSAPGANRVTVALKEELLSQLSQAYGIERSDIPEPKSGTSQFWSSYPFEGDWTVWKAGYHCEYTQYIIERPSLIDDVFVVGSDHVNCIENAWTESAFLSVENVFEKYF Acyl-CoA-Sus scrofa87MSQAEFEKAAEEVKNLKTKPADDEMLFIYSHbinding proteinYKQATVGDINTERPGILDLKGKAKWDAWNGL(ACBP)KGTSKEDAMKAYINKVEELKKKYGI(Diazepambindinginhibitor) (DBI)(Endozepine)(EP) [Contains:DBI(32-86)] AdenoregulinPhyllomedusa81MAFLKKSLFLVLFLGLVSLSICEEEKRENEDEprecursorbicolorEEQEDDEQSEMKRGLWSKIKEVGKEAAKAA(DermaseptinAKAAGKAALGAVSEAVGEQBII)(DermaseptinB2) Alpha-defensinMacaca96MRTLAILAAILLVALQAQAEPLQARTDEATAA1mulattaQEQIPTDNPEVVVSLAWDESLAPKDSVPGLRKNMACYCRIPACLAGERRYGTCFYMGRVWAFCC Alpha-defensinMacaca96MRTLAILAAILLVALQAQAEPLQARTDEATAA1AmulattaQEQIPTDNPEVVVSLAWDESLAPKDSVPGLRKNMACYCRIPACLAGERRYGTCFYLGRVWAFCC Alpha-defensinMacaca94MRTLAILAAILLFALLAQAKSLQETADDAATQE2mulattaQPGEDDQDLAVSFEENGLSTLRASGSQARRTCRCRFGRCFRRESYSGSCNINGRIFSLCCR Alpha-S2Bos taurus222MKFFIFTCLLAVALAKNTMEHVSSSEESIISQEcaseinTYKQEKNMAINPSKENLCSTFCKEVVRNANEprecursorEEYSIGSSSEESAEVATEEVKITVDDKHYQKA[Contains:LNEINQFYQKFPQYLQYLYQGPIVLNPWDQVCasocidin-I]KRNAVPITPTLNREQLSTSEENSKKTVDMESTEVFTKKTKLTEEEKNRLNFLKKISQRYQKFALPQYLKTVYQHQKAMKPWIQPKTKVIPYVRYL AndroctoninAndroctonus25RSVCRQIKICRRRGGCYYKCTNRPYaustralis AndropinDrosophila57MKYFVVLVVLALILAITVGPSDAVFIDILDKMEprecursormauritianaNAIHKAAQAGIGIAKPIEKMILPK AndropinDrosophila57MKYFVVLVVLALILAISVGPSDAVFIDILDKVENprecursormelanogasterAIHNAAQVGIGFAKPFEKLINPK AndropinDrosophila67MKYFLVLVVLTLILAISVGQSDALFVDIIDNVENprecursororenaAIHKAAKTGIGMVKPIENIFIPNQQKKSTEASN AndropinDrosophila57MKYFVVLVVLALILAITVDPSDAVFIDILDKMENprecursorsechelliaAIHKAAQAGIGLAKPIENMILPK AndropinDrosophila60MKYFVVLVVALILAIAVGPSDAVFIDILDKMEprecursorsimulansNAIHKAAQAGIGIAKPIENMILPKLTK AndropinDrosophila62MKYFSVLVVL