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WO2009119792A1 - GHRELIN ET DÉRIVÉ DE CELUI-CI, OU AGENT THÉRAPEUTIQUE DESTINÉ AUX INFECTIONS CHRONIQUES DES VOIES RESPIRATOIRES COMPRENANT UN AGONISTE DU RÉCEPTEUR 1a DU SÉCRÉTAGOGUE DE L’HORMONE DE CROISSANCE EN TANT QU’INGRÉDIENT ACTIF - Google Patents

GHRELIN ET DÉRIVÉ DE CELUI-CI, OU AGENT THÉRAPEUTIQUE DESTINÉ AUX INFECTIONS CHRONIQUES DES VOIES RESPIRATOIRES COMPRENANT UN AGONISTE DU RÉCEPTEUR 1a DU SÉCRÉTAGOGUE DE L’HORMONE DE CROISSANCE EN TANT QU’INGRÉDIENT ACTIF Download PDF

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Publication number
WO2009119792A1
WO2009119792A1 PCT/JP2009/056262 JP2009056262W WO2009119792A1 WO 2009119792 A1 WO2009119792 A1 WO 2009119792A1 JP 2009056262 W JP2009056262 W JP 2009056262W WO 2009119792 A1 WO2009119792 A1 WO 2009119792A1
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Prior art keywords
amino acid
substance
acid residue
amino
acid sequence
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English (en)
Japanese (ja)
Inventor
雅光 中里
淳一 芦谷
剛士 小玉
友二郎 林
賢治 寒川
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University of Miyazaki NUC
National Cerebral and Cardiovascular Center
Asubio Pharma Co Ltd
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University of Miyazaki NUC
National Cerebral and Cardiovascular Center
Asubio Pharma Co Ltd
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Publication of WO2009119792A1 publication Critical patent/WO2009119792A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the application of a substance acting on a growth hormone secretagogue receptor to the treatment of chronic respiratory infections. More specifically, the present invention relates to a therapeutic agent for chronic respiratory infections containing the substance as an active ingredient, a method for treating the disease, a use for the treatment, or the substance for the treatment.
  • Non-patent Document 1 The death from respiratory infections was number one in around 1920, but it was drastically reduced by the improvement of hygiene and the emergence of antibiotics such as penicillin, and the recognition that it was an important disease was weakened.
  • mortality from pneumonia and influenza was reported to have increased by 59%, and an increase in the proportion of people aged 65 and over was reported to be the main cause. Yes.
  • the situation in Japan is even more serious, and in 2015, a super-aging society in which one in four people will be 65 years old or older is imminent. In the future, it is suggested that there is a possibility that the number of people who die from respiratory infections will increase rapidly in conjunction with rapid aging in Japan (Non-patent Document 1).
  • Non-Patent Document 2 Opportunistic infections infecting elderly people and immunosuppressed individuals (patients) or lethal pathology due to nosocomial pneumonia include Gram-negative bacilli such as Pseudomonas aeruginosa, Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA), fungi, etc. Increase (Non-Patent Document 2).
  • MRSA is the most frequent hospital-causing pathogen and is transmitted by contact infection. More facilities than ever have taken preventive measures for nosocomial infections based on the guidelines of the US Centers for Disease Control, but MRSA is still showing a steady increase, especially in the US since the late 1990s, MRSA infections have also emerged as city infections. In-hospital and city infections due to MRSA continue to increase.
  • mupirocin as a topical medicine for oral vancomycin powder and MRSA eradication for nasal cavity for MRSA enteritis. Recently, newly approved linezolid has been recommended (Non-Patent Document 4).
  • Non-Patent Document 5 In Scandinavian countries that have succeeded in suppressing MRSA, thorough monitoring culture for high-risk groups and thorough isolation preventive measures until test results are obtained (Non-Patent Document 5) can be mentioned.
  • Pseudomonas aeruginosa exerts its pathogenicity mainly as an opportunistic infection for humans. Since this bacterium is originally widely resistant to antibiotics, its antibiotic therapy is often difficult. For severe Pseudomonas aeruginosa infections, carbapenems, third and fourth generation cephems, new quinolones, aminoglycoside antibacterials, and combinations thereof have been performed. Recently, however, a multidrug-resistant Pseudomonas aeruginosa that exhibits resistance to all of these antibacterial drugs has emerged and has become a problem (Non-patent Document 6).
  • Non-patent Documents 7-9 Chronic respiratory infections associated with airway pulmonary disorders such as bronchiectasis, Cystic Fibrosis and panbronchiolitis are characterized by neutrophil-dependent inflammation, and repeated infection with multidrug-resistant bacteria causes a hexemia condition. It falls into a terminal state (Non-patent Documents 7-9). Although neutrophils in the lung continue to try to sterilize bacteria in the respiratory tract, host cells are damaged by excess proteolytic enzymes and myeloperoxidase released from neutrophils (Non-patent Document 10). .
  • Non-Patent Documents 11-14 Damage to airways and alveolar epithelial cells due to accumulation of neutrophils leads to deterioration of lung function (Non-Patent Documents 11-14), and excessive energy consumption and weight loss of individuals (patients) (Non-Patent Document 15).
