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WO2011086557A1 - Peptides destinés au traitement de maladies respiratoires - Google Patents

Peptides destinés au traitement de maladies respiratoires Download PDF

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Publication number
WO2011086557A1
WO2011086557A1 PCT/IL2011/000045 IL2011000045W WO2011086557A1 WO 2011086557 A1 WO2011086557 A1 WO 2011086557A1 IL 2011000045 W IL2011000045 W IL 2011000045W WO 2011086557 A1 WO2011086557 A1 WO 2011086557A1
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WO
WIPO (PCT)
Prior art keywords
group
amino acid
ile
glu
arg
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Application number
PCT/IL2011/000045
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English (en)
Inventor
Abd Al-Roof Higazi
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Thrombotech Ltd.
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Publication of WO2011086557A1 publication Critical patent/WO2011086557A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans

Definitions

  • the present invention relates to uses of peptides derived from human plasminogen activator inhibitor- 1 (PAI-1) for inhibiting airway smooth muscle contractility.
  • PAI-1 human plasminogen activator inhibitor- 1
  • the present invention relates to peptides of 7 to 30 amino acid residues corresponding to the amino acids 363-392 of human PAI-1 for the treatment of asthma.
  • NMDA-Rs N-methyl-D-aspartate receptors
  • NMDA-Rs Clues to the function of NMDA-Rs within the lung may come from their activity in other tissues.
  • NMDA-Rs play important physiological as well as pathological roles within the central nervous system (CNS).
  • plasminogen activators PAs
  • tissue type plasminogen activators tPA
  • uPA urokinase-type plasminogen activator
  • Tissue type PA forms a complex with the NMDA-R1 expressed by cortical neuronal cells in culture. This precedes the cleavage of its NR1 subunit, which is followed by enhancement of intracellular Ca ++ concentrations and cell death. It is uncertain whether cell death results from occupancy or cleavage of the NR1 subunit or from events downstream of the binding. It has recently been shown that tPA also causes vasodilatation in the mouse whisker barrel cortex due to phosphorylation of neuronal nitric oxide synthase leading to release of NO. Even less is known about the interaction between uPA and NMDA-R1.
  • PAs have been implicated in the development of asthma.
  • the level of uPA and PAI-1 is elevated in the sputum of asthmatic patients and associations between asthma and polymorphisms in the uPA and PAI-1 genes have been identified (Kowal et al., 2007, Int. Arch. Allergy Immunol., 144:240-246; Kowal et al., 2008, Folia Histochem Cytobiol 46: 193-198; Chu et al., 2006, Amer. J. Respir. Cell Mol. Biol. 35:628-638; Cho et al., 2004, Exp. Biol. Med. 229:138-146).
  • uPA is induced in human bronchial epithelial cells by mechanical activation in vitro and in vivo (Chu et al., 2006, Amer. J. Respir Cell. Mol. Biol. 35:628-638).
  • uPA is activated by mast cell tryptase, promotes the adhesion of airway eosinophils to ICAM-1 and VCAM-1 after allergen challenge, and potentiates PDGF-induced chemotaxis of human airway SMC.
  • uPA and PAI-1 have also been implicated in the deposition of extracellular matrix and in other aspects of airway remodeling. Each of these outcomes suggests that chronic activation of the PA system may contribute to the development of asthma.
  • subepithelial fibrin which is characteristic of chronic asthma, enhances airway hyperresponsiveness, and aerosolized tPA and uPA have been reported to reduce airway remodeling through their fibrinolytic activity.
  • NMDA-Rs in airways suggests a mechanism by which airway contractility may be regulated physiologically or may be disordered in reactive airway disease in response to endogenous PAs.
  • a direct role for either uPA or tPA in regulating bronchial contractility and their role, if any, in the activation of NMDA-Rs in this process have not been demonstrated.
  • WO 01/51085 discloses methods for treating asthma or chronic obstructive pulmonary disease comprising administering a plasminogen activator inhibitor- 1 (PAI-1) antagonist to reduce PAI-1 activity in the lung tissue.
  • PAI-1 plasminogen activator inhibitor- 1
  • compositions comprising one or more domains of urokinase-type plasminogen activator (uPA) to modulate the contractility and or angiogenic activity of a mammalian muscle or endothelial cell or tissue for use in the treatment of a disease having as a symptom of abnormal muscle cell or tissue contractility and/or abnormal angiogenic activity.
  • uPA urokinase-type plasminogen activator
  • WO 03/095476 to the inventor of the present invention teaches administration of the peptide EEIIMD or the peptide acetyl-RMAPEEIIMDRPFLYVVR-amide in combination with one or more fibrinolytic agents for enhancing the fibrinolytic activity, reducing the side effects due to vasoactivity caused by the fibrinolytic agents, and/or for prolonging the half lives of the fibrinolytic agents.
