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WO2019209035A1 - Composition pharmaceutique pour la prévention ou le traitement d'une maladie infectieuse de flavivirus - Google Patents

Composition pharmaceutique pour la prévention ou le traitement d'une maladie infectieuse de flavivirus Download PDF

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Publication number
WO2019209035A1
WO2019209035A1 PCT/KR2019/004974 KR2019004974W WO2019209035A1 WO 2019209035 A1 WO2019209035 A1 WO 2019209035A1 KR 2019004974 W KR2019004974 W KR 2019004974W WO 2019209035 A1 WO2019209035 A1 WO 2019209035A1
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Prior art keywords
virus
sulfate
flavivirus
composition
dengue
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English (en)
Korean (ko)
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원철희
민달희
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Lemonex Inc
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Lemonex Inc
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Priority to US17/051,117 priority Critical patent/US12295967B2/en
Priority to EP19792006.9A priority patent/EP3785718B1/fr
Priority to CN202311462578.4A priority patent/CN120053460A/zh
Priority to CN201980028691.7A priority patent/CN112040954A/zh
Priority to CN202311462579.9A priority patent/CN120570898A/zh
Priority claimed from KR1020190048075A external-priority patent/KR102269663B1/ko
Publication of WO2019209035A1 publication Critical patent/WO2019209035A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • 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
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating flavivirus infection.
  • Flaviviruses are small, coated, enveloped positive-strand RNA viruses, some of which are or are likely to present or threaten the health of humans worldwide today or in the future. Yellow fever viruses, for example, have been the cause of epidemics in certain jungles in sub-Saharan Africa or in parts of South Africa. Many yellow fever infections are not serious, but they can lead to serious, life-threatening illnesses.
  • the condition of the disease has two phases. The early acute phase is characterized by high fever, chills, headache, back pain, myalgia, anorexia, nausea, and vomiting. After three to four days, these symptoms disappear. In some patients, these symptoms recur when the disease enters the so-called toxic phase.
  • Dengue (DEN) viruses are another example of flaviviruses.
  • the dengue virus is transmitted to humans by mosquitoes (primarily Aedes aegypti) and is causing an increasingly serious public health problem worldwide.
  • About 50 out of 100 million seahorses are infected with the dengue virus
  • four antigenic dengue viruses (Dengue types 1-4) are spread throughout the Caribbean, Asia and the Americas.
  • Hemorrhagic Fever / Dengue Shock Syndrome (DHF / DSS)] is an immunopathological disease that occurs in individuals sequentially infected by DENs of different antigenic types: more than 3.6 million dengue hemorrahagic fevers and 58,000 people with DHF.
  • Flaviviruses including yellow fever and dengue viruses, have two important biological characteristics responsible for the induction of disease in humans and animals.
  • One of these two features is neurotropism, which refers to the tendency of a virus to infect and infect the host's nervous system.
  • Nerve-friendly flavivirus infections can cause infection and injury of the brain and spinal cord (ie, encephalitis), unconsciousness, paralysis, and convulsions.
  • a second feature of flavivirus infection is visceral organ affinity, ie the virus tends to invade and infect vital visceral organs including the liver, kidneys and heart.
  • Visceral organ-friendly flavivirus infections result in infection and damage of the liver (hepatitis), kidney (nephritis), and heart muscle (myocarditis), preventing these organs from functioning normally. Neural tissue affinity and visceral organ affinity are judged to be distinct features of Flavivirus.
  • flaviviruses are basically neuronal affinity (eg West Nile virus), others are visceral organ affinity (eg yellow fever virus and dengue virus), and others exhibit both properties. (Eg, Kyasanur Forest Disease Virus). However, both neural affinity and visceral organ affinity are present to some extent in all flaviviruses. Interactions between neural tissue affinity and visceral organ affinity appear to occur in the host because infection of the visceral organ occurs prior to the attack of the central nervous system. Neuronal affinity thus depends on the virus's ability to replicate in the extraneous organs (intestines). Such extraneural replication causes viremia and this viremia attacks the brain and spinal cord.
  • a pharmaceutical composition for preventing or treating flavivirus infection is provided.