  • Prolonged lower respiratory tract infections of multidrug-resistant Pseudomonas aeruginosa and Staphylococcus aureus will lead to further neutrophil influx into the respiratory tract of individuals (patients) with chronic respiratory infections (Non-patent literature) 16). Since tissue damage by neutrophils provides an environment in which these bacteria can easily propagate, preventing excessive neutrophil influx is an appropriate treatment for reactive respiratory infections.
  • Non-patent Document 17 discloses a neutrophil elastase
  • Non-patent Document 18 Non-patent Document 18
  • Penicillin antibiotics were the first choice for H. influenzae, but ⁇ -lactamase-producing H. influenzae has increased to about 10-15% in recent years. Third generation cephem agents are also effective. Chronic respiratory tract infections are susceptible to recurrence, and caution is necessary because long-term chemotherapy causes Pseudomonas aeruginosa infection (Non-patent Document 19).
  • Non-patent Document 20 The frequency of bacterial pneumonia remains almost unchanged. Although treatment has become easier compared to the days before the use of antibacterial drugs, the frequency of death among highly susceptible hosts and the elderly remains high.
  • the pathogens of community-acquired pneumonia include Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma, and hospital-acquired pneumonia. Cytomegalovirus is involved.
  • new resistant bacteria such as penicillin-resistant pneumococci and ESBLs-producing Gram-negative bacilli have emerged due to the use of antibacterial drugs, which has become an important problem worldwide (Non-patent Document 20).
  • Non-patent Document 21 It is said that in order to recover the drug resistance pattern of multi-drug resistant Pseudomonas aeruginosa, it is necessary to discontinue antibacterial drugs, and administration of unnecessary antibacterial drugs should be discontinued (Non-patent Document 21).
  • Ghrelin is a hormone discovered from the stomach in 1999, has an amino acid sequence consisting of 28 residues, and the third amino acid from the amino terminus of this sequence is acylated with a fatty acid. It is a peptide having a structure (Non-patent Document 22, Patent Document 1). Ghrelin acts on the growth hormone secretagogue receptor receptor 1a (Growth Hormone Secretagogue Receptor 1a: GHS-R1a) (Non-patent Document 23), and promotes the secretion of growth hormone (GH) from the pituitary gland. It is a hormone (Non-patent Document 22).
  • Ghrelin is the first GHS-R1a endogenous GHS isolated and purified from rats for the first time, and vertebrates other than rats, such as humans, mice, pigs, chickens, eels, cows, horses, sheep, frogs, rainbow trout, and dogs. Is also known, the amino acid sequence of ghrelin having a similar primary structure (Patent Document 1).
  • the peptide is a peptide having a specific structure in which the side chain hydroxyl group of the 3-position serine residue (S) or threonine residue (T) is acylated with a fatty acid such as octanoic acid or decanoic acid.
  • a physiologically active peptide having a hydrophobic modification structure isolated from a living body other than ghrelin is not limited to ghrelin.
  • GHS-R1a substances acting on GHS-R1a include GHRP-2, which is a peptide compound, and MK-0677, which is a low molecular compound.
  • Non-patent Documents 24 to 26 Recent studies also show that ghrelin enhances appetite, increases body weight and body fat by subcutaneous administration (Non-patent Documents 24 to 26), and improves cardiac function. (Non-Patent Documents 27 to 29).
  • ghrelin has a GH secretion promoting action and an appetite enhancing action, and the action of burning fat through the action of GH to convert it into energy, or expressing the anabolic action of GH and strengthening the muscle is an increase in appetite. Therefore, it is expected to be effectively extracted (Non-patent Document 30).
  • the present invention relates to an application of a substance acting on a growth hormone secretion promoting factor receptor to the treatment of chronic respiratory infection, and a therapeutic agent for chronic respiratory infection, a method for treating the disease, or a use for the treatment Or it relates to the provision of the substance for the treatment.
  • a substance acting as an agonist to a growth hormone secretagogue factor receptor such as ghrelin
  • an increase in dietary intake, body composition and nutritional parameters It has been found that symptom can be improved by improving improvement of respiratory inflammation, improvement of exercise and respiratory function. That is, a substance that acts on the growth hormone secretion promoting factor receptor is caused by multidrug-resistant Pseudomonas aeruginosa and / or multidrug-resistant MRSA infection in elderly people (for example, humans 70 to 80 years) whose physical strength and resistance are reduced.
  • BMI BodyBMass Index
  • serum C-Reactive protein which is an indicator of inflammatory condition, decreased, decreased sputum, purulent sputum changed to serous sputum, decreased neutrophils in the sputum, IL-8 and myeloperoxidase, It was shown that the inflammatory condition was improved and that the multi-drug resistant Pseudomonas aeruginosa and multi-drug resistant MRSA were eradicated.
  • the infection can be treated by administering a substance acting on the growth hormone secretion promoting factor receptor to an individual (patient) having a chronic respiratory infection.
  • the present invention relates to a therapeutic agent for chronic respiratory infections comprising a substance that acts on a growth hormone secretagogue receptor as an active ingredient, or a method for treating the disease or a use for the treatment.
  • the present invention relates to the following items.
  • a therapeutic agent for chronic respiratory infections in humans or animals comprising a substance that acts on a growth hormone secretagogue receptor or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the substance is: (1) A peptide in which the third amino acid residue from the amino terminus is a modified amino acid residue in which a fatty acid is introduced into the side chain of the amino acid residue in the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 21 Compound; (2) In the amino acid sequence described in any one of SEQ ID NOs: 1 to 21, one to several amino acids in the amino acid sequence from the amino terminus to the fifth to carboxyl terminus are deleted, substituted, and / or added.
