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EP4149433A1 - Solutés compatibles pour assurer la prophylaxie ou le traitement d'infections à sars-cov-2 - Google Patents

Solutés compatibles pour assurer la prophylaxie ou le traitement d'infections à sars-cov-2

Info

Publication number
EP4149433A1
EP4149433A1 EP21725470.5A EP21725470A EP4149433A1 EP 4149433 A1 EP4149433 A1 EP 4149433A1 EP 21725470 A EP21725470 A EP 21725470A EP 4149433 A1 EP4149433 A1 EP 4149433A1
Authority
EP
European Patent Office
Prior art keywords
solute
compatible
mixture
composition
use according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21725470.5A
Other languages
German (de)
English (en)
Inventor
Eva Galik
Dieter Oesterhelt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bitop AG
Original Assignee
Bitop AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bitop AG filed Critical Bitop AG
Publication of EP4149433A1 publication Critical patent/EP4149433A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy

Definitions

  • the present invention relates to the use of organic and highly water-soluble compatible solutes or a mixture of solutes, preferably in the form of an inhalable, oropharyngeal, nasal and intravenous composition, in the prevention or treatment of diseases caused by ss (+) RNA viruses of the Coronavriridae family , preferably those diseases that are caused by SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-HKLH, HCoV-OC43, HCoV-NL63 and / or HCoV-229E.
  • solutes within the meaning of the invention are ectoin and its derivatives, glycoin, mannosylglycerate (Firoin) and mannosylglyceramide (Firoin-A), which, due to their strong water-binding capacity, bind the viruses to the receptors of the host cell in the transitional epithelium, e.g. the eye, inside Epithelium, for example lungs, and in the endothelium are reduced and thus the multiplication of viruses is reduced or prevented.
  • the invention prevention through a reduced infectious sputum and breath as well as treatment and rehabilitation of the affected tissue through the membrane-protecting properties of the compatible solutes according to the invention are made possible.
  • SARS-CoV-2 The new SARS coronavirus 2 (SARS-CoV-2) has quickly developed into a global challenge. Within a very short time, the spread was declared a pandemic. Although the course of the disease is mild in many to most cases and only shows mild symptoms such as malaise, fever and possibly cough, the disease can develop into acute respiratory distress syndrome (ARDS) and severe acute respiratory syndrome (severe acute respiratory syndrome, SARS). The mortality rate increases with the severity of the disease and can reach up to 49% in critically ill patients. There is currently no targeted treatment of the Covid-19 diseases caused by the Sars-CoV-2 virus, synonymous with "Coronavirus Disease 2019". At the moment, only supportive measures can be used because at the moment there is no effective therapeutic agent against Covid-19 diseases and no vaccination against the SARS-CoV-2 virus is available.
  • ARDS acute respiratory distress syndrome
  • SARS severe acute respiratory syndrome
  • the present invention is based on the object of providing a compound, an agent, a medical product and / or a medicament which is used for the prevention and / or treatment of diseases which are triggered by ss (+) RNA viruses of the Coronavriridae family, in particular viral infections and / or inflammations caused by the virus SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-HKU1, HCoV-OC43, HCoV-NL63 and / or HCoV-229E.
  • the task is to prevent the penetration of the aforementioned viruses, in particular SARS-CoV-1, SARS-CoV-2 and / or MERS-CoV, to prevent or reduce in a host cell, where word cells are eukaryotic cells of humans and animals.
  • This is intended to provide a compound, an agent, medical product and / or medicament for use in the prevention and treatment of the aforementioned diseases in humans and animals.
  • the present invention has the further object of providing a method which identifies precisely those compounds which are suitable for the treatment and prevention of the aforementioned diseases.
  • Another object of the present invention is to provide suitable medical products for individual prevention for daily use as well as an isolated and complementary therapy for the treatment of damaged epithelial tissue and the endothelium. It is therefore a further object to provide suitable formulations and dosage forms.
