EP1392729A2 - Utilisation d'un peptide qui active la guanylate-cyclase c pour le traitement de maladies des voies respiratoires par les voies aeriennes, medicament, dispositif d'inhalation et methode de diagnostic - Google Patents

Utilisation d'un peptide qui active la guanylate-cyclase c pour le traitement de maladies des voies respiratoires par les voies aeriennes, medicament, dispositif d'inhalation et methode de diagnostic

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Publication number
EP1392729A2
EP1392729A2 EP02745124A EP02745124A EP1392729A2 EP 1392729 A2 EP1392729 A2 EP 1392729A2 EP 02745124 A EP02745124 A EP 02745124A EP 02745124 A EP02745124 A EP 02745124A EP 1392729 A2 EP1392729 A2 EP 1392729A2
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Prior art keywords
peptide
medicament
peptides
seq
disorders
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EP02745124A
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German (de)
English (en)
Inventor
Yalcin Cetin
Yüksel Savas
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Individual
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Individual
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0065—Inhalators with dosage or measuring devices
    • 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
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4705—Regulators; Modulating activity stimulating, promoting or activating activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans

Definitions

  • the invention relates to the use of a peptide which activates guanylate cyclase C for the treatment of respiratory diseases and disorders associated with ventilation disorders and / or disorders of mucus secretion, an associated medicament, an inhalation device and a method for diagnosing the aforementioned disorders.
  • Obstructive ventilation disorders are a serious clinical problem. They are associated with a narrowing of the airways and thus an increase in flow resistance, spasms of the bronchial muscles, edematous swellings of the bronchial wall and increased secretion (hypercrine) of mucus with a tough consistency.
  • the diseases associated with ventilation disorders and / or disorders of mucus secretion include Bronchial asthma, chronic bronchitis and cystic fibrosis.
  • the invention has for its object to provide a new effective agent for the treatment of respiratory diseases and generally diseases that are associated with ventilation disorders and / or disorders of mucus secretion, which agent should allow liquefaction and better removal, especially of bronchial mucus.
  • the object is achieved by the use of a peptide which activates guanylate cyclase C for the manufacture of a medicament for the treatment of respiratory diseases and diseases which are associated with ventilation disorders and / or disorders of mucus secretion, via the airways, the medicament is formulated in such a way that the peptide is supplied on the air side of the respiratory tract, namely towards the apical membrane of the mucosal epithelial cells.
  • peptides can also be administered together or in succession. Equivalent to the use of these peptides themselves is the use of homologous, essentially functionally identical peptides, in particular those peptide variants with the addition of single and / or several amino acids by deletion, insertion or exchange of single and / or several amino acids, and / or chemical derivatization (in particular the terminal amino acids) linked sequence modification.
  • Pharmacologically acceptable derivatives are preferably amidated, acetylated, phosphorylated and glycosylated forms of the peptides and other post-translational derivatizations, including salts of these peptides and peptide derivatives.
  • the peptide is in particular at least one of the peptides called guanylin, uroguanylin and lymphoguanylin or a heat-resistant enterotoxin. These peptides are known as such.
  • a peptide homologous to the peptides mentioned and having essentially the same function can also be used.
  • the homologs here are understood to mean those peptides which largely correspond to the sequences described below and are still attributed to the guanylin peptides by the person skilled in the art on the basis of their function and sequence homology. It is known to those skilled in the art that e.g. Point mutations, deletions and insertions do not have to affect the function of a peptide. Peptides modified in this way would therefore be classified as homologues.
  • Seq. ID 1 (Guanylin, 15 AS): PGTCEICAYAACTGC Pro-Gly-Thr-Cys-Glu-Ile-Cys-Ala-Thr-Ala-Ala-Cys-Thr-Gly-Cys
  • a 115 amino acid precursor molecule containing the above sequence is also often referred to as "guanylin". Both peptides are suitable for the purposes of the invention; the peptide with Seq is preferred. ID 1, which is a relatively small peptide that can be delivered via inhalation.
  • a 15-AS peptide with the sequence PGTCEICAYAACTGC was first isolated from rat intestinal extracts and referred to as "guanylin". After cloning and characterization of the cDNA for the human Guanylin it was obvious that the Guanylin as a precursor molecule with 115 AS (SEQ ID 4. MNAFLLFALC LLGAWAALAG GVTVQDGNFS FSLESVKKLK DLQEPQEPRV GKLRNFAPIP GEPWPILCS NPNFPEELKP LCKEPNAQEI LQRLEEIAED PGTCEICAYAACTGC) is synthesized. It is now known that it is not the precursor molecule that circulates in the blood as a bioactive protein, but the guanylin with 94 AS (Proguanylin 22-