  • a peptide compound which is a modified amino acid residue having a fatty acid introduced into its side chain, which acts on a growth hormone secretagogue receptor De compounds;
  • the therapeutic agent according to [1] above which is a peptide compound selected from the group consisting of: [3] A peptide in which the substance is a modified amino acid residue in which a serine residue located at the third position from the amino terminus in the amino acid sequence shown in SEQ ID NO: 1 has a fatty acid introduced into the hydroxyl group of the side chain of the residue
  • the above substance is a peptide compound in which the hydroxyl group of the side chain of the serine residue located third from the amino terminus is acylated with an n-octanoyl group in the amino acid sequence set forth in SEQ ID NO: 1.
  • the therapeutic agent according to [3].
  • the chronic respiratory infection is chronic multidrug resistant bacterial respiratory infection caused by multidrug resistant Pseudomonas aeruginosa and / or multidrug resistant methicillin resistant Staphylococcus aureus (MRSA).
  • MRSA multidrug resistant methicillin resistant Staphylococcus aureus
  • a method for treating chronic respiratory infection comprising administering to an individual a substance acting on a growth hormone secretagogue receptor or a pharmaceutically acceptable salt thereof.
  • the substance is: (1) A peptide in which the third amino acid residue from the amino terminus is a modified amino acid residue in which a fatty acid is introduced into the side chain of the amino acid residue in the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 21 Compound; (2) In the amino acid sequence described in any one of SEQ ID NOs: 1 to 21, one to several amino acids in the amino acid sequence from the amino terminus to the fifth to carboxyl terminus are deleted, substituted, and / or added.
  • a peptide compound which is a modified amino acid residue having a fatty acid introduced into its side chain, which acts on a growth hormone secretagogue receptor De compounds;
  • the method according to [7] above which is a peptide compound selected from the group consisting of: [9]
  • a peptide in which the substance is a modified amino acid residue in which a serine residue located third from the amino terminus in the amino acid sequence shown in SEQ ID NO: 1 has a fatty acid introduced into the hydroxyl group of the side chain of the residue
  • the above substance is a peptide compound in which the hydroxyl group of the side chain of the serine residue located third from the amino terminus in the amino acid sequence set forth in SEQ ID NO: 1 is acylated with an n-octanoyl group
  • Any one of the above [7] to [11] wherein the chronic respiratory infection is a chronic multidrug resistant bacterial respiratory infection caused by multidrug resistant Pseudomonas aeruginosa and / or multidrug resistant MRSA The treatment method according to item.
  • the substance is: (1) A peptide in which the third amino acid residue from the amino terminus is a modified amino acid residue in which a fatty acid is introduced into the side chain of the amino acid residue in the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 21 Compound; (2) In the amino acid sequence described in any one of SEQ ID NOs: 1 to 21, one to several amino acids in the amino acid sequence from the amino terminus to the fifth to carboxyl terminus are deleted, substituted, and / or added.
  • a peptide compound which is a modified amino acid residue having a fatty acid introduced into its side chain, which acts on a growth hormone secretagogue receptor De compounds;
  • the substance is: (1) A peptide in which the third amino acid residue from the amino terminus is a modified amino acid residue in which a fatty acid is introduced into the side chain of the amino acid residue in the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 21 Compound; (2) In the amino acid sequence described in any one of SEQ ID NOs: 1 to 21, one to several amino acids in the amino acid sequence from the amino terminus to the fifth to carboxyl terminus are deleted, substituted, and / or added.
  • a peptide compound which is a modified amino acid residue having a fatty acid introduced into its side chain, which acts on a growth hormone secretagogue receptor De compounds;
  • the substance according to [19] above or a pharmaceutically acceptable salt thereof which is a peptide compound selected from the group consisting of: [21]
  • a peptide in which the substance is a modified amino acid residue in which a serine residue located third from the amino terminus in the amino acid sequence set forth in SEQ ID NO: 1 has a fatty acid introduced into the hydroxyl group of the side chain of the residue
  • the above substance is a peptide compound in which the hydroxyl group of the side chain of the serine residue located third from the amino terminus in the amino acid sequence set forth in SEQ ID NO: 1 is acylated with an n-octanoyl group
  • a substance acting on a growth hormone secretagogue receptor improves chronic respiratory infections, particularly chronic multidrug resistant bacterial respiratory infections caused by multidrug resistant Pseudomonas aeruginosa and / or multidrug resistant MRSA. It was clarified that it has an action to make. Based on this action, by administering a substance that acts on the growth hormone secretagogue receptor to an individual (patient) having a chronic respiratory infection, it is possible to treat these infections.
  • Growth hormone secretagogue receptor includes growth hormone secretagogue receptor (GHS-R), and growth hormone secretagogue receptor (GHS-R) is a receptor to which growth hormone secretory factor (GHS) binds. It is known that subtypes such as GHS-R-1a and GHS-R 1b exist. Of these, only GHS-RGH1a is known to activate phospholipase C -related signaling-related receptors and increase intracellular calcium. In the present specification, “growth hormone secretagogue receptor” or “GHS-R” refers to GHS-R 1a unless otherwise specified.