  • the flavivirus infection is sanction virus ( acea virus), Aroa virus (Aroa virus), Bagaga virus (Bagaza virus), Ringzi virus (Banzi virus), Bouboui virus (Bouboui virus), Bucarasa bat virus, Cacipacore virus, Carey Island virus, Cowbone Ridge virus, Dakar bat virus, Dengue virus (Dengue virus, Edge Hill virus, Entebbe bat virus, Gadgets Gully virus, Ilheus virus, Israel turkey meningoencephalomyelitis virus, Japanese encephalitis virus, Jugra virus, Jutiapa virus, Kadam virus, Kedogai Kedougou virus, Kokobera virus, Kotango virus, Kyasanur Forest disease virus, Langat virus, Louping ill virus, Meaban virus, Modoc virus, Montana myotis leukoencephalitis virus, Murray Valley encephalitis virus, Ntaya virus , Omsk hemorrhagic fever virus, Phnom Penh bat virus, Powassan virus
  • composition of 1 above, wherein the flavivirus infection is a dengue virus induced infection.
  • composition 1 wherein the composition is tobramycin, trifluoroperazine 2HCl, amikacin hydrate, hydroxychloroquine sulfate, thiolidazine HCl, dihydrostreptomycin sulfate, gentamicin sulfate, netylmycin sulfate, capp At least one of leumycin sulfate, paromomycin sulfate, resminostat, montelukast, norfloxacin, nedaplatin, bleomycin, nystatin, cephalosin, mycafungin sodium, epavirenz and miltopesin; Or at least one of pharmaceutically acceptable salts thereof.
  • the flavivirus is issus virus (AN), Aroa virus (Aroa virus), Bagaza virus (Bagaza virus), Ringzi virus (Banzi virus), Bouboui virus, Boo Carrasa bat virus, Cascipacore virus, Carey Island virus, Cowbone Ridge virus, Dakar bat virus, Dengue virus ( Dengue virus, Edge Hill virus, Entebbe bat virus, Gadgets Gully virus, Ilheus virus, Israel turkey meningoencephalomyelitis virus ), Japanese encephalitis virus, Jugra virus, Jutiapa virus, Kadam virus, Kedog virus ugou virus, Kokobera virus, Kotango virus, Kyasanur Forest disease virus, Langat virus, Louping ill virus, Miban virus (Meaban virus), Modoc virus, Montana myotis leukoencephalitis virus, Murray Valley encephalitis virus, Ntaya virus, Om Omsk hemorrhagic fever virus, Phnom Penh bat virus, Powassan virus
  • composition of claim 5, wherein the flavivirus is a dengue virus.
  • the composition is tobramycin, trifluoroperazine 2HCl, amikacin hydrate, hydroxychloroquine sulfate, thiolidazine HCl, dihydrostreptomycin sulfate, gentamicin sulfate, netylmycin sulfate, capp At least one of leumycin sulfate, paromomycin sulfate, resminostat, montelukast, norfloxacin, nedaplatin, bleomycin, nystatin, cephalosin, mycafungin sodium, epavirenz and miltopesin; Or at least one of pharmaceutically acceptable salts thereof.
  • composition of the present invention is excellent in inhibiting the proliferation of viruses of the genus Flaviviruses and increasing the survival rate for these derived infections.
  • Figure 4 shows the dengue virus helicase activity inhibitory effect.
  • Figure 5 shows the effect of reducing dengue virus.
  • Figure 7 shows the effect of inhibiting dengue virus growth and increase the survival rate of infection.
  • the present invention relates to a pharmaceutical composition for preventing or treating flavivirus infection.
  • Flavivirus is a genus of the togavirus family and has a common antigen in the genus due to its cohesion of erythrocytes.
  • flavivirus refers to any species of virus known in the art to be included in the genus without limitation, and flavivirus infection refers to a disease or carrier condition caused by infection of the virus.
  • the composition of the present invention can exhibit a killing, growth inhibitory effect on various species of the Flavivirus genus.