  • Human uroguanylin is a peptide to which the following amino acid sequences have been assigned:
  • the uroguanylin was first isolated from the urine as a 16-AS peptide (NDDC ELCVNVACTG CL). The cloning and characterization of the cDNA for human uroguanylin resulted in a uroguanylin precursor molecule with 112 AS (Seq.
  • Lymphoguanylin is a guanylin peptide expressed in lymphoid tissues, which has been described by Forte et al. was found (Forte et al. Endocrinology 1999, 140, 1800-1806). It is a 15 amino acid peptide with the following amino acid sequence:
  • Seq. ID 3 (lymphoguanylin, 15 aa): QEECELCINMACTGY Gln-Glu-Glu-Cys-Glu-Leu-Cys-Ile-Asn-Met-Ala-Cys-Thr-Gly-Tyr
  • the precursor molecule for lymphoguanylin contains 109 amino acids (SEQ ID 6: MKVLALPMAV TAMLLIL AQN TQSVYIQYEG FQVNLDSVKK LDKLLEQLRG FHHQMGDQRD PSILCSDPALPSDLQPVCEN SQAVNEGRELCINM
  • lymphoguanylin come from the opossum.
  • the human sequence is not yet known.
  • the 15-amino acid lymphoguanylin also activates human guanylate cyclase C.
  • guanylate cyclase a G protein-coupled receptor that catalyzes the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP).
  • cGMP cyclic guanosine monophosphate
  • GTP guanosine triphosphate
  • guanylate cyclase activating peptides were discovered in succession, which are considered to be endogenous ligands for guanylate cyclase C. The first of these peptides was named guanylin (Currie, H.G. et al. Proc. Natl. Acad. Sei. USA 1992, 89, 947-951).
  • the guanylate cyclase C thus not only acts as a receptor for the heat-stable enterotoxins, but it also represents the genuine receptor of the endogenous guanylin peptides.
  • a sequence of a heat-stable enterotoxin which is suitable in the context of the invention is:
  • these guanylin peptides listed above and the heat-stable enterotoxins lead to an increase in cGMP in the enterocytes via the activation of the common receptor.
  • the increased cGMP level activates the cGMP-dependent protein kinase II (cGKII) in the enterocytes.
  • cGKII cGMP-dependent protein kinase II
  • This activated protein kinase phosphorylates and thereby opens the CFTR chloride channel in the apical membrane of the enterocytes. This results in the secretion of chloride ions and water into the lumen of the intestine.
  • the CFTR chloride channel is now considered the final effector of the signal transduction chain of the guanylin peptides.
  • These peptides are therefore a direct regulator of the CFTR chloride channel.
  • the peptides mentioned circulate in the blood as endogenous activators. They can also be obtained from blood or haemofiltrate.
  • DE 195 28 544 describes a guanylin peptide which was obtained from human blood and is intended for diagnostic, medical and commercial use as a medicament. This peptide was named GCAP-II. Due to the known effect of the guanylin peptides on guanylate cyclase C (see above), GCAP-II was specially designed for the treatment of diseases which are associated with disorders in the electrolyte transport in the cells. The application should preferably be by injection.
  • guanylin The endogenous activator guanylin is found in various places in the body. Guanylin has been proven e.g. B. in the human pancreas (Kulaksiz et al, Histochem Cell Biol. (2001) 115, 131-145), in the kidney (Forte et al, Annu Rev. Physiol 2000, 62, 673-695), in the intestinal tract (Quian et al, Endocrinology 2000, 141, 3210-24) and in the lungs (Cetin et al, Proc. Natl. Acad. Sci. USA, 92, 5925 - 5929, 1995).
  • the common receptor for heat-stable enterotoxins and guanylin peptides is located in the mucosa of the airways and is expressed there to a high degree on the apical membrane (air side) of the respective epithelial cells. but not on the basolateral membrane (blood side).
  • the receptor located in the lungs can therefore not be stimulated via the bloodstream, but only via the airways.
  • FIG. 1 shows schematically the signal transduction of the guanylin peptides on epithelial cells.
  • GC-C Guanlyate cyclase
  • GC-C is an enzyme-receptor complex that is localized as a membrane protein exclusively in the apical cell domain, which is directed towards the airway clearing. It lacks the basolateral membrane of the cells (blood side), which is known to be in contact with the circulating blood.
  • GC-C Guanylin peptides that bind to the receptor (GC-C) via the airway clearing set in motion a specific intracellular mechanism that contains various protein modules.
  • the GC-C activated externally by the guanylin peptides forms cGMP from GTP in high amounts intracellularly.
  • This second messenger (cGMP) activates a membrane-associated cGMP-dependent protein kinase type II (cKGII), which carries out the phosphorylation and thus activation of the CFTR protein on its regulatory (R) domain.
  • CFTR is a membrane protein in the apical membrane of the epithelial cells and is an important chloride channel that, after activation, secretes chloride ions from the cell towards the airway clearing.