  • GHS-R The presence of GHS-R can be confirmed using methods known to those skilled in the art. For example, using a technique known to those skilled in the art, RNA is extracted from a tissue in which the presence of GHS-R is to be confirmed, and cDNA is obtained from the RNA. The obtained cDNA was amplified by PCR using a sense primer specific to GHS-R (eg, SEQ ID NO: 22) and an antisense primer (eg, SEQ ID NO: 23), then electrophoresed, and GHS- The presence of GHS-R can be confirmed by observing the expression of R mRNA.
  • a sense primer specific to GHS-R eg, SEQ ID NO: 22
  • an antisense primer eg, SEQ ID NO: 23
  • GHS-R a frozen section from a tissue to be confirmed for the presence of GHS-R using a method known to those skilled in the art, immunostaining with an anti-GHS-R antibody, and observing with a fluorescence microscope, GHS- The existence of R can be confirmed.
  • whether or not “has an activity of increasing the intracellular calcium ion concentration” can be determined by measuring the intracellular calcium ion concentration using a method known to those skilled in the art.
  • FLIPR Fluorometric Imaging Plate Reader, Molecular Devices Co., Ltd.
  • Fluo-4 AM Fluo-4 AM
  • methods known to those skilled in the art can be used to confirm whether a peptide having an intracellular calcium concentration-increasing activity has growth hormone secretagogue factor activity in vitro and in vivo.
  • growth hormone is secreted and added to pituitary cells that have been confirmed to express GHS-R. It can be measured by immunoassay.
  • the growth hormone concentration in the serum after injecting a peptide having an intracellular calcium concentration increasing activity into the peripheral vein of the animal may be measured.
  • the medicament of the present invention can be used as a medicament for animals (individuals) including humans.
  • the “substance acting on the growth hormone secretagogue receptor” is a substance (ligand) acting on the growth hormone secretagogue receptor (GHS-R), preferably by binding to GHS-R. It is a substance having an activity to increase intracellular calcium ion concentration.
  • growth hormone secretion promoting factor GLS
  • known peptide compounds and low molecular weight compounds can be used as GHS, but ghrelin is particularly desirable.
  • “Peptide” refers to a compound in which a plurality of amino acids (or expressed as amino acid residues) are linked by peptide bonds.
  • amino acids include amino acids of the general formula: NH 2 —CH (R ′) — COOH, as well as natural amino acids having a group in which R ′ exists in nature, and D, L-optical isomers thereof.
  • a natural amino acid in a peptide is replaced with a modified amino acid (or expressed as a modified amino acid residue).
  • Modified amino acids include not only amino acids in which the substituent R ′ of the above general formula is further modified, or D, L-optical isomers thereof, but also, for example, in the substituent R ′ of the above general formula, esters, ethers, thioesters, thioethers, Also included are non-natural amino acids to which various substituents are bonded, with or without amide, carbamide, thiocarbamide or the like.
  • R ′ As such R ′, —OCOY, —OY, —OCSY, —S—COY, —S—CSY, —SY, —CONHY, —NH—CO—NHY, —NH—CS—NH—Y, or —SSY (Y represents an organic group such as an alkyl group having 1 to 30 carbon atoms, an aryl group, an aralkyl group, or a 4- to 6-membered heterocyclic group) is preferable. Also included are unnatural amino acids in which the amino group of the amino acid is substituted with a lower alkyl group.
  • peptide derivative refers to, for example, a compound in which at least one amino acid in the peptide is substituted with a non-amino acid compound, a compound in which the amino terminal and / or carboxyl terminal of the peptide is modified (for example, the carboxyl terminal is an amide A compound in which at least one amino acid in the peptide is substituted with a non-amino acid compound and the amino terminus and / or the carboxyl terminus is further modified, and the above “peptide” and "peptide derivative” are collectively referred to as In the present specification, it is referred to as “peptide compound”.
  • amino acid includes all amino acids such as L-amino acid, D-amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, natural amino acid, synthetic amino acid and the like.
  • modified amino acid means an amino acid in which any group of the amino acid is chemically modified.
  • a modified amino acid in which a group bonded to the ⁇ carbon in the ⁇ -amino acid (for example, the group represented by the above R ′) is chemically modified is preferable.
  • ghrelin is a peptide in which the hydroxyl group of the side chain of the third amino acid residue from the amino terminus of the peptide having any one of SEQ ID NOs: 1 to 21 is acylated with a fatty acid.
  • the number of carbon atoms of the fatty acid is preferably 2, 4, 6, 8, 10, 12, 14, 16 or 18, more preferably octanoic acid and decanoic acid or monoene fatty acid or polyene fatty acid thereof, particularly octanoic acid ( Carbon number: 8, octanoyl group) is desirable.
  • those having the fatty acids described in the “Background Art” section are also preferable.
  • ghrelin derived from humans ghrelin derived from other animals such as rats, mice, pigs, cows, and the like, and derivatives thereof can be used.
  • ghrelin derived from the species to which the individual belongs is preferably used.
  • human-derived ghrelin is preferably used for humans.
  • Human-derived ghrelin is a peptide having the sequence of SEQ ID NO: 1 consisting of 28 amino acids, wherein the side chain hydroxyl group of the third serine residue from the amino terminus is acylated with a fatty acid (n-octanoyl group). Can be mentioned.