  • Flavivirus genus For example, aba virus, Aroa virus, Bagaza virus, Banzi virus, Bouboui virus, Bucarasa bat virus , Cacipacore virus, Carey Island virus, Cowbone Ridge virus, Dakar bat virus, Dengue virus, Edge Hill virus Hill virus, Entebbe bat virus, Gadgets Gully virus, Ilheus virus, Israel turkey meningoencephalomyelitis virus, Japanese encephalitis virus ), Jugra virus, Jutiapa virus, Kadam virus, Kedougou virus, Cocovera virus kobera virus, Kotango virus, Kyasanur Forest disease virus, Langat virus, Louping ill virus, Meaban virus, blasphemy virus ( Modoc virus, Montana myotis leukoencephalitis virus, Murray Valley encephalitis virus, Ntaya virus, Omsk hemorrhagic fever virus
  • Louis Encephalitis Virus (Saint Louis encephalitis virus), Sal Vieja virus, San Perlita virus, Saumarez leaf virus (Sauma) rez Reef virus, Sepik virus, Tembusu virus, Tick-borne encephalitis virus, Tyuleniy virus, Kenya S virus, Excellent Usutu virus, Wesselsbron virus, West Nile virus, Yaounde virus, Yellow fever virus, Yokose virus, Zika Virus (Zika virus), and the like, specifically, dengue virus, and more specifically, dengue virus serotype2, but are not limited thereto.
  • the pharmaceutical composition of the present invention is gentamicin sulfate (Gentamicin Sulfate), netylmicin (Netilmicin), Tobramycin (Pabraomycin), Paromomycin (Amikacin), Capreomycin (Capreomycin), Triple Trifluoperazine, Dihydrostreptomycin, Hydrochlorochloroquine, Thiolidazine HCl, Efavirenz, Miltefosine, Nystatin, Nystatin, Micafungin, Bleomycin, Resminostat, Monteukast, Norfloxacin, Nedaplatin And at least one of cephalothin; Or at least one of their pharmaceutically acceptable salts.
  • gentamicin sulfate (Gentamicin Sulfate), netylmicin (Netilmicin), tobramycin (Tobramycin), Paromomycin (Aromikacin), Capreomycin (Capreomycin), tripleru Trifluoperazine, Dihydrostreptomycin, Hydroxychloroquine, Thioridazine HCl, Resminostat, Montelukast, Norfloxacin and Norfloxacin At least one of daplatin; Or at least one of pharmaceutically acceptable salts thereof.
  • tobramycin trifluoroperazine 2HCl, amikacin hydrate, hydroxychloroquine sulfate, thiolidazine HCl, dihydrostreptomycin sulfate, gentamicin sulfate, netylmycin sulfate, capreomycin
  • sulfate paromomycin sulfate, resminostat, montelukast, norfloxacin, nedaplatin, bleomycin, nystatin, cephalosin, mycafungin sodium, epavirenz and mittefosin; Or at least one of pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups which may be present in each of the above drugs (compounds).
  • pharmaceutically acceptable salts may include, but are not limited to, sodium salts, calcium salts, potassium salts, hydrochlorides, sulfates, hydrates, and the like, and may be prepared through methods for preparing salts known in the art. .
  • Such substances may act as enzyme inhibitors that inhibit the activity of helicase and RNA dependent RNA polymerase (RdRp), which are enzymes required for viral replication, for example, and may exhibit efficacy against flavivirus infection.
  • RdRp RNA dependent RNA polymerase
  • RNA-dependent RNA polymerase (RdRp) in the flavivirus genome is known to have a very high genetic preservation rate among various RNA virus families including Flavivirus at the gene level, and also has a high degree of conservation at the protein level (polypeptide motif level). Viruses. 2018 Feb; 10 (2): 76.),
  • the pharmaceutical compositions of the present invention may show efficacy against various species of the genus Flavivirus.
  • the amino acid sequences of the enzyme active sites are very similarly conserved in the flaviviruses, and these sequences are known to contribute to the recognition of viral RNA. It is known to have similar functions (contributing to hydrogen bonding, hydrophobic interactions, etc. with adjacent specific sequences) and to enzymatic activity. For example, the sites where dengue virus helicases and zika virus helicases bind to ssRNA substrates have been found to be very similar (12904-12920 Nucleic Acids Research, 2017, Vol. 45, No. 22).
  • the pharmaceutical composition of the present invention may be formulated containing the above substances.
  • compositions of the present invention may be formulated for delivery via any route of administration.
  • Route of administration can refer to any route of administration known in the art including, but not limited to, aerosol, nasal, oral, transmucosal, transdermal, parenteral or intestine.
  • the pharmaceutical composition of the present invention may also contain any pharmaceutically acceptable carrier.