  • WO 03/095476 relates to combination compositions comprising the polypeptide EEIIMD and/or the Ac-RMAPEEIIMDRPFLYVVR-amide peptide and one or more currently used plasminogen activators.
  • PAI-1 plasminogen activator inhibitor- 1
  • the present invention provides methods for inhibiting airway smooth muscle contractility comprising administering to a subject in need of such treatment an isolated peptide consisting of 7 to 30 amino acid residues corresponding to the amino acid segment 363-392 of human plasminogen activator inhibitor-1 (PAI-1).
  • PAI-1 human plasminogen activator inhibitor-1
  • tissue-type plasminogen activator
  • tPA urokinase
  • uPA urokinase
  • SMCs tracheal smooth muscle cells
  • the present invention provides a method for treating asthma comprising administering to a subject having or at risk of having asthma a pharmaceutical composition comprising a therapeutically effective amount of an isolated peptide of the amino acid sequence as set forth in SEQ ID NO:2: R i - Arg-Met- Ala-Pro-X i -X 2 -Ile-Ile-Met-X 3 -Arg-Pro-Phe-Leu-X4-Val-Val- Arg-R 2 wherein Rj is selected from the group consisting of a hydrogen, acyl, alkyl, an amino blocking group, and 1 to 6 amino acid residues; X ⁇ is selected from the group consisting of Asp, Glu, and Arg; X 2 is selected from the group consisting of Asp and Glu; X 3 is selected from the group consisting of Asp and Glu; X4 is selected from the group consisting of Phe and Tyr; and R 2 is selected from the group consisting of a carboxyl, amide, alcohol, este
  • Xi is Glu
  • X 2 is Glu
  • X 3 is Asp
  • Ri is acetyl and R 2 is amide.
  • the peptide to be used for treating asthma is selected from the group consisting of SEQ ID NOs: l, 3 to 9. According to a certain embodiment, the peptide to be used has the amino acid sequence as set forth in SEQ ID NO: l . According to another embodiment, the peptide to be used has the amino acid sequence as set forth in SEQ ID NO:6.
  • asthma is selected from the group consisting of allergic or extrinsic asthma and idiosyncratic or intrinsic asthma.
  • the present invention discloses a method for inhibiting airway smooth muscle contractility comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of an isolated peptide of the amino acid sequence as set forth in SEQ ID NO:2:
  • R -Arg-Met- Ala-Pro-X, -X 2 -Ile-Ile-Met-X 3 -Arg-Pro-Phe-Leu-X 4 -Val-Val-Arg-R 2
  • R ⁇ is selected from the group consisting of a hydrogen, acyl, alkyl, an amino blocking group, and 1 to 6 amino acid residues
  • X] is selected from the group consisting of Asp, Glu, and Arg
  • X 2 is selected from the group consisting of Asp and Glu
  • X 3 is selected from the group consisting of Asp and Glu
  • X4 is selected from the group consisting of Phe and Tyr
  • R 2 is selected from the group consisting of a carboxyl, amide, alcohol, ester, a carboxyl blocking group, and 1 to 6 amino acid residues; or a fragment thereof, wherein the fragment consists of 7 to 17 amino acid residues comprising the amino acid sequence Xi-X 2 -Ile-Ile-Met-X 3
  • Xj is Glu
  • X 2 is Glu
  • X 3 is Asp
  • Ri is acetyl and R 2 is amide.
  • the peptide to be used for inhibiting airway smooth muscle contractility is selected from the group consisting of SEQ ID NOs: l , 3 to 9. According to a certain embodiment, the peptide to be used has the amino acid sequence as set forth in SEQ ID NO: l . According to another embodiment, the peptide to be used has the amino acid sequence as set forth in SEQ ID NO:6.
  • airway smooth muscle contractility is bronchial smooth muscle contractility or bronchospasm.
  • bronchospasm is associated with bronchitis.
  • airway smooth muscle contractility is tracheal smooth muscle contractility.
  • the pharmaceutical composition is administered by intranasal, intravenous, subcutaneous, intramuscular, intraperitoneal, oral, topical, intradermal, transdermal, epidural, ophthalmic, vaginal or rectal administration route.
  • the pharmaceutical composition is administered by intranasal administration route such as by inhalation.
  • the pharmaceutical composition is formulated in a form selected from the group consisting of a solution, spray, suspension, emulsion, tablet, capsule, gel, powder, cream, depot, and a sustained- release formulation.
  • the present invention provides a pharmaceutical composition comprising an isolated peptide of the amino acid sequence as set forth in SEQ ID NO:2:
  • Ri is selected from the group consisting of a hydrogen, acyl, alkyl, an amino blocking group, and 1 to 6 amino acid residues
  • X] is selected from the group consisting of Asp, Glu, and Arg
  • X 2 is selected from the group consisting of Asp and Glu
  • X 3 is selected from the group consisting of Asp and Glu
  • X4 is selected from the group consisting of Phe and Tyr
  • R 2 is selected from the group consisting of a carboxyl, amide, alcohol, ester, a carboxyl blocking group, and 1 to 6 amino acid residues; or a fragment thereof, wherein the fragment consists of 7 to 17 amino acid residues comprising the amino acid sequence Xi-X 2 -Ile-Ile-Met-X 3 , for treating asthma.