  • ghrelin-like activity such as an increase in intracellular calcium
  • it has at least an amino acid sequence from the amino terminus to the fourth amino acid, and the third amino acid residue from the amino terminus is present in the side chain of the amino acid residue.
  • derivatives of ghrelin include, for example, amino acid sequences described in SEQ ID NOs: 1 to 21 in the amino terminal position from the fifth to the carboxyl terminal (preferably , Having an amino acid sequence in which one to several amino acids are substituted, inserted, or deleted in the amino acid residues from the amino terminus to the carboxyl terminus), and the growth hormone secretagogue receptor (GHS-R) Any peptide that acts can be used.
  • GLS-R growth hormone secretagogue receptor
  • the sequence from the amino terminus to the 4th for example, at least the 5th, preferably the 10th, is retained, and the amino acid residue from the amino terminus to the 3rd amino acid residue side
  • the hydroxyl group of the chain is acylated with a fatty acid, it can be suitably used as ghrelin.
  • ghrelin (1-5) -Lys-NH 2 (GSS (n-octanoyl) FLK-NH 2 ) and ghrelin (1-7) -Lys-NH 2 (GSS (n-octanoyl) FLSPK-NH 2 ) having at least the fifth sequence from the amino terminus of ghrelin can be used.
  • the addition of basic amino acids enhanced the increase of intracellular calcium in GHS-R-expressing cells, and these derivatives mimicked peptide bonds by amidating amino acid carboxyl ends without terminating with carboxylic acids. Since it is possible to find the minimum active unit with a shorter amino acid sequence, it is possible to add a basic amino acid to the carboxyl terminus or to form an amide such as -Lys-NH 2 if desired. An amino acid introduced may be used.
  • a peptide comprising the amino acid sequence or a derivative thereof is desired.
  • it is not particularly limited as long as it has the above functions, it is, for example, about 1 to 9, 1 to 6, or 1 to 4.
  • the amino acid has similar properties (charge and / or polarity), the desired function is not lost even if a large number of amino acids are substituted.
  • the amino acid sequence of the peptide or derivative thereof is 70% or more, preferably 80% or more, more preferably 90% or more, particularly preferably 95% or more, and most preferably 97% or more compared to the natural amino acid sequence. It is desirable to have the homology of The same applies to ghrelin derived from other animals (SEQ ID NOs: 2 to 21).
  • preferred peptides or derivatives thereof include: It has any one of the amino acid sequences described in SEQ ID NOs: 1 to 21, preferably SEQ ID NOs: 1 to 9, more preferably SEQ ID NO: 1, and the third amino acid from the amino terminus is a fatty acid introduced into the side chain.
  • a modified amino acid peptide or derivative thereof is an ester, an ether, a thioether, a thioester, an amide, a carbamide, with or without an alkylene group having 1 to 10 carbon atoms on the ⁇ -carbon of the amino acid, It is a modified amino acid residue having a saturated or unsaturated linear, branched or cyclic alkyl chain having 1 to 35 carbon atoms introduced through a thiocarbamide or disulfide bond, or having 1 carbon atom on the ⁇ carbon of the amino acid
  • a peptide or derivative thereof which is a modified amino acid residue into which ⁇ 35 saturated or unsaturated alkyl chains have been introduced;
  • the fatty acid introduced into the side chain of ghrelin is a fatty acid having 2, 4, 6, 8, 10, 12, 14, 16 or 18 carbon atoms (preferably octanoic acid and decanoic acid or a monoene fatty acid thereof or
  • the peptide compound used as an active ingredient in the present invention is preferably an amino acid sequence described in any one of SEQ ID NOS: 1 to 21, wherein the OH group of the side chain of the third amino acid is -OCO-Z,- OZ, -SZ, -OCS-Z, -S-CO-Z, -S-CS-Z, -CO-NH-Z, -NH-CO-NH-Z, -NH-CS-NH
  • a peptide compound in addition to the above, as a substance acting on the growth hormone secretagogue receptor used in the present invention, a peptide compound, growth hormone releasing peptide-2 (GHRP-2: D-Ala-D- ⁇ Nal-Ala- Trp-D-Phe-Lys-NH 2 ) and growth hormone releasing peptide-6 (GHRP-6: His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 ) (Muccioli, G et al .: J. Endocrino., 157; 99-106 (1998)) and their derivatives can be used.
  • GHRP-2 D-Ala-D- ⁇ Nal-Ala- Trp-D-Phe-Lys-NH 2
  • growth hormone releasing peptide-6 GHRP-6: His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2
  • Examples of substances that act on the growth hormone secretagogue receptor used in the present invention include L-692,429 (MK-0751) and L-163,191 (MK-0677) (Patchett et al .: Proc. Acad. Sci., USA, 92, pp. 7001-7005 (1995)) and the like can be used.
  • the substance that acts on the growth hormone secretagogue receptor according to the present invention can be obtained by a conventional method (see, for example, J. Med. Chem., 43, pp. 4370-4376, 2000, Patent Document 1).
  • it can be isolated from natural sources or can be produced by recombinant DNA techniques and / or chemical synthesis.
  • a modification reaction can be performed according to a known means.
  • a host cell transformed with an expression vector having a DNA encoding the peptide compound of the present invention is cultured, and the target peptide compound is collected from the culture.