  • an object of the present invention is a compatible solute or mixture of solutes for use in the prevention or treatment of diseases caused by ss (+) RNA viruses of the family Coronavriridae, wherein the at least one compatible solute of organic and highly water-soluble, preferably bio-based, compounds , is preferably selected from hydroxyectoine and ectoine and the derivatives. If “ectoin and / or the derivatives” or “ectoin and / or its derivatives” are mentioned in the present document, this includes all compounds of the formulas I and II.
  • viruses of the Coronaviridae family considered by the present invention are differentiated from the viruses of the Picornaviridae family (order Picornavirales), the Adenoviridae family (disorder unknown) and the Filoviridae family (Mononegavirales order).
  • Viruses of the Picornaviridae family include rhinoviruses that have single-stranded RNA genome positive polarity.
  • Viruses of the family Adenoviridae include adenoviruses based on ds-DNA and viruses of the family Filoviridae, to which e.g. B.
  • the Ebola virus are also single-stranded RNA genomes but with negative polarity.
  • Viruses for the purposes of this invention belong to the Coronaviridae family, which is divided into two subfamilies Coronavirinae and Torovirinae.
  • Coronavirinae are divided into the genera of alpha, beta coronaviruses, which infect only mammals, and gamma and delta coronaviruses, which infect both mammals and birds.
  • E229 and NL63 are human-pathogenic alphacoronaviruses, while OC43 and HKU1 and all new CoVs viruses, including the SARS-CoV2, belong to the genus Betacoronavirus.
  • the present invention therefore also provides the use of at least one compatible solute or mixture of solutes, preferably of ectoin and its derivatives, in which the disease is triggered by an SS (+) RNA virus of the genus Betacoronavirus and / or Alphacoronavirus and preferably by a virus selected from SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-HKlM, HCoV-OC43, HCoV-NL63 and / or HCoV-229E.
  • viruses HCoV-HKlM, HCoV-OC43, HCoV-NL63 and HCoV-229E cause rhinitis, conjunctivitis, pharyngitis, occasionally laryngitis and / or otitis media and thus mainly diseases of the upper respiratory tract.
  • the remaining viruses can cause more severe lower respiratory diseases with or without systemic infections and / or inflammation.
  • particularly preferred viruses are ARS-CoV (-1), SARS-CoV-2 and / or MERS-CoV.
  • Each of the above viruses comprises a surface protein bound in the virus envelope, which interacts with specific surface proteins of the host cells, binds to them, whereby the infection of the word cell is ultimately induced (Tay et al.). Therefore, in a particular embodiment of the present invention, at least one compatible solute or a solute mixture, preferably ectoin, is used, in which the ss (+) RNA virus interacts with at least one membrane-bound protein or component thereof on human cells (host cells) and this protein or uses the component of it as a receptor for binding to the cell. In the context of the invention, the at least one solute acts on all surface proteins of human cells which are bound by viral pathogens as receptors through pathogenic surface proteins.
  • the ss (+) RNA virus interacts with a receptor selected from angiotensin-converting enzyme 2 (ACE2), aminopeptidase N (APN) and / or dipeptidyl peptidase 4 (DPP4).
  • ACE2 angiotensin-converting enzyme 2
  • APN aminopeptidase N
  • DPP4 dipeptidyl peptidase 4
  • “Viral receptors” within the meaning of the invention are all membrane-bound proteins which are recognized by the ss (+) RNA viruses mentioned here as receptors on their word cells, preferably on human cells, particularly preferably on cells of the transitional epithelial tissue, the inner epithelial tissue and / or the endothelium. Therefore, in a special embodiment of the following method according to the invention for identifying potential compatible solutes within the meaning of the invention, the corresponding combinations according to Fang Li 2016 are tested in order to identify the most suitable compatible solute for the respective virus, which consists of organic and highly water-soluble, preferably bio-based, compounds, preferably selected from hydroxyectoine and ectoine and the derivatives. These solutes particularly preferably have a water binding capacity of greater than or equal to 7 mol / mol FhO / solute.