  • the present invention provides a pharmaceutical composition comprising an isolated peptide of the amino acid sequence as set forth in SEQ ID NO:2:
  • R ⁇ is selected from the group consisting of a hydrogen, acyl, alkyl, an amino blocking group, and 1 to 6 amino acid residues
  • Xi is selected from the group consisting of Asp, Glu, and Arg
  • X 2 is selected from the group consisting of Asp and Glu
  • X 3 is selected from the group consisting of Asp and Glu
  • X4 is selected from the group consisting of Phe and Tyr
  • R 2 is selected from the group consisting of a carboxyl, amide, alcohol, ester, a carboxyl blocking group, and 1 to 6 amino acid residues; or a fragment thereof, wherein the fragment consists of 7 to 17 amino acid residues comprising the amino acid sequence Xi-X 2 -Ile-Ile-Met-X 3
  • FIGs. 1A-B show the effect of uPA on the contraction of tracheal rings.
  • FIG. 1 A shows the effect of increasing concentrations of acetylcholine (Ach). Contraction of tracheal rings was induced by Ach at the indicted concentrations in the absence ( ⁇ ) or presence of 20 nM uPA ( ⁇ ). The molar concentration of Ach is displayed in logarithmic units and the response expressed as a percent of the maximum contraction observed using KCl.
  • FIG. IB shows the effect of increasing concentrations of uPA on Ach EC 50 of tracheal ring contraction. The mean ⁇ SD of 6 experiments is shown.
  • FIG. 2 shows the effect of tPA on the contraction of murine tracheal rings. Contraction of tracheal rings was induced by Ach at the indicted concentrations in the absence ( ⁇ ) or presence of 1 nM ( ⁇ ) or 20 nM (i.) tPA. The mean ⁇ SD of 6 experiments is shown.
  • FIGs. 3A-B show the involvement of PA catalytic activity in the contraction of tracheal and aortic rings.
  • FIG. 3A shows that catalytically inactive PAs variants fail to stimulate contractility of tracheal rings.
  • FIG. 3B shows that catalytically inactive PAs variants stimulate contractility of aortic rings. Contraction of aortic rings was induced by phenylephrine in the absence (Cont) or presence of 20 nM catalytically inactive mut tPA or mut uPA. The mean ⁇ SD of 3 experiments is shown.
  • FIGs. 4A-C show the involvement of NMDA-Rs in the contraction of tracheal rings.
  • FIG. 4A NMDA-Rs mediate the relaxation of tracheal SMC induced by glutamate. Contraction of tracheal rings was induced by Ach in the absence (Control) or presence of tPA (20 nM), uPA (20 nM), the NMDA-R antagonist MK801 (MK801) (100 nM) or the NMDA-R agonist glutamate (150 ⁇ ). The mean ⁇ SD of 3 experiments is shown.
  • FIG. 4B Involvement of NOS in NMDA-R mediated relaxation of tracheal SMC induced by glutamate.
  • FIG. 4C Involvement of the epithelium in NMDA-R mediated relaxation of tracheal SMC induced by glutamate.
  • FIG. 5 shows that the 18-mer peptide derived from PAI-1 inhibits the effect of PAs on tracheal contractility.
  • the PAI-1 derived peptide inhibits the pro-contractile activity of tPA and uPA. Contraction of tracheal rings was induced by Ach in the absence or presence of tPA (20 nM) or uPA (20 nM) in the absence or presence of the PAI-1 derived peptide of SEQ ID NO: l (1 ⁇ ). The mean ⁇ SD of 3 experiments is shown. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention is based in part on the unexpected findings that 18-mer peptides corresponding to amino acids 369-386 of human PAI-1 were capable of inhibiting airway contractility induced by tPA or uPA in animal models.
  • the present invention discloses peptides derived from the docking site of PAI-1 which bind to plasminogen activators and hence inhibit their contractility activity on tracheal smooth muscle.
  • the present invention discloses that inhibition of the pro-contractile activity of tPA or uPA on airway smooth muscle by peptides corresponding to the amino acid sequence 363-392 of human PAI-1 is beneficial for the treatment of respiratory diseases associated with smooth muscle contractility, such as asthma and bronchitis.
  • the present invention discloses that the mechanism of action of plasminogen activators on airway smooth muscle contraction is different from that of vascular smooth muscle contraction. While catalytically inactive plasminogen activators were shown to enhance the contractility of isolated aortic rings, such catalytically inactive plasminogen activators did not exert procontractile activity on tracheal rings.