  • the peptide compound according to the present invention can also be obtained.
  • a compound in which the target peptide compound is modified for example, acylated
  • a modification reaction such as acylation may be performed according to known means if desired.
  • Examples of the vector into which the gene is incorporated include E. coli vectors (pBR322, pUC18, pUC19, etc.), Bacillus subtilis vectors (pUB110, pTP5, pC194, etc.), yeast vectors (YEp type, YRp type, YIp type), or animal cells. These vectors (retrovirus, vaccinia virus, etc.) can be used, and any other vector can be used as long as it can stably hold the target gene in the host cell.
  • the vector is introduced into a suitable host cell.
  • a method for incorporating a target gene into a plasmid or a method for introducing it into a host cell for example, the method described in Molecular® Cloning® (Sambrook® et al., 1989) can be used.
  • a promoter is connected upstream of the gene so as to function.
  • the promoter used in the present invention may be any promoter as long as it is appropriate for the host cell used for expression of the target gene.
  • the host cell to be transformed is Escherichia
  • SPO1 promoter, SPO2 promoter, etc. can be used.
  • GAP promoter, PHO5 promoter, ADH promoter and the like can be used, and in the case of animal cells, SV40-derived promoter, retrovirus-derived promoter and the like can be used.
  • the host cell is transformed with the vector containing the target gene obtained as described above.
  • bacteria eg, Escherichia genus, Bacillus genus, etc.
  • yeast Sacharomyces genus, Pichia genus, Candida genus, etc.
  • animal cells CHO cells, COS cells etc.
  • a liquid medium is suitable as a medium for culturing, and it is particularly preferable that the medium contains a carbon source, a nitrogen source and the like necessary for the growth of the transformed cells to be cultured. If desired, vitamins, growth promoting factors, serum and the like can be added.
  • the host cell In order to directly produce a fatty acid-modified (acylated) peptide compound, the host cell has a processing protease activity capable of cleaving the precursor polypeptide of the peptide compound at an appropriate position, and serine contained in the peptide compound. Cells that have the ability to acylate residues are desirable. A host cell having such processing protease activity and serine acylation activity is transformed with an expression vector containing cDNA encoding the precursor polypeptide, and the transformed cell has calcium-elevating activity or growth hormone secretion. Selection can be made by confirming that a fatty acid-modified peptide having promoting activity is produced.
  • the peptide compound according to the present invention is separated and purified from the culture by a conventional method.
  • a protein denaturant eg, guanidine hydrochloride
  • the cells or cells are collected after culturing, suspended in a buffer solution containing a protein denaturant (eg, guanidine hydrochloride), and then the cells by ultrasound.
  • the cells are disrupted and then centrifuged.
  • gel filtration, ultrafiltration, dialysis, SDS-PAGE various chromatographies are performed in consideration of the molecular weight, solubility, charge (isoelectric point), affinity, etc. of the target substance. Separation and purification methods such as chromatography can be appropriately combined.
  • the substance (for example, ghrelin and its derivatives) acting on the growth hormone secretagogue receptor according to the present invention can be chemically synthesized by a conventional method.
  • an amino acid with a protecting group is condensed by a liquid phase method and / or a solid phase method, the peptide chain is extended, all protecting groups are removed with an acid, and the resulting crude product is purified by the above purification method.
  • the side chain of the amino acid at the target position can be selectively acylated with an acylating enzyme or an acyltransferase.
  • peptide compounds as substances according to the present invention can also be easily produced according to known methods, for example, classical peptide synthesis methods may be used. However, it can be easily produced according to a solid phase method.
  • a method using a combination of recombinant DNA technology and chemical synthesis may be used. Fragments containing modified amino acid residues are produced by chemical synthesis, and other fragments not containing modified amino acid residues are produced using recombinant DNA technology. Can also be produced by the method of fusing each fragment and then fusing each fragment (see Patent Document 1).
  • the salt relating to the substance acting on the growth hormone secretagogue receptor (for example, ghrelin and its derivatives) that can be used in the present invention is preferably a pharmaceutically acceptable salt, such as a salt with an inorganic base, an organic base, and the like. , Salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.
  • salt with an organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
  • sodium salts and potassium salts are most preferable.
  • a substance for example, ghrelin
  • ghrelin ghrelin
  • it is effective against a chronic multidrug resistant bacterial respiratory infection caused by infection with multidrug resistant Pseudomonas aeruginosa and / or multidrug resistant MRSA.
  • Such therapeutic action can occur through the growth hormone secretory factor receptor.
  • the substance (for example, ghrelin) or a pharmaceutically acceptable salt thereof acting on the growth hormone secretion factor receptor according to the present invention is used for chronic respiratory infections, particularly multidrug resistant Pseudomonas aeruginosa and / or multidrug resistant. It can be used as an active ingredient in the treatment of chronic multi-drug resistant bacterial respiratory infections caused by MRSA. Furthermore, there is no effective antibacterial agent for multi-drug resistant Pseudomonas aeruginosa, and Pseudomonas aeruginosa is easy to acquire multi-drug resistance (Hiragata: latest medicine 61: 224-229 (2006)). Possible treatment methods without the use of antibacterial agents for the treatment of Pseudomonas aeruginosa infections can be extremely important in elderly individuals (patients) who have lost their resistance. It is also suitable for use in the treatment of chronic respiratory infections.