  • a further object of the present invention is namely a method for the identification of a compatible solute according to the invention for use in the prevention or treatment of diseases caused by ss (+) RNA viruses of the Coronavriridae family, in which the at least one compatible solute from organic and highly water-soluble, preferably bio-based, compounds is selected.
  • the process comprises the following steps:
  • a cell line which has membrane surface proteins as potentially viral receptors preferably a cell line from Table 5,
  • a compound which is potentially a compatible solute within the meaning of the invention preferably ectoin and / or another compound of the formula I and / or II, glyceryl glucoside (Glycoin), mannosyl glycerate (Firoin), mannosyl glycramide (Firoin- A), preferably an experimental approach to control without one of the potential solutes, adding a viral receptor binding domain which comprises a measurable signal, preferably a binding domain of the angiotensin-converting enzyme 2 (ACE2), the aminopeptidase N (APN) and / or dipeptidyl peptidase 4 ( DPP4), preferably the S1 protein or another according to Fang Li 2016,
  • ACE2 angiotensin-converting enzyme 2
  • API aminopeptidase N
  • DPP4 dipeptidyl peptidase 4
  • Example 1 demonstrates the functionality of the assay.
  • the cells are preferably incubated with propidium iodide, so that membrane-damaged, preferably dead cells, are subtracted from the measurement signal.
  • the potential compounds are made up of organic and highly water-soluble, preferably bio-based compounds are selected which preferably have a water binding capacity of greater than or equal to 7 mol / mol hhO / solute.
  • Compatible solutes within the meaning of the invention are preferably screened using the above method.
  • the method according to the invention can be designed in two different embodiments.
  • compatible solutes with a water binding capacity of greater than or equal to 7 mol / mol hhO / solute are selected in an upstream method, in particular measured by atomic force spectroscopy according to Rouychoudhury et al 2011 and then fed to the biological assay described above.
  • potential solutes are first identified in the aforementioned biological assay and then the water-binding capacity according to Rouychoudhury et al 2011 is determined.
  • ectoin is carried along as an internal standard in order to identify compatible solutes according to the invention as measured by ectoin.
  • a compatible solute according to the invention can be of biological (bio-based) origin or it can also be produced synthetically.
  • Bio-based compatible solutes preferably compounds of the formula I and / or II, can be produced using natural strains (see also Costa et al), e.g. B. Halomonas elongata et al. (Table 1), or using genetically modified microorganisms, e.g. B Corynebacterium glutamicum, produced biotechnologically.
  • the use of genetically modified microorganisms enables the production of larger quantities of compatible solutes according to the invention.
  • the synthetic production of compatible solutes according to the invention is advantageous in terms of quantity and cost.
  • the water-binding capacity and the reducing / disruptive effect of the respective compatible solute on the binding between ss (+) RNA viruses and host cells are essential for the purposes of the invention, preferably on the binding between the viral peplomers or spike proteins, preferably the receptor binding domains (RBD), and the viral receptors on the host cell, preferably ACE2, APN and / or DPP4 (see above).
  • Compatible solutes according to the invention have a water binding capacity of greater than or equal to 7 mol / mol H 2 O / solute, preferably determined according to Rouychoudhury et al 2011.
  • Enantiomerically pure forms of the solute or mixture of solutes according to the invention particularly preferably have S and / or (S, S) isomers.
  • S-ectoine and (S, S) -hydroxyectoine are each present with a purity greater than or equal to 90%, greater than or equal to 95%, preferably greater than or equal to 97%, greater than or equal to 99%, particularly preferably equal to 100%.
  • racemates are preferred: S-ectoine and R-ectoine,
  • the invention also relates to diastereomers, racemates, zwitterions, cations and mixtures of the aforementioned compounds.
  • Derivatizations can be carried out with hydroxy, sulfonic acid, carboxy acid derivatives, such as amides, esters, etc., carbonyl, ethers, alkoxy and hydroxyl groups.