  • the present invention provides isolated peptides derived from PAI-1 for inhibiting airway smooth muscle contractility, and particularly for the treatment of asthma and bronchitis. Particularly, the present invention provides uses of a peptide having the amino acid sequence as set forth in SEQ ID NO:2:
  • Rj is selected from the group consisting of a hydrogen, acyl, alkyl, an amino blocking group, and 1 to 6 amino acid residues
  • Xj is selected from the group consisting of Asp, Glu, and Arg
  • X 2 is selected from the group consisting of Asp and Glu
  • X 3 is selected from the group consisting of Asp and Glu
  • X4 is selected from the group consisting of Phe and Tyr
  • R 2 is selected from the group consisting of a carboxyl, amide, alcohol, ester, a carboxyl blocking group, and 1 to 6 amino acid residues; or a fragment thereof, wherein the fragment consists of 7 to 17 amino acid residues comprising the amino acid sequence Xi-X 2 -Ile-Ile-Met-X 3 , for inhibiting airway smooth muscle contractility.
  • the present invention provides uses of 7 to 30-mer peptides comprising preferably the sequence EEIIMD as set forth in SEQ ID NO: 10 derived from human PAI-1 (SEQ ID NO: 1 1) or analogs or derivatives thereof for inhibiting airway smooth muscle contractility, and particularly, for the treatment of respiratory diseases associated with bronchospasm, such as asthma and bronchitis.
  • Ri consists of 1 to 6 amino acid residues corresponding to the amino acid sequence AVIVSA (SEQ ID NO: 12) at positions 363- 368 of human PAI-1.
  • R 2 consists of 1 to 6 amino acid residues corresponding to the amino acid sequence HNPTGT (SEQ ID NO: 13) at positions 387-393 of human PAI-1.
  • the present invention encompasses peptides of 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acid residues which comprise the sequence X]-X 2 -Ile-Ile-Met-X 3 .
  • the present invention relates to the following peptides:
  • peptide designates a linear series of amino acid residues connected one to the other by peptide bonds.
  • amino acid residues are represented throughout the specification and claims by one- letter or three-letter codes according to IUPAC conventions.
  • amino acid or “amino acid residue” is understood to include the 20 naturally occurring amino acids.
  • the peptides of the present invention can be isolated by any protein purification method known in the art.
  • PAI-1 can be subjected to one or more proteolytic enzymes to yield a mixture of peptides, which can further be purified by any protein purification method known in the art to obtain the isolated peptides.
  • PAI-1 can be cleaved by chemical agents such as, for example, CNBr to yield a mixture of peptides that can be further purified to obtain isolated peptides.
  • the peptides of the present invention can also be prepared by methods well known in the art including chemical synthesis or recombinant DNA technology.
  • a preferred method of synthesizing the peptides of the present invention involves solid-phase peptide synthesis utilizing a solid support as described by Merrifield (see J. Am. Chem. Soc, 85:2149, 1964). Large-scale peptide synthesis is described, for example, by Andersson et al. (Biopolymers 55(3): 227-50, 2000). Examples of solid phase peptide synthesis methods include the BOC method, which utilizes tert-butyloxycarbonyl as the a-amino protecting group, and the FMOC method, which utilizes 9-fluorenylmethyloxcarbonyl to protect the a-amino of the amino acid residues, both methods are well-known by those of skill in the art. Alternatively, the peptides of the present invention can be synthesized by standard solution synthesis methods (see, for example, Bodanszky, M., Principles of Peptide Synthesis, Springer- Verlag, 1984).
  • the peptides useful for practicing the present invention need not be identical to the amino acid sequence RMAPEEIIMDRPFLFVVR (SEQ ID NO:7) derived from amino acids 369-386 of human PAI-1 so long as each of these peptides is capable of reducing, preventing and/or abolishing airway contraction or alternatively capable of treating a respiratory disease such as asthma or bronchitis.
  • analog includes any peptide comprising altered sequence by amino acid substitutions, deletions, or chemical modifications of the peptides listed herein above and which displays inhibitory activity on airway smooth muscle contractility.
  • amino acid substitutions it is meant that functionally equivalent amino acid residues are substituted for residues within the sequence resulting in a silent change.
  • one or more amino acid residues within the sequence can be substituted by another amino acid of a similar polarity, which acts as a functional equivalent, resulting in a silent alteration.
  • Substitutes for an amino acid within the sequence may be selected from other members of the class to which the amino acid belongs.
  • the non-polar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine.
  • the polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine.
  • the positively charged (basic) amino acids include arginine, lysine and histidine.
  • the negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Such substitutions are known as conservative substitutions.
  • a non-conservative substitution may be made so long as the inhibitory effect on airway smooth muscle contraction of the peptide analog is maintained if compared to that of the peptide of SEQ ID NO: l .
  • the present invention encompasses peptide analogs, wherein at least one amino acid is substituted by another amino acid to produce a peptide analog having increased stability or longer half-life as compared to the peptides listed herein above.