  • the water follows the secreted chlorine ions and flows into the clearing of the respiratory tract.
  • the water comes from the epithelial cells and from the spaces between the cells (paracellular). Some of the chloride ions secreted into the clearing are taken up again in the cells; for this, bicarbonate ions are secreted from the cells. This exchange of ions is accomplished by the Type II (AE2) anion exchanger.
  • AE2 Type II
  • the AE2 protein is also located in the apical membrane of the epithelial cells.
  • the bicarbonate ions are produced intracellularly by the enzyme carbonic anhydrase type II (CAM) from water and carbon dioxide.
  • CAM carbonic anhydrase type II
  • GC-C guanylate cyclase C
  • cGKM cGMP-dependent protein kinase type II
  • CFTR cystic fibrosis transmembrane conductance regulator
  • AE-2 anion exchanger type 2
  • CAM carbonic anhydrase type II.
  • a central finding of the concept according to the invention is that the activation of the receptor by application of the endogenous ligands has to be carried out specifically via the airways.
  • the person skilled in the art must therefore adjust the supply of the peptide or the medicament which contains the peptide in such a way that the peptide is fed - if possible exclusively - on the air side to the apical membrane of the respiratory tract and does not reach the bloodstream to a greater extent. This enables targeted local therapeutic use in the respiratory tract, especially since the receptor in the respiratory tract is located exclusively on the air side.
  • the supply of the peptides according to the invention is a directed and direct supply to the receptor located on the air side.
  • the appropriate means are available to the person skilled in the art for this. It can influence the directed supply to the air side via the adjustment of the peptide concentration in the pharmaceutical formulation, the dosage and the adjustment of the particle / droplet size within the formulation or the inhalation agent in such a way that practically no peptide on the blood side of the respiratory tract (to the basolateral membrane) and thus in enters the bloodstream.
  • the optimal conditions for each selected peptide can be determined in targeted preliminary tests.
  • the invention enables therapy with doses that are much lower than those that would be required to increase the blood concentration, while minimizing or eliminating the systemic side effects of the respective peptides.
  • the peptides according to the invention act as stimulants in the sense of secretolysis by dissolving the viscous mucus present in the airways, the ion composition and the pH of the liquid being adjusted directly on the epithelial cells (“microclimate”) in such a way that the viscous mucus increasingly "liquefied”.
  • the removal of mucus and microparticles from the respiratory tract is made possible by epithelial cells that have cilia on their apical side (air side).
  • the "cleaning" function is achieved by beating the cilia.
  • guanylin peptides in addition to their function of increasing the electrolyte and water secretion, in particular also activate the cilia-bearing epithelial cells, these cells have an increased beat frequency of the cilia. In the sense of a concerted action, the secretions and tiny particles on the mucous membrane of the respiratory tract are removed much more efficiently, which underlines the physiological and therapeutic importance of the guanylin peptides.
  • the aforementioned newly found properties of the peptides according to the invention act synergistically in the sense of the invention and lead to the very good effect of the peptides supplied by the airways for the treatment of the disorder and diseases mentioned at the beginning.
  • the peptides according to the invention can additionally be used for the production of diagnostics for respiratory diseases and diseases which are associated with ventilation disorders and / or disorders of mucus secretion.
  • the peptides themselves are suitable as reference substances for diagnostics.
  • a lack / deficiency or an excess of these peptides, for example in bronchial mucus, exudate or lavage, can indicate the presence of disorders requiring treatment.
  • the peptides can be detected using the customary and known means, such as spectrocopically, chromatographically or chemically.
  • the person skilled in the art can use conventional methods and means to produce antibodies against the peptides according to the invention, which can then be used within molecular biological or enzymatic assays.
  • To achieve the object of the invention therefore also contributes to a method for diagnosing the diseases mentioned, in which at least one of the peptides that activate guanylate cyclase C is detected, preferably in bronchial mucus, exudate, lavage, nasal secretions or saliva.
  • the detection can be carried out by detecting one of the sequences for Seq. ID 1 to ID 6
  • Seq. ID 4 (Guanylin precursor molecule): MNAFLLFALC LLGAWAALAG GV QDGNFS FSLESVKKLK DLQEPQEPRV GKLRNFAPIP GEPWPILCS NPNFPEELKPLCKEPNAQEI LQRLEEIAED PGTCEICAYA ACTGC