  • a "pharmaceutically acceptable carrier” is a pharmaceutical composition involved in the transport or transport of a compound of interest from one tissue, organ or part of the body to another tissue, organ or part of the body. It refers to acceptable materials, compositions or vehicles.
  • the carrier may be a liquid or solid filler, diluent, excipient, solvent or encapsulating material or combinations thereof.
  • Each component of the carrier must be “pharmaceutically acceptable", ie compatible with the other ingredients of the formulation. It should also be suitable for use when in contact with any tissue or organ to which it can be contacted, which should not involve the risk of any other complications that are too great than toxic, irritant, allergic reactions, immunogenicity or its therapeutic advantages. do.
  • composition of the present invention may be administered to an individual who is trying to prevent a flavivirus infection or to an individual suffering from a flavivirus infection.
  • the subject may be a mammal, including a human, and specifically a human.
  • the pharmaceutical composition of the present invention may be delivered in a therapeutically effective amount.
  • the exact therapeutically effective amount is that amount of the composition that produces the most effective result for therapeutic efficacy in a given subject. This amount includes the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics and bioactivity), the physiological condition of the subject (age, sex, disease type and stage, general physical health, response to a given dosage and type of medicament) ), The nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration, and will depend upon a number of factors. One skilled in the clinical and pharmacological arts will determine the therapeutically effective amount through routine experimentation, for example by monitoring the subject's response to administration of the compound and adjusting the dosage accordingly.
  • the present invention also relates to a composition for inhibiting or killing flavivirus growth.
  • composition of the present invention is a gentamicin sulfate (Gentamicin Sulfate), netylmicin (Netilmicin), Tobramycin (Pabraomycin), Paromomycin (Amikacin), Capreomycin (Capreomycin), Trifluoropera Trifluoperazine, Dihydrostreptomycin, Hydroxychloroquine, Thioridazine HCl, Efavirenz, Miltefosine, Nystatin, Nystatin (Micafungin), bleomycin, lesminostat, montelukast, norfloxacin, nedaplatin And at least one of cephalothin; Or at least one of their pharmaceutically acceptable salts.
  • gentamicin sulfate (Gentamicin Sulfate), netylmicin (Netilmicin), tobramycin (Tobramycin), Paromomycin (Aromikacin), Capreomycin (Capreomycin), tripleru Trifluoperazine, Dihydrostreptomycin, Hydroxychloroquine, Thioridazine HCl, Resminostat, Montelukast, Norfloxacin and Norfloxacin At least one of daplatin; Or at least one of pharmaceutically acceptable salts thereof.
  • tobramycin trifluoroperazine 2HCl, amikacin hydrate, hydroxychloroquine sulfate, thiolidazine HCl, dihydrostreptomycin sulfate, gentamicin sulfate, netylmycin sulfate, capreomycin
  • sulfate paromomycin sulfate, resminostat, montelukast, norfloxacin, nedaplatin, bleomycin, nystatin, cephalosin, mycafungin sodium, epavirenz and mittefosin; Or at least one of pharmaceutically acceptable salts thereof.
  • compositions of the present invention can inhibit or kill the growth of various species of the Flavivirus genus.
  • Flavivirus genus For example, aba virus, Aroa virus, Bagaza virus, Banzi virus, Bouboui virus, Bucarasa bat virus , Cacipacore virus, Carey Island virus, Cowbone Ridge virus, Dakar bat virus, Dengue virus, Edge Hill virus Hill virus, Entebbe bat virus, Gadgets Gully virus, Ilheus virus, Israel turkey meningoencephalomyelitis virus, Japanese encephalitis virus ), Jugra virus, Jutiapa virus, Kadam virus, Kedougou virus, Cocovera virus kobera virus, Kotango virus, Kyasanur Forest disease virus, Langat virus, Louping ill virus, Meaban virus, blasphemy virus ( Modoc virus, Montana myotis leukoencephalitis virus, Murray Valley encephalitis virus, Ntaya virus, Omsk hemorrhagic fever virus ), Phnom Pen
  • Louis Encephalitis Virus (Saint Louis encephalitis virus), Sal Vieja virus, San Perlita virus, Saumarez leaf virus (Sauma) rez Reef virus, Sepik virus, Tembusu virus, Tick-borne encephalitis virus, Tyuleniy virus, Kenya S virus, Excellent Usutu virus, Wesselsbron virus, West Nile virus, Yaounde virus, Yellow fever virus, Yokose virus, Zika Virus (Zika virus), and the like, specifically, dengue virus, and more specifically, dengue virus serotype2, but are not limited thereto.