  • a substance for example, ghrelin
  • a pharmaceutically acceptable salt thereof acting on the growth hormone secretagogue receptor may be used for chronic respiratory infections, particularly multidrug resistant Pseudomonas aeruginosa and / or multidrug. It can be used in the manufacture of a therapeutic agent for chronic multi-drug resistant bacterial respiratory infection caused by infection with resistant MRSA.
  • a drug of the present invention containing a substance acting on a growth hormone secretagogue receptor (for example, ghrelin) or a pharmacologically acceptable salt thereof as an active ingredient is a pharmacologically acceptable carrier, excipient, increasing amount. It can be used for individuals (for example, mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.) by mixing with agents.
  • the agent (therapeutic agent) of the present invention is administered to an individual who is treating chronic respiratory infection parenterally, for example, intravenously, subcutaneously or intramuscularly, in a predetermined amount once or multiple times.
  • the administration is preferably divided into two, but nasal administration, pulmonary administration, and suppository administration are desirable particularly when the individual is a human adult and is treated at home.
  • the dosage of the drug is not particularly limited, and can be appropriately selected according to the purpose of use and the age, weight, individual type, symptom, nutritional status, concomitant drug, etc. of the individual to be administered.
  • the range of 0.001 mg to 100 mg is preferable, with a substance acting on the growth hormone secretagogue receptor (for example, ghrelin) or a pharmaceutically acceptable salt thereof as an active ingredient. 01 mg to 10 mg is more desirable.
  • the above dose is preferably administered once to several times a day, preferably for 2 to 24 weeks, more preferably for 3 to 12 weeks.
  • the therapeutic agent of the present invention is produced by mixing the peptide compound with a pharmaceutical additive such as a pharmacologically acceptable carrier.
  • a pharmaceutical additive such as a pharmacologically acceptable carrier.
  • various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations; solvents, dissolution aids in liquid preparations , Suspending agents, isotonic agents, buffering agents, soothing agents and the like are added to the therapeutic agent of the present invention as formulation additives.
  • preservatives antioxidants, coloring agents, sweeteners, and the like can be used as formulation additives as necessary.
  • excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • the solvent include distilled water, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate;
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • the tonicity agent include sodium chloride, glycerin, D-mannitol and the like.
  • buffer solutions such as phosphate, acetate, carbonate and citrate.
  • a preferred example of the soothing agent is benzyl alcohol.
  • preservative examples include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfite and ascorbic acid.
  • the pharmaceutical dosage form of the present invention is preferably a dosage form suitable for parenteral administration.
  • the dosage form suitable for parenteral administration include injection for intravenous administration, intradermal administration, subcutaneous administration or intramuscular administration.
  • Agents, infusions, suppositories, transdermal absorption agents, transmucosal absorption agents, inhalants, etc. but the above-mentioned injection preparations are preferred, especially when the individual is a human adult and is treated at home.
  • preparation forms such as transmucosal absorbents, inhalants, suppositories and the like.
  • formulation forms are variously known to those skilled in the art, and those skilled in the art appropriately select a formulation form suitable for a desired administration route, and if necessary, add one or more formulation additives available in the art. It can be used to produce a preparation in the form of a pharmaceutical composition.
  • a medicine in the form of an injection or infusion is an appropriate buffer solution, sugar solution, isotonic agent, pH regulator, soothing agent together with a substance (for example, ghrelin) that acts on the active ingredient GHS-R1a.
  • a substance for example, ghrelin
  • 1 or 2 or more formulation additives such as preservatives are dissolved in distilled water for injection and sterilized (filtered) and then ampoules or vials are filled, or the sterilized filtered solution is lyophilized to obtain a lyophilized formulation Can be prepared and provided.
  • additives include sugars such as glucose, mannitol, xylitol, and lactose, hydrophilic polymers such as polyethylene glycol, alcohols such as glycerol, amino acids such as glycine, proteins such as serum albumin, NaCl, sodium citrate Salts such as acetic acid, tartaric acid, ascorbic acid, surfactants such as Tween 80, reducing agents such as sodium sulfite, and the like can be used. Such a preparation can be used as an injection or an instillation by adding and dissolving distilled water for injection or physiological saline at the time of use.
  • intranasal administration agents such as nasal sprays and intranasal sprays are suitable, and inhalation agents are also suitable for transpulmonary administration.
  • the content of a substance (for example, ghrelin) or a pharmaceutically acceptable salt thereof acting on a growth hormone secretory factor receptor in one preparation is 0.001 mg to 100 mg, preferably 0.01 mg to 10 mg, and once a day. It is desirable to administer several times.
  • the amount indicates the amount as a substance (for example, a peptide compound) except in special cases. That is, regarding salts, it is described as a considerable amount of a corresponding substance (for example, a peptide compound) except in special cases.
  • Test protocol Chemically synthesized human ghrelin (a peptide compound having the amino acid sequence of SEQ ID NO: 1, wherein the hydroxyl group of the side chain of the third serine is acylated with an n-octanoyl group) was used for the test. 4 (W / V)% D-mannitol aqueous solution was added to ghrelin, and a ghrelin stock solution with a concentration of 60 ⁇ g / mL was prepared and sterilized (0.22 ⁇ m Millex filter (Millipore, Bedford, MA, USA)).