  • Seq. ID 2 (Uroguanylin): NDDC ELCVNVACTGCL Seq. ID 5 (Uroguanylin precursor molecule): MGCRAASGLLPGVAWLLLL LQSTQSVYIQ YQGFRVQLES MKKLSDLEAQ WAPSPRLQAQ SLLPAVCHHPALPQDLQPVC ASQEASSIFK TLRTIAN DDC ELCVNVACTG
  • Seq. ID 6 (lymphoguanylin precursor molecule): MKVLALPMAVTAMLLILAQN TQSVYIQYEG FQVNLDSVKK LDKLLEQLRG FHHQMGDQRD PSILCSDPALPSDLQPVCEN SQAVNIFRAL RYIN QEECELCINM Seq. ID 7 (heat-stable enterotoxin): NSSNYCCELCCNPACTGCY (19 AS) from enteropathogenic E. coli.
  • a positive test result for the detection of a disorder is evaluated if a concentration of at least one of the peptides that activate guanylate cyclase C that deviates from comparison samples of healthy volunteers is found.
  • peptides according to the invention further consists in formulating a medicament which is supplied via the airways and contains at least one peptide which activates guanylate cyclase C.
  • At least one further active ingredient and optionally auxiliaries and additives can be present in the drug.
  • Other active ingredients are, for example, muscle relaxants, local antibiotics, primarily for the treatment of simultaneously grafted bacterial infections, or also additional mucolytics, secretolytics, antitussives or bronchodilating substances. The specialist will make the selection on the basis of the respective needs in the treatment of the diseases mentioned at the beginning.
  • the drug can be prepared in solid or liquid form and is conveniently supplied by the user via the airways. For this purpose it can be administered with a commercially available nebulizer or inhalation device.
  • the medicament is present as an inhalation agent and contains at least one propellant.
  • Chlorofluorocarbons are particularly suitable as blowing agents. Suitable blowing agents are known to those skilled in the art. In general, all suitable aerosol formers or smoke formers can be used. Depending on the excipient, an aerosol or smoke is inhaled, with an aerosol being preferred.
  • an inhalation device which contains the medicament, ie that the medicament is present in the inhalation device ready-made.
  • Such an inhalation device can consist of a spray device, in particular a metering spray device or a metering inhaler (English: MDI, metered dose inhaler).
  • MDI metered dose inhaler
  • Suitable inhalers are known to the person skilled in the art and are described, for example, in US Pat. No. 3,915,165, EP 166476 and US Pat. No. 6,099,517.
  • Ultrasonic nebulizers are also suitable.
  • the peptides according to the invention should first be converted into a finely dispersed form for administration.
  • compositions for this purpose, they can first be brought into solution or suspension and, if necessary, stabilized in this form with pharmaceutically acceptable additives.
  • Compatible surfactants such as Tween ® can be used for stabilization. be used.
  • commercially available food-grade emulsifiers for example lecithin, are also suitable. Salts, buffers, sugar, sorbitol, amino acids and others can be present as further additives.
  • the overall preparation should be isotonic. To stabilize the fine distribution, microencapsulation of the peptides in question or encapsulation in liposomes can also be provided.
  • the peptides to be administered can also be pulverized in the solid state, for example freeze-dried, spray-dried or crystallized from solution, and are then preferably mixed with dry chlorofluorocarbons as propellants and aerosol formers.
  • solid additives in particular stabilizers, for example sugar or sugar-like substances, lactose and the like, can be added.
  • Inhalation devices are also known in which the aerosol formers or propellants, on the one hand, and the actual pharmaceutical preparation, on the other hand, are stored in different chambers and released together in a predetermined dosage. This avoids inaccurate dosing due to segregation during storage.
  • the size of the particles to be inhaled is less critical than in many other applications, since the peptides according to the invention should not be transported into the blood transmembrane, but only have to reach the guanylate cyclase C receptor located apically in the lungs. Particle sizes between 0.5 and 10 ⁇ m appear suitable.
  • obstructive and restrictive ventilation disorders These respiratory diseases are characterized by endobronchial obstruction with bronchospasm, edema of the mucous membrane and by hypersecretion of viscous mucus (dyscrine). These phenomena lead to the patient being exhausted by increased and insufficient breathing work. As a restrictive component, gas emissions exchange due to the mucosal edema significantly deteriorated, the oxygen uptake of the lungs significantly reduced.
  • the use of the peptides is aimed at an action which counteracts these pathomechanisms.
  • the inhalation application relaxes the smooth airway muscles, so that the bronchial resistance and thus the breathing work of the patient decreases. The exhaustion of the patient is reduced or prevented by making breathing work easier.
  • the peptides perform different functions, which in their combination and synergy lead to a significant improvement in breathing.