  • amino acid residues of the peptide sequences set forth herein above are all in the "L” isomeric form
  • residues in the "D” isomeric form can substitute any L- amino acid residue so long as the peptide analog retains the relaxation activity on airway smooth muscle exhibited by the peptide of SEQ ID NO: 1.
  • Production of a retro- inverso D-amino acid peptide analog where the peptide is made with the same amino acids as disclosed, but at least one amino acid, and perhaps all amino acids are D-amino acids is well known in the art.
  • the present invention further encompasses peptide derivatives of the peptides listed herein above.
  • derivative refers to a peptide having an amino acid sequence that comprises the amino acid sequence of the peptide of the invention, in which one or more of the amino acid residues is subjected to chemical derivatizations by a reaction of side chains or functional groups, where such derivatizations do not destroy the anti-contractive activity of the peptide derivative.
  • Chemical derivatization of amino acid residues include, but are not limited to, acetylation, amidation, glycosylation, oxidation, reduction, myristylation, sulfation, acylation, ADP- ribosylation, cyclization, disulfide bond formation, hydroxylation, iodination, and methylation.
  • Blocking groups are well known to those of skill in the art as are methods of coupling such groups to appropriate residue(s) of the peptides of the present invention (see, e.g., Greene et al., (1991) Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. Somerset, N.J.).
  • the terminal amino acids of the peptides of the invention are blocked with a protecting or blocking group.
  • a wide number of blocking groups are suitable for this purpose. Such groups include, but are not limited to, acetyl and alkyl groups for N-terminal protection.
  • alkyl chains as in fatty acids, e.g., propeonyl, formyl, and others, can be used.
  • Carboxyl blocking groups include, but are not limited to, amides, esters, and ether-forming blocking groups.
  • blocking groups include, but are not limited to Fmoc, t-butoxycarbonyl (t-BOC), 9- fluoreneacetyl group, 1-fluorenecarboxylic group, 9-florenecarboxylic group, 9- fluorenone-l-carboxylic group, benzyloxycarbonyl, Xanthyl (Xan), Trityl (Trt), 4- methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethylbenzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl (Tos), 2,2,5, 7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4- methoxybenzyl (MeOBzl), Benzyloxy (BzlO),
  • peptides which contain one or more naturally occurring amino acid derivatives of the twenty standard amino acid residues.
  • 4-hydroxyproline may be substituted for proline
  • 5- hydroxylysine may be substituted for lysine
  • 3-methylhistidine may be substituted for histidine
  • homoserine may be substituted or serine
  • ornithine may be substituted for lysine.
  • the peptides may also contain non-natural amino acids.
  • non-natural amino acids are norleucine, ornithine, citrulline, diaminobutyric acid, homoserine, isopropyl Lys, 3-(2'-naphtyl)-Ala, nicotinyl Lys, amino isobutyric acid, and 3-(3'-pyridyl-Ala).
  • the peptides may also contain non-protein side chains.
  • the peptides of the present invention may also include one or more non-amino acid monomers (e.g., fatty acids, complex carbohydrates, and the like).
  • the present invention includes conjugates of the peptides of the invention.
  • conjugates are meant to define a peptide of the present invention coupled to or conjugated with another protein or polypeptide. Such conjugates may have advantages over the peptides themselves.
  • conjugates can be made by protein synthesis, e. g., by use of a peptide synthesizer, or by ligating the appropriate nucleic acid sequences encoding the desired amino acid sequences to each other by methods known in the art, in the proper coding frame, and expressing the chimeric protein by methods commonly known in the art.
  • a peptide of the present invention may also be conjugated to itself or aggregated in such a way as to produce a large complex containing the peptide.
  • Such large complexes may be advantageous because they may have new biological properties such as longer half-life in circulation or greater activity.
  • compositions and administration routes are provided.
  • the present invention provides methods for inhibiting smooth muscle contractility, and particularly for treating a respiratory disease associated with bronchospasm such as asthma or bronchitis comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a peptide of SEQ ID NO:2 and a pharmaceutically acceptable carrier.
  • pharmaceutical composition refers to a preparation of one or more of the peptides described herein with other chemical components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of an active ingredient to an organism.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • compositions of the present invention can be formulated as pharmaceutically acceptable salts of the peptides of the present invention.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • Salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • carrier refers to a diluent or vehicle that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An adjuvant is included under this term.
  • Pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • compositions of the invention can further comprise an excipient.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, trehalose, gelatin, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene glycol, and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates.
  • Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned.
  • compositions of the present invention can be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • compositions which contain peptides as active ingredients are prepared as injectable, either as liquid solutions or suspensions.
  • solid forms which can be suspended or solubilized prior to injection, can also be prepared.
  • the compositions can also take the form of emulsions, tablets, capsules, gels, syrups, slurries, powders, creams, depots, sustained-release formulations and the like.