  • Example 1 Improvement of body composition and nutritional markers by ghrelin Meal intake was measured over 3 days before and during the last week of ghrelin treatment. The result is expressed by a 10-level evaluation, and the maximum value 10 is 1800 Kcal. In addition, body weight, BMI, lean body mass, fat mass, bone mass, and fat percentage were measured before and after treatment. The results are shown in Table 1. Ghrelin treatment increased dietary intake, body weight and BMI (p ⁇ 0.005).
  • GH growth hormone
  • IGF-1 insulin-like growth factor-1
  • leptin with an appetite-reducing effect
  • adrenaline and noradrenaline sympathetic neurotransmitters that increase energy consumption, etc. It was measured. The results are shown in Table 3. Ghrelin treatment tended to increase GH secretion, increased IGF-1 (p ⁇ 0.05), and decreased noradrenaline (p ⁇ 0.05).
  • Example 2 Improvement of inflammation marker by ghrelin
  • CRP inflammation marker C-reactive protein
  • IAM-1 soluble intercellular adhesion molecule- Type 1
  • the soot was collected and weighed during the test period. For observation of cells in the sputum, the first sputum after waking up in the morning was used.
  • the koji was mixed with 0.1% dithiothreitol for 30 minutes, and after filtration, centrifuged (500 g), and the supernatant and the cell precipitate fraction were collected. The supernatant was stored at ⁇ 40 ° C.
  • Interleukin-8 (IL-8) (Central Laboratory of the Netherlands Red Cross, Amsterdam, Netherlands), tumor necrosis factor ⁇ (TNF- ⁇ ) (Invitrogen Corp.), Polymorphonuclear neutrophil (PMN) elastase (Bender MedSystems GmbH, Vienna, Austria) and myeloperoxidase (MPO) (Assay Designs, AnnArbor, MI, USA) were used for the measurement.
  • the cell precipitate fraction was resuspended in phosphate buffer, and the total cell count and neutrophil count were counted.
  • Observation of cells in sputum and measurement of inflammatory markers in sputum supernatant were performed on specimens before ghrelin treatment and the last week of treatment. Table 4 shows the results regarding inflammatory markers in blood and serum. It was shown that ghrelin treatment reduced serum CRP and soluble ICAM-1 and alleviated inflammation. There was no change in the number of white blood cells, neutrophils and lymphocytes in the blood.
  • the result regarding the inflammation marker in sputum is shown in FIG.1 and FIG.2.
  • the amount of sputum decreased (p ⁇ 0.05), and the neutrophil ratio and the number of neutrophils in sputum also decreased (p ⁇ 0.05) (FIG. 1).
  • IL-8, TNF- ⁇ and myeloperoxidase in sputum decreased (P ⁇ 0.02) (FIG. 2).
  • serum inflammatory markers CRP and soluble ICAM-1
  • sputum is decreased, and the ratio of neutrophils, neutrophil count and IL- 8.
  • Example 3 Improvement of exercise / respiratory function with ghrelin Exercise tolerance before and after ghrelin treatment (6-minute walk test) and oxygen analysis parameters (arterial oxygen partial pressure (PaO2), arterial carbon dioxide partial pressure (PaCO2), pH and lungs The alveolar-arterial gradient in oxygen (P (Aa) O2) was measured. The results are shown in Table 5.
  • Ghrelin treatment increased the 6-minute walking distance from 294 m to 348 m (p ⁇ 0.05).
  • the alveolar air artery blood oxygen partial pressure difference (P (Aa) O2) which is a parameter that increases when gas exchange in the alveoli decreases, decreased. It was shown that the exchange ability was improved.

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Abstract

La présente invention concerne l'application d'une substance capable d'agir sur un récepteur du sécrétagogue de l'hormone de croissance (par exemple la ghréline) ou un sel pharmaceutiquement acceptable de celle-ci, dans le but de traiter les infections chroniques des voies respiratoires. Plus spécifiquement, la présente invention concerne : un agent thérapeutique pour infections chroniques des voies respiratoires, qui comprend ladite substance en tant qu'ingrédient actif; un procédé destiné au traitement des infections chroniques des voies respiratoires, qui comprend l'administration de cette substance à un corps individuel; l'utilisation de ladite substance dans la production d'un agent thérapeutique pour infections chroniques des voies respiratoires; et l'utilisation de la substance dans le procédé destiné au traitement des infections chroniques des voies respiratoires.
PCT/JP2009/056262 2008-03-28 2009-03-27 GHRELIN ET DÉRIVÉ DE CELUI-CI, OU AGENT THÉRAPEUTIQUE DESTINÉ AUX INFECTIONS CHRONIQUES DES VOIES RESPIRATOIRES COMPRENANT UN AGONISTE DU RÉCEPTEUR 1a DU SÉCRÉTAGOGUE DE L’HORMONE DE CROISSANCE EN TANT QU’INGRÉDIENT ACTIF Ceased WO2009119792A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011087102A1 (fr) * 2010-01-15 2011-07-21 国立大学法人宮崎大学 Agent thérapeutique pour encourager la récupération d'un animal sous traitement médical
US9078868B2 (en) 2010-01-15 2015-07-14 University Of Miyazaki Therapeutic agent for accelerating recovery of animal under medical treatment

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