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Abstract

Utilisation d'un peptide qui active la guanylate-cyclase C pour le traitement de maladies des voies respiratoires et de maladies associées à des troubles de la ventilation et / ou à des troubles de la sécrétion des muqueuses, par les voies aériennes, ainsi que médicament qui est administré par les voies aériennes. La présente invention concerne en outre un dispositif d'inhalation qui contient le médicament et une méthode de diagnostic de maladies associées à des troubles de la ventilation et à des troubles de la muqueuse dans les voies respiratoires, par détection d'un peptide activant la guanylate-cyclase C. Les peptides utilisés sont la guanyline, l'uroguanyline et la lymphoguanyline ou une entérotoxine thermorésistante.
EP02745124A 2001-06-05 2002-06-05 Utilisation d'un peptide qui active la guanylate-cyclase c pour le traitement de maladies des voies respiratoires par les voies aeriennes, medicament, dispositif d'inhalation et methode de diagnostic Withdrawn EP1392729A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10127119 2001-06-05
DE10127119 2001-06-05
PCT/DE2002/002040 WO2002098912A2 (fr) 2001-06-05 2002-06-05 Utilisation d'un peptide qui active la guanylate-cyclase c pour le traitement de maladies des voies respiratoires par les voies aeriennes, medicament, dispositif d'inhalation et methode de diagnostic

Publications (1)

Publication Number Publication Date
EP1392729A2 true EP1392729A2 (fr) 2004-03-03

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Country Status (6)

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US (1) US20050032684A1 (fr)
EP (1) EP1392729A2 (fr)
AU (1) AU2002316771A1 (fr)
CA (1) CA2464511A1 (fr)
DE (1) DE10292434D2 (fr)
WO (1) WO2002098912A2 (fr)

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EP2970384A1 (fr) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
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CA2464511A1 (fr) 2002-12-12
WO2002098912A3 (fr) 2003-07-31

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