  • composition of the present invention may be formulated as the pharmaceutical composition illustrated above, but is not limited thereto.
  • the present invention is a gentamicin sulfate (Gentamicin Sulfate), netylmicin (Netilmicin), Tobramycin (Tobramycin), Paromomycin (Aromikacin), Capreomycin (Capreomycin), Trifluoropera Trifluoperazine, Dihydrostreptomycin, Hydroxychloroquine, Thioridazine HCl, Efavirenz, Miltefosine, Nystatin, Nystatin (Micafungin), bleomycin, lesminostat, montelukast, norfloxacin, nedaplatin And at least one of cephalothin; Or at least one of pharmaceutically acceptable salts thereof; and relates to a use for the preparation of a composition for preventing or treating flavivirus infection.
  • gentamicin sulfate (Gentamicin Sulfate), netylmicin (Netilmicin), tobramycin (Tobramycin), Paromomycin (Aromikacin), Capreomycin (Capreomycin), tripleru Trifluoperazine, Dihydrostreptomycin, Hydroxychloroquine, Thioridazine HCl, Resminostat, Montelukast, Norfloxacin and Norfloxacin At least one of daplatin; Or at least one of their pharmaceutically acceptable salts.
  • tobramycin trifluoroperazine 2HCl, amikacin hydrate, hydroxychloroquine sulfate, thiolidazine HCl, dihydrostreptomycin sulfate, gentamicin sulfate, netylmycin sulfate, capreomycin
  • sulfate paromomycin sulfate, resminostat, montelukast, norfloxacin, nedaplatin, bleomycin, nystatin, cephalosin, mycafungin sodium, epavirenz and mittefosin; Or at least one of their pharmaceutically acceptable salts.
  • Flavivirus infections in the use of the present invention may be caused by the aforementioned viruses.
  • the compounds (drugs) or pharmaceutically acceptable salts thereof may exhibit excellent flavivirus growth inhibition and killing effects, and thus may be used in the preparation of a composition for preventing or treating flavivirus infection.
  • the present invention is a gentamicin sulfate (Gentamicin Sulfate), netylmicin (Netilmicin), Tobramycin (Tobramycin), Paromomycin (Aromikacin), Capreomycin (Capreomycin), Trifluoropera Trifluoperazine, Dihydrostreptomycin, Hydroxychloroquine, Thioridazine HCl, Efavirenz, Miltefosine, Nystatin, Nystatin (Micafungin), bleomycin, lesminostat, montelukast, norfloxacin, nedaplatin And at least one of cephalothin; Or at least one of pharmaceutically acceptable salts thereof; and a method for preventing or treating flavivirus infection.
  • gentamicin sulfate (Gentamicin Sulfate), netylmicin (Netilmicin), tobramycin (Tobramycin), Paromomycin (Aromikacin), Capreomycin (Capreomycin), tripleru Trifluoperazine, Dihydrostreptomycin, Hydroxychloroquine, Thioridazine HCl, Resminostat, Montelukast, Norfloxacin and Norfloxacin At least one of daplatin; Or at least one of their pharmaceutically acceptable salts.
  • tobramycin trifluoroperazine 2HCl, amikacin hydrate, hydroxychloroquine sulfate, thiolidazine HCl, dihydrostreptomycin sulfate, gentamicin sulfate, netylmycin sulfate, capreomycin
  • sulfate paromomycin sulfate, resminostat, montelukast, norfloxacin, nedaplatin, bleomycin, nystatin, cephalosin, mycafungin sodium, epavirenz and mittefosin; Or at least one of their pharmaceutically acceptable salts.
  • the individual may be any individual that may be infected with Flavivirus infection, and specifically, may be a mammal including a human, more specifically a human, but is not limited thereto.
  • Flavivirus infections may be caused by the viruses described above.
  • CCK-8 analysis was performed according to the manufacturer's instructions.