  • At least one compatible solute is selected from glyceryl glucoside (Glycoin), glycine betaine, mannosyl glycerate (Firoin), mannosyl glycramide (Firoin-A), ectoin and its derivatives of the formula I and / or II and the physiologically compatible ones Salts, amides and esters of the aforementioned compounds, where in formula I and in formula II
  • R1 H or alkyl
  • R3 and R4 each independently of one another H or OH
  • Alkyl an alkyl radical with C1-C4 carbon atoms.
  • preferred compatible solutes within the meaning of the invention are compounds from the group comprising ectoin and derivatives thereof, glycoin (glyceryl glucoside), L-proline, mannosylglycerate, N-acetyl-diaminobutyric acid (NADA), trimethylamine N-oxide (TMAO) and / or Glycine betaine.
  • Preferred derivatives of ectoine include S / R-ectoine, (S, S) / (R, R) -hydroxyectoine, (S, S) / (R, R) -hydroxyectoine and S-homoectoine, and the physiologically acceptable salts, amides and esters of the foregoing compounds.
  • a solute mixture of at least two of the aforementioned compounds is also used, preferably a solute mixture comprising at least two compounds according to formula I and / or according to formula II.
  • the respective compatible solute according to formula I or II is preferably in enantiomerically pure form with a Purity greater than or equal to 90%.
  • a particularly preferred solute mixture within the meaning of the invention of compounds of the formula I or II contains, based on the sum of all compounds with a total content of 100% by weight, greater than or equal to 85% by weight of S-ectoin and less than or equal to 15% by weight % (S, S) - Hydroxyectoin.
  • compatible solutes according to the invention are bio-based, bio-based being understood to mean that the compound has a biological origin.
  • Biological sources of solutes according to the invention include, for example, from algae, fungi, phototrophic bacteria, methanogenic bacteria, Actinopolyspora halophila, Gammaproteobacteria, Nocardiopsis sp., Brevibacteria, gram-positive cocci, many bacilli, algae, some bacilli and related species (Planococcus citreus), Staphylococcuscus sp., strain M96 / 12b, Sporosarcina halophila, methanogenic bacteria (ß-glutamine, Ne-acetyl-ß-lysine), Ectothiorhodospira marismortui (CGA), other anoxigenic phototrophic bacteria, Azospirillum brasilense, Rhizobium meliloti and many more.
  • compatible solutes are compounds from the classes of sugars, amino acids and polyols which are characterized by OH groups and / or amino and / or amide groups which have a high reactivity with water. These also include betaines, compounds of the formula I / II, proline, carboxamides, NAc-O, NAc-L and mannosyl glycerate.
  • a compatible solute according to the invention is an organic and highly water-soluble, preferably bio-based, compound which, in a particular embodiment, has a water-binding capacity of greater than or equal to 7 mol / mol FhO / solute.
  • the water-binding capacity is preferably greater than or equal to 7.2, greater than or equal to 7.5, greater than or equal to 7.7, greater than or equal to 8.0, greater than or equal to 8.2, greater than or equal to 8.5, greater than or equal to 8.7, greater than or equal to 9, in each case as [mol / mol FfeO / solute].
  • the preferred solute in the context of the invention is ectoin with a water binding capacity greater than or equal to 9.0 mol / mol FhO / solute.
  • solute or solute mixture within the meaning of the invention can be used alone or in combination with other physiological solutions, e.g. various infusion solutions used in clinics, NaCl solutions.
  • solutes according to the invention are used in the prevention or treatment of viral diseases which include infection and / or inflammation of the transitional epithelial tissue and / or internal epithelial tissue.
  • viral diseases which include infection and / or inflammation of the transitional epithelial tissue and / or internal epithelial tissue.
  • the viral disease comprises an infection and / or inflammation of the endothelium.
  • Viral diseases in the context of the invention include an infection and / or inflammation of the endothelium, in particular the endothelium of the eye, the upper and / or lower respiratory tract, io the trachea, the lungs, the bronchi, the bronchial tree, the heart, the endothelium of the heart, blood-lymphatic vessels, brain vessels, kidney vessels, esophagus, gastric mucosa and / or thin / intestinal mucosa.