  • Methods of introduction of a pharmaceutical composition comprising a peptide of the invention include, but are not limited to, intravenous, subcutaneous, intramuscular, intraperitoneal, oral, topical, intradermal, transdermal, intranasal, epidural, ophthalmic, vaginal and rectal routes.
  • the pharmaceutical compositions can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other therapeutically active agents.
  • the administration may be localized, or may be systemic. Pulmonary administration can also be employed, e.g., by use of an inhaler or neubilizer.
  • compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers and optionally comprising excipients which facilitate processing of the active ingredients into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the active ingredients of the pharmaceutical composition may be formulated in aqueous solutions, preferably in physiologically compatible solutions such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • the pharmaceutical composition can be formulated readily by combining the active ingredients with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the pharmaceutical composition to be formulated as tablets, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable excipients as desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, and sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a neubilizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane, or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane, or carbon dioxide.
  • the dosage may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with, optionally, an added preservative.
  • the compositions may be suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water-based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the active ingredients, to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., a sterile, pyrogen-free, water-based solution, before use.
  • a suitable vehicle e.g., a sterile, pyrogen-free, water-based solution
  • compositions of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, for example, traditional binders and carriers such as triglycerides, microcrystalline cellulose, gum tragacanth or gelatin.
  • the pharmaceutical composition may be in the form of tablets or capsules, which can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide.
  • dosage unit form can contain, in addition to materials of the above type, a liquid carrier such as oil.
  • dosage unit forms can contain other materials which modify the physical form of the dosage unit, for example, coating
  • a peptide of the invention can be delivered in a controlled release system.
  • the peptide can be administered in combination with a biodegradable, biocompatible polymeric implant, which releases the peptide over a controlled period of time at a selected site.
  • a biodegradable, biocompatible polymeric implant which releases the peptide over a controlled period of time at a selected site.
  • preferred polymeric materials include polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, polyethylene vinyl acetate, copolymers and blends thereof (See, Medical applications of controlled release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla.).
  • a controlled release system can be placed in proximity of the therapeutic target, thus requiring only a fraction of a systemic dose.
  • the present invention provides uses of the peptides as disclosed herein above for the treatment, prophylaxis and/or inhibition of a respiratory disease associated with bronchospasm such as asthma or bronchitis in a subject in need of such treatment.
  • the present invention further provides uses of the peptides as disclosed herein above for the inhibition of airway smooth muscle contractility. It will be appreciated that the term "treatment” as used herein includes both treatment and/or prophylactic use of the peptides disclosed.
  • prophylactic use of the peptides comprises administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising a peptide as disclosed herein above to prevent the onset of a respiratory disease associated with bronchospasm such as asthma or bronchitis or to prevent the onset of airway smooth muscle contraction; and to prevent the progression of said diseases or conditions.
  • a "therapeutically effective amount” means an amount of a peptide effective to prevent, alleviate, or ameliorate symptoms of a condition or disease associated with airway smooth muscle contraction in the subject being treated.
  • airway smooth muscle refers to the smooth muscle lining the bronchi or tracheal region.
  • the peptides of the invention can be administered as therapeutic agents for the treatment or prevention of a respiratory disorder.
  • respiratory disorder refers to any impairment of lung function which involves constriction of airways and changes in blood gas levels or lung function. Examples of respiratory diseases include, but are not limited to, asthma and bronchitis.
  • Asthma is a respiratory tract condition characterized by bronchial smooth muscle contractility and enhanced pulmonary vascular permeability. Increases in bronchial smooth muscle contractility leads to airway hyperactivity. Enhanced pulmonary vascular permeability causes extravasation of fluid into the extravascular space which acts as a barrier for the diffusion of oxygen from the airway into the blood.
  • Asthma is manifested physiologically by a widespread narrowing of the air passages which may be relieved spontaneously or as a result of therapy. Asthma is manifested clinically by paroxysms of dyspnea, cough, wheezing, shortness of breath, hypoxemia, and in severe cases, status asthmaticus, resulting in death. It is an episodic disease, acute exacerbations being interspersed with symptom-free periods. Typically, most attacks are short-lived, lasting minutes to hours, however, there can be a phase in which the patient experiences some degree of airway obstruction daily.
  • Allergic asthma is dependent upon an IgE response controlled by T and B lymphocytes and activated by the interaction of antigen with mast cell-bound IgE molecules. Allergic asthma is often associated with a personal and/or family history of allergic diseases such as rhinitis, urticaria, and eczema; positive wheal-and-flare skin reactions to intradermal injection of extracts of airborne antigens; increased levels of IgE in the serum; and/or positive response to provocation tests involving the inhalation of specific antigen.
  • asthmatic asthma A significant segment of the asthmatic population will present with negative family or personal histories of allergy, negative skin tests, and normal serum levels of IgE, and therefore cannot be classified on the basis of defined immunologic mechanisms. These are termed idiosyncratic asthma. Many of these will develop a typical symptom complex upon contracting an upper respiratory illness.