  • VeroE6 cells Prior to the experiment, VeroE6 cells were seeded at densities of 10.5 ⁇ 10 4 cells / cm 2 and 7.0 ⁇ 10 4 cells / cm 2 , respectively. After 24 hours of incubation at 37 ° C., 5% CO 2 , montelukast was treated at a continuously diluted concentration for 48 hours. CCK-8 reagents were treated in each group at a concentration of 10% v / v and incubated for 1-4 hours at normal cell culture conditions. Quantitative analysis of changes in colorimetric intensity was performed by measuring the optical density of formazan salt at 450 nm using a microplate reader (Molecular Devices, Inc., USA). The experiment was performed in triplicate with data represented as mean ⁇ SEM.
  • VeroE6 cells were seeded at densities of 10.5 ⁇ 10 4 cells / cm 2 and 7.0 ⁇ 10 4 cells / cm 2 , respectively.
  • dengue virus serotype2 was inoculated into each cell culture with MOI of 0.1, 0.5 and 2.5, respectively, in serum-free medium for 2 hours.
  • the culture plate was shaken gently every 30 minutes to evenly distribute the virus in the cells.
  • Montelukast solutions were prepared at serially diluted concentrations in each complete culture medium containing 0.75% methyl cellulose. After incubation, virus medium was removed and cells were washed once with sterile PBS and then treated with compound solution.
  • the cells were incubated for 48 hours under the culture chamber. After incubation, each group was prepared for focal formation assay (FFA) and relative viral RNA expression analysis.
  • FFA focal formation assay
  • the compound solution was removed and the cells washed once with sterile PBS and then fixed with 4% paraform aldehyde. Cells were washed with TRIZOL for viral RNA expression analysis and stored at ⁇ 70 ° C. for further analysis.
  • FFA was performed on NS1 protein of DV serotype2. 4% paraformaldehyde fixed cells were washed three times with PBS. The blocking solution was treated for 1 hour at room temperature. After washing with PBS, the primary antibody (Mouse anti-Flavivirus NS1, 1: 2000) was treated in each group for 2 hours at room temperature or overnight at 4 ° C. After washing with PBS, a secondary antibody (anti-mouse IgG-FITC, 1: 500) was applied to each group for 1 hour at room temperature. After rinsing, PBS containing 10 ⁇ g / ml HOECHST 33342 was treated in each group for nuclear staining. Fluorescent stained viral focus forming units were observed and analyzed under a microscope (Olympus, Japan).
  • AG129 mice (10-12 weeks) were inoculated by intraperitoneal injection of various viral titers of 10 6 , 5 ⁇ 10 6 and 10 7 FFU.
  • To assess the antivirality of montelukast AG129 mice (10-12 weeks) were injected with 10 7 FFU (IP) and then 200 ⁇ l of montelukast (IP, 10 mg / kg / day) or PBS. Medication was performed once a day.
  • Negative controls (uninfected group) received 300 ⁇ l of PBS (IP) instead of virus.
  • 200 ⁇ l of montelukast (IP, 10 mg / kg / day) was administered alone to uninfected AG129 mice.
  • Weight loss and mortality status were monitored daily. In the survival analysis, euthanized mice with severe disease-related symptoms or rapid weight loss were recorded as current deaths after the war. Each body weight was analyzed as a relative percentage of 0 days.
  • each primer was designed taking into account the overlap between two exons of the target gene with a GC content of less than 50% and an expected amplicon size of about 100 bps. Primer sequences were identified as shown in Table 2. Quantitative real time PCR (qRT-PCR) was performed to quantify viral RNA. Each reaction was performed in 20 ⁇ L volume using SYBR green master mix. Quantstudio3 TM (Applied Biosystems Inc., USA) was used for this study in the two step amplification process. For the analysis of viremia, a linear correlation standard curve was established between the viral titer (FFU / mL) and the corresponding threshold cycle (CT) value.
  • FFU titer
  • CT threshold cycle
  • Virus in plasma was calculated according to the equation of the standard curve. Standard curves were derived for serially diluted virus titers. For cell-based group and mouse organ samples (including whole blood), semi-quantitative viral RNA was analyzed for GAPDH, an endogenous control.
  • Organ samples fixed with 4% paraformaldehyde were subjected to a series of procedures such as paraffin insertion, sectioning and staining with hematoxylin and eosin.
  • the degree of inhibition of dengue virus helicase activity was confirmed according to the concentrations of the six compounds (IC 50 values presented, FIG. 4).