  • such viral diseases are included, each triggered by SARS-CoV-1, SARS-CoV-2, MERS-CoV, HC0V-HKUI, HCoV-OC43, HCoV-NL63 and / or HCoV-229E, the one Show infection and / or inflammation of the upper and / or lower airways, windpipe, lungs, bronchi and / or bronchial tree.
  • These diseases are characterized and detectable in that the tissues affected in the aforementioned organs were infected by the virus and thus at least one component (viral RNA) of the virus can be detected in these tissues.
  • Affected tissue within the meaning of the invention include
  • Transitional epithelial tissue including upper respiratory tract, oral cavity, oral mucosa, gums, tongue, tongue mucosa, nasal cavity, paranasal sinuses, nasal mucosa, eye, vocal folds, pharynx and genitals and / or inner epithelial tissue including lower respiratory tract, trachea, bronchi, bronchial tree, lungs, inner endothelium tissue continuous endothelium, in particular continuous endothelium of the lungs and heart, endothelium of the heart, blood and lymph vessels, esophagus, gastric mucosa and / or thin / intestinal mucosa.
  • Table 2 Epithelial tissue within the meaning of the invention Treatment and prevention within the meaning of the invention is to be interpreted broadly and also includes support for the rehabilitation of tissue damaged by the virus. This is particularly relevant when immunization by vaccines is the priority and the tissue damaged by the virus is to be rehabilitated using a solute according to the invention using a combination according to the invention, or the tissue is to be protected preventively.
  • the at least one solute or mixture of solutes preferably in the form of a composition according to the invention, is used in the prevention or treatment of diseases of the respiratory tract caused by the aforementioned viruses, preferably by SARS-Cov-2.
  • Compositions according to the invention contain at least one compatible solute, which is selected from organic and highly water-soluble, preferably bio-based, compounds, preferably from hydroxyectoine and ectoine and the derivatives, and preferably have a water-binding capacity of greater than or equal to 7 mol / mol FhO / solute.
  • Viral diseases of the respiratory tract within the meaning of the invention include not only endothelial infections and / or inflammations, but also infections and / or inflammations of the alveolar epithelial cells.
  • Viral diseases within the meaning of the invention which are caused by ss (+) - RNA viruses, preferably by SARS-Cov-2, include pneumonia, SARS (Severe Acute Respiratory Syndrome) and organ-wide damage to the aforementioned tissues.
  • SARS-Cov-2 or COVID-19 patients have typical symptoms such as fever, malaise, tiredness and cough. Most adults or children infected with SARS-CoV-2 have mild flu-like symptoms. In some patients, especially those in the risk groups, these can quickly lead to acute respiratory distress syndrome (SARS), respiratory failure, multiple organ failure and even death.
  • SARS acute respiratory distress syndrome
  • the products according to the invention are particularly suitable for prevention or treatment in patients with the aforementioned symptoms of the upper and / or lower respiratory tract.
  • Inhalable compositions and products are particularly preferred (FIG. 6).
  • the products according to the invention (FIG. 6) are preferred which contain at least one compatible solute which is made up of organic and highly water-soluble, preferably bio-based, compounds, preferably from hydroxyectoine, ectoine and / or the derivatives is selected.
  • These compatible solutes particularly preferably have a water binding capacity of greater than or equal to 7 mol / mol hhO / solute.
  • the at least one compatible solute or mixture of solutes preferably contained in a composition according to the invention
  • the at least one compatible solute preferably ectoine
  • S1 recognizes and binds to host receptors, and subsequent conformational changes in S2 facilitate fusion between the virus envelope and the cell membrane.
  • the mechanism of infection lies in the steps of binding the viral receptor-binding domain to the receptor of the host cell, followed by fusion of the membranes, penetration of the viral RNA into the host cell, multiplication of the viral RNA using the cellular machinery of the host cell and The virus escapes from the word cell
  • the membrane of the transitional epithelia, the inner epithelial tissue and / or the endothelium is shielded with compatible solutes.