  • asthma is primarily a disease of airways, virtually all aspects of pulmonary function are compromised during an acute attack.
  • the pathophysiologic hallmark of asthma is a reduction in airway diameter brought about by contraction of smooth muscle, edema of the bronchial wall, and thick tenacious secretions.
  • the syndromes or disease conditions associated with asthma include an increase in airway resistance, decreased forced expiratory volumes and flow rates, hyperinflation of the lungs and thorax, increased work of breathing, changes in elastic recoil of the lung tissue, abnormal distribution of both ventilation and pulmonary blood flow, mismatched ratios, and altered arterial blood gases.
  • electrocardiographic evidence of right ventricular hypertrophy in very symptomatic patients there frequently is electrocardiographic evidence of right ventricular hypertrophy.
  • the present invention encompasses asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, bronchial asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, emphysematous asthma, exercise-induced asthma, cold air induced asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, and non-allergic asthma.
  • bronchospasm means the state when the bronchial muscle undergoes tight contraction.
  • the most common cause of bronchospasm is asthma, though other causes include, but are not limited to, respiratory infection, chronic lung disease (including emphysema and chronic bronchitis), anaphylactic shock, or an allergic reaction to chemicals.
  • the time of treatment can be of importance. Administration can be before or after onset of a respiratory disease or an airway contraction has occurred. Administration before an airway contraction has occurred can be of value for prophylactic treatment, for example when the subject is considered to be at risk of airway contraction condition. Such conditions could be, for example in asthmatic patients or subjects at risk of bronchitis.
  • the more common time of administration is after onset of an airway contraction has occurred or is suspected, for example in the conditions of treating a respiratory disease or condition, and in such cases it is desirable to make the administration as soon as possible after the event to get best results-- preferably within an hour or less, though administration later than that time can still be beneficial.
  • the subject is a mammal.
  • the mammal is a human.
  • the precise amount of the peptide administered to a particular subject, preferably a mammal, more preferably a human being, in the method of treatment of the present invention will depend on a number of factors, for example the specific mode of administration and/or the use for which it is intended; the age, body mass and/or past clinical history of the patient to be treated, and always lies within the sound discretion of the person administering and/or supervising the treatment, for example a medical practitioner such as nurse and/or physician.
  • a suitable daily dose of the peptide for administration to a mammal is generally from about 0.01 mg/day per kg of the mammal's body mass to about 80 mg/kg/day, more usually 0.2-40 mg/kg/day given in a single dose and/or in divided doses at one or more times during the day.
  • the pharmaceutical composition can contain from about 0.1% to about 99% by weight of the peptide and is generally prepared in unit dose form, a unit dose of a peptide generally being from about 0.1 mg to about 500 mg.
  • the following examples are intended to be merely illustrative in nature and to be construed in a non-limitative fashion.
  • SMCs Smooth muscle cells
  • Dawley rats were killed by exanguination.
  • the tracheas were removed with care to avoid damage to the epithelium, dissected free of fat and connective tissue, and cut into transverse rings 5mm in length.
  • the tracheal rings were mounted in a 10-ml bath containing an oxygenated (95% 0 2 , 5%C0 2 ) solution of Krebs- Henseliet (KH) buffer.
  • KH Krebs- Henseliet
  • the rings were equilibrated for 1.5 hrs at 37° C and maintained under a resting tension of 2 g throughout the experiment.
  • Each ring was then contracted by adding acetylcholine (Ach) in stepwise increments from 10 "10 to 10 "5 M.
  • the absolute maximal contraction was determined by adding 30 mM KC1.
  • the term 100% contraction used in the graphs represents the maximal tension induced by Ach, defined by the concentration at which tension reached a plateau.
  • FIG. 1A shows that addition of uPA to isolated rat tracheal rings increased contractility induced by Ach.
  • Addition of 10 nM uPA decreased the EC 50 of Ach by 5- fold, from 40 to 8 nM (FIG. 1A).
  • the effect of uPA was dose-dependent and saturable with EC 50 of approximately 5 nM (FIG. IB).
  • Addition of uPA alone had no effect on rat tracheal contractility (see also Nassar et al., Amer. J. Respir. Cell Mol. Biol. 43: 703- 71 1 , 2010, the content of which is incorporated by reference as if fully set forth herein).
  • FIG. 2 shows the effect of tPA on tracheal contractility induced by Ach.
  • tPA increased the contractility of isolated rat tracheal rings induced by Ach even when added at physiological concentrations. Addition of tPA alone had no effect on the tracheal contractility. While tPA was shown to exert opposing effects on the contraction of isolated aortic rings depending on its concentration, i.e. a low concentration (1 nM) of tPA inhibited, whereas a higher (20 nM) concentration of tPA simulated vascular tone, tPA enhanced tracheal contractility at both concentrations tested (FIG. 2).