  • the dengue infection model (AG129 mouse) was used to confirm DENV viremia reduction in mouse blood after drug treatment (FIG. 5).
  • Micafungin sodium was injected with I.P. (Intraperitoneal) injection, Miltefosine was injected with Oral injection, and Vechicle control was injected with PBS.
  • the montelukast-administered group has a low weight loss, high survival rate, and low blood pressure.
  • Relative dengue virus RNA expression was measured from each tissue sample and is shown in FIG. 8.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant au moins l'un parmi le sulfate de gentamicine, la nétilmicine, la tobramycine, la paromomycine, l'amikacine, la capréomycine, la trifluopérazine, la dihydrostreptomycine, l'hydroxychloroquine, l'HCl de thioridazine, l'éfavirenz, le miltéfosine, la nystatine, la micafungine, la bléomycine, le résinminostat, le montélukast, la norfloxacine, la nédaplatine et la céphalofine, qui peut présenter une excellente inhibition de la croissance et tuer les effets sur divers virus de la famille des Flaviviridae.
PCT/KR2019/004974 2018-04-27 2019-04-24 Composition pharmaceutique pour la prévention ou le traitement d'une maladie infectieuse de flavivirus Ceased WO2019209035A1 (fr)

Priority Applications (5)

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US17/051,117 US12295967B2 (en) 2018-04-27 2019-04-24 Pharmaceutical composition for prevention or treatment of flavivirus infection
EP19792006.9A EP3785718B1 (fr) 2018-04-27 2019-04-24 Composition pharmaceutique pour la prévention ou le traitement d'une maladie infectieuse de flavivirus
CN202311462578.4A CN120053460A (zh) 2018-04-27 2019-04-24 用于预防或治疗黄病毒感染症的药物组合物
CN201980028691.7A CN112040954A (zh) 2018-04-27 2019-04-24 用于预防或治疗黄病毒感染症的药物组合物
CN202311462579.9A CN120570898A (zh) 2018-04-27 2019-04-24 用于预防或治疗黄病毒感染症的药物组合物

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US201862663312P 2018-04-27 2018-04-27
US62/663,312 2018-04-27
KR1020190048075A KR102269663B1 (ko) 2018-04-27 2019-04-24 플라비바이러스 감염증의 예방 또는 치료용 약학적 조성물
KR10-2019-0048075 2019-04-24

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US20110183892A1 (en) * 2007-10-11 2011-07-28 Dinman Jonathan D Methods for the treatment of viral conditions
WO2015051281A1 (fr) * 2013-10-06 2015-04-09 Morrison Thomas E Thérapies antivirales
JP2017526728A (ja) * 2014-09-15 2017-09-14 インフラマトリー・レスポンス・リサーチ・インコーポレイテッド 炎症介在性状態の治療におけるレボセチリジン及びモンテルカスト
KR20170105113A (ko) * 2015-01-28 2017-09-18 아르노 테라퓨틱스 인코포레이티드 바이러스 감염을 억제하기 위한 조성물 및 방법
WO2017181098A2 (fr) * 2016-04-15 2017-10-19 Visterra, Inc. Molécules d'anticorps se liant au virus zika et leurs utilisations

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US20110183892A1 (en) * 2007-10-11 2011-07-28 Dinman Jonathan D Methods for the treatment of viral conditions
WO2015051281A1 (fr) * 2013-10-06 2015-04-09 Morrison Thomas E Thérapies antivirales
JP2017526728A (ja) * 2014-09-15 2017-09-14 インフラマトリー・レスポンス・リサーチ・インコーポレイテッド 炎症介在性状態の治療におけるレボセチリジン及びモンテルカスト
KR20170105113A (ko) * 2015-01-28 2017-09-18 아르노 테라퓨틱스 인코포레이티드 바이러스 감염을 억제하기 위한 조성물 및 방법
WO2017181098A2 (fr) * 2016-04-15 2017-10-19 Visterra, Inc. Molécules d'anticorps se liant au virus zika et leurs utilisations

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NUCLEIC ACIDS RESEARCH, vol. 45, no. 22, 2017, pages 12904 - 12920
VIRUSES, vol. 10, no. 2, February 2018 (2018-02-01), pages 76

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