  • Bruton's tyrosine kinase inhibitors which include acalabrutinib, ibrutinib and zanubrutinib, as well as the drugs spebrutinib, fenebrutinib, HM71224, ABBV-105 and ONO-4059, which are still in development.
  • compositions for use in the prevention or treatment of diseases caused by ss (+) RNA viruses of the Coronavriridae family in which at least one compatible solute or a solute mixture within the meaning of the present invention Invention is included.
  • the composition preferably contains a solute selected from the group comprising glyceryl glucoside (Glycoin), mannosyl glycerate (Firoin), mannosyl glycramide (Firoin-A), ectoin and compounds of the formula I and / or II. Ectoin, hydroxyectoin and glycoin are particularly preferred.
  • An infusion solution is preferably administered at approximate body temperature.
  • An average infusion bag has a volume of 500 ml. Based on a single dose of the full volume of an infusion bag, the infusion solution has a maximum concentration of 4% (isotonic) so that the body does not suffer an osmotic shock. Repeated administration can be used, but depends on the doctor's decision.
  • composition according to the invention is preferably used in the prevention or treatment of diseases caused by ss (+) RNA viruses of the Coronavriridae family, an infusion being administered in combination with an inhalant.
  • a medical product (e.g. FIG. 6) that can be self-administered in between is the subject of the present invention.
  • healthcare workers in particular are at high risk. This includes doctors and nursing staff in hospitals and staff in other facilities such as retirement homes, fire departments, kindergartens and schools.
  • the risk can be reduced by using a nasal spray, eye drops, lozenge, mouth rinse and / or mouth sprays according to the invention. This significantly reduces the risk of droplet infection and protects the caring and treating people.
  • Possible products in particular medical products, can be subdivided into the following applications: lungs, nose, mouth / throat and eye, as shown in FIG. 6.
  • Each of the applications shown in FIG. 6 can be combined with the at least one solute according to the invention or a solute mixture.
  • Fig. 6 is not an exhaustive list, but only the most frequently used products. For the purposes of the invention, these are suitable for use in the prevention and treatment of diseases caused by ss (+) - RNA viruses.
  • Fig.1 Gating strategy for excluding dead cells from the analysis.
  • A) FL1 shows the green fluorescence resulting from the detection of cell-bound SARS-Cov-2 S1. Dead cells were counterstained with propidium iodide. The staining of dead cells is visible through a shift on the FL2 axis. Thus cells in gate R2 are living cells.
  • B) The cells in gate R2 were plotted as a histogram and the mean fluorescence intensity of these cells was determined.
  • 4A shows the results as a relative increase in fluorescence.
  • the increase in the fluorescence of A549 cells due to the binding of the Cov2 S1 protein to the cell surface was calculated by dividing the mean fluorescence intensity of the cells stimulated with the protein by the intensity of the cells not stimulated with the protein.
  • Example 1 Inhibition of the binding of the SARS-CoV-2 spike S1 protein to A549 cells by compatible solutes
  • SARS-CoV-2 Spike S1 protein trenzyme life Science Services, Cat. No. P2020-001, Lot No .: 1IPO
  • A549 cells from the American Type Culture Collection (ATCC) expressing angiotensin-converting enzyme 2 (ACE2) were used (Uhal et al. 2013).
  • the adherent cells were routinely cultured in T-75 flasks in DMEM with 10% FCS containing penicilin and streptomycin as antibiotics in a CC> 2 incubator (5% CO2, 37 ° C). When the bottom of the flask was 2/3 covered with cells, these were detached by Accutase
  • the A549 cells were cultured to confluence in DMEM with 10% FCS, and the confluent culture was continued for four more days during which the cell culture medium was replaced.
  • HIS-labeled SARS-Cov2-S1 protein is added to each tube and incubated for a further 60 minutes on a tumble shaker at 450 rpm and room temperature.