  • tPA-Ser 481 Ala and uPA-Ser 356 Ala was examined.
  • the tPA-Ser 481 Ala and uPA-Ser 356 Ala variants were prepared as follows: cDNAs encoding mature human tPA or single-chain uPA were cloned into the pMT/BiP/V5-HisA plasmid (Invitrogen Corp., Carlsbad, CA).
  • the catalytically inactive variants were generated by PCR with the QuickChange Mutagenesis kit (Stratagene, La Jolla, CA), and the complete sequences were verified. Proteins were expressed in S2 Drosophila Expression System (Invitrogen) according to the manufacturer's protocol, and were purified by antibody affinity chromatorgraphy with anti-tPA or anti-uPA coupled to cyanogens-Br-activated sepharose. The final products migrated as single bands on SDS-PAGE at the expected sizes, and their plasminogen activator activity was confirmed with the plasmin chromogenic substrate, Spectrazyme PL.
  • NMDA-Rs including NMDA-R1
  • NMDA-Rs have been identified in the respiratory system, but their function and agonists have not been fully characterized.
  • the effect of the NMDA-R antagonist MK-801 on tracheal contraction was examined.
  • the NMDA- R antagonist MK-801 stimulated the contraction of tracheal rings induced by Ach (FIG. 4A), which suggests that NMDA-Rs contribute to the constitutive relaxation of tracheal SMC.
  • tPA and uPA may therefore stimulate contractility by either: 1) inhibiting NMDA-R mediated induction of NOS activity lowering the threshold for contraction; or 2) acting directly on NMDA-Rs to initiate NOS-independent contractile mechanisms.
  • L-NAME 50 ⁇
  • Ach NMDA-R antagonist MK-801
  • MK-801 lost its procontractile effect (and indeed somewhat inhibited Ach-induced contractility) in the presence of L-NAME (FIG. 4B).
  • L-NAME glutamate stimulated the contractile effects of Ach (FIG. 4B).
  • L-NAME enhanced the procontractile effect of tPA and uPA, reducing the EC 50 of Ach from 3.4 to 2.2 nM and 5.8 to 2.5 nM respectively (FIG. 4B).
  • NOS is present in the airways epithelial cells. Therefore, to examine the role of NOS in NMDA-R mediated bronchial contractility in situ, tracheal rings were denuded of epithelium by rotating a stainless steel rod along the surface of the tracheal rings, and the denuded rings were then used. In contrast to the procontractile effect of L-NAME on intact rings, the NOS inhibitor had no effect on the contractility of denuded tracheal rings induced by Ach (FIG. 4C). Moreover, the procontractile activity of uPA, tPA and glutamate on denuded tracheal rings was inhibited by MK-801 (FIG. 4C).

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Abstract

La présente invention concerne des utilisations de peptides dérivés de l'inhibiteur 1 de l'activateur du plasminogène (PAI-1) pour l'inhibition de la contractilité des muscles lisses des voies respiratoires. La présente invention concerne particulièrement des peptides de 7 à 30 résidus d'acides aminés correspondant aux acides aminés 363 à 392 du PAI-1 humain pour le traitement de l'asthme.
PCT/IL2011/000045 2010-01-13 2011-01-13 Peptides destinés au traitement de maladies respiratoires WO2011086557A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050158295A1 (en) * 2002-03-04 2005-07-21 Rafal Swiercz Modified plasminogen inhibitor type-1 and methods based thereon
WO2009013753A1 (fr) * 2007-07-24 2009-01-29 Thrombotech Ltd. Peptides issus de l'inhibiteur 1 de l'activateur du plasminogène et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050158295A1 (en) * 2002-03-04 2005-07-21 Rafal Swiercz Modified plasminogen inhibitor type-1 and methods based thereon
WO2009013753A1 (fr) * 2007-07-24 2009-01-29 Thrombotech Ltd. Peptides issus de l'inhibiteur 1 de l'activateur du plasminogène et leurs utilisations

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHU ET AL.: "Induction of the Plasminogen Activator System by Mechanical Stimulation of Human Bronchial Epithelial Cells.", AM J RESPIR CELL MOL BIOL., vol. 35, no. 6, 2006, pages 628 - 38 *
CHUNG.: "Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?", EUR RESPIR J., vol. 15, 2000, pages 961 - 968 *
COTTRELL.: "THE FIRST PEPTIDE-GATED ION CHANNEL.", J EXP BIOL., vol. 200, 1997, pages 2377 - 86 *
DO ET AL.: "Fontan patient with plastic bronchitis treated successfully using aerosolized tissue plasminogen activator: a case report and review of the literature.", PEDIATR CARDIOL., vol. 30, no. 3, 2009, pages 352 - 355 *
MATTHAY ET AL.: "Coagulation-dependent mechanisms and asthma.", J CLIN INVEST., vol. 114, no. 1, 2004, pages 20 - 23 *

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