  • Table 4 MFI values for FIG. 2. The corresponding coefficient of variation in percent (CV%) of the
  • the assay can be performed in a modified form using the cell lines mentioned below.
  • Any cell line which expresses angiotensin-converting enzyme 2 (ACE2), aminopeptidase N (APN) and / or dipeptidyl peptidase 4 (DPP4) is a suitable cell line for the purposes of the assay according to the invention.
  • ACE2 angiotensin-converting enzyme 2
  • APN aminopeptidase N
  • DPP4 dipeptidyl peptidase 4
  • the detailed properties of the cell lines listed below can be looked up in the protein atlas: https://www.proteinatlas.org/ENSG0000013Q234-ACE2/cell and are known to the person skilled in the art.
  • a suitable antibody which detects the expression of the receptor on the cell surface is preferably included in the assay.
  • Cell lines which have a low mRNA expression for ACE are cultivated in DMEM with at least 10% FCS.
  • Hep 2G cells show a high expression of the RNA for ACE.
  • HUVEC cells express ACE2 and are cultured in Vascular Cell Basal Medium using the Endothelial Cell Growth Kit- (ATCC).
  • MRC5 cells which do not express the ACE receptor are also used as a control.
  • Hoffmann et al. It was shown in 2020 that the cells are not infected by SARS CoV2. Therefore, the MRC5 cells represent an excellent control for the specificity of the binding assay used.
  • MRC5 cells are cultured in DMEM with 10% FCS.
  • Example 3 Influence of ectoin on the binding of the SARS-Cov2-S1 protein to A549 cells
  • Example 7 Atomic force spectroscopy to determine the effect of compatible solutes on the stability of membranes
  • the binding domain to be tested or the complete protein is bound to a surface.
  • the surface can be a membrane and even a whole cell that expresses the receptor such as ACE2, APN and / or DPP4.
  • ACE2 ACE2, APN and / or DPP4.
  • a compatible solute Estoin 1 M
  • a buffer 300 mM KCl and 20 mM Tris at pH 7.8
  • one approach contains the human viral receptor in the buffer without solute.

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Abstract

La présente invention concerne l'utilisation de solutés compatibles organiques et hautement solubles dans l'eau ou d'un mélange de solutés, de préférence sous forme de composition pouvant être inhalée, ou administrée par voie oropharyngée, nasale et intraveineuse, dans la prophylaxie ou le traitement de pathologies induites par des virus à ARN sb(+) de la famille des Coronaviridae, de préférence de pathologies induites par SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-HKU1, HCoV-OC43, HCoV-NL63 et/ou HCoV-229E. Les solutés particulièrement appropriés selon l'invention sont l'ectoïne et ses dérivés, la glycoïne, le mannosylglycérate (firoïne) et le mannosylglycéramide (firoïne A), qui réduisent la fixation des virus aux récepteurs de la cellule hôte dans l'épithélium de transition, par ex. l'œil, dans l'épithélium interne, par ex. les poumons, et dans l'endothélium, et réduisent ou empêchent ainsi la propagation des virus. L'invention permet ainsi d'assurer une prophylaxie par diminution des expectorations et expirations infectieuses ainsi qu'un traitement et une réadaptation des tissus touchés, grâce aux propriétés de protection membranaire des solutés compatibles selon l'invention.
EP21725470.5A 2020-05-10 2021-05-10 Solutés compatibles pour assurer la prophylaxie ou le traitement d'infections à sars-cov-2 Pending EP4149433A1 (fr)

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BRPI1012951A2 (pt) * 2009-06-09 2016-07-26 Defyrus Inc "administração de interferon para profilaxia ou tratamento de infecção por patôgeno"
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Title
JENS SMIATEK ET AL: "Properties of compatible solutes in aqueous solution", ARXIV.ORG, CORNELL UNIVERSITY LIBRARY, 201 OLIN LIBRARY CORNELL UNIVERSITY ITHACA, NY 14853, 20 October 2010 (2010-10-20), XP080457833, DOI: 10.1016/J.BPC.2011.09.007 *
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