WO2022113069A1 - Bloqueurs de canal de la protéine e et inhibiteurs de l'orf3 utilisés en tant qu'agents anti-covid-19 - Google Patents

Bloqueurs de canal de la protéine e et inhibiteurs de l'orf3 utilisés en tant qu'agents anti-covid-19 Download PDF

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WO2022113069A1
WO2022113069A1 PCT/IL2021/051396 IL2021051396W WO2022113069A1 WO 2022113069 A1 WO2022113069 A1 WO 2022113069A1 IL 2021051396 W IL2021051396 W IL 2021051396W WO 2022113069 A1 WO2022113069 A1 WO 2022113069A1
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cov
sars
subject
protein
pharmaceutical composition
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PCT/IL2021/051396
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WO2022113069A9 (fr
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Isaiah Arkin
Prabhat Pratap SINGH TOMAR
Anamika Singh
Miriam KRUGLIAK
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Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
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Publication of WO2022113069A1 publication Critical patent/WO2022113069A1/fr
Publication of WO2022113069A9 publication Critical patent/WO2022113069A9/fr
Priority to US17/977,349 priority Critical patent/US20230190769A1/en

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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
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
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    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention is in the field of anti- viral therapy.
  • Coronaviruses are positive-sense, single-stranded RNA viruses that are often associated with mild respiratory tract infections in humans.
  • SARS-CoV-1 was the etiological agent of the SARS epidemic in the winter of 2002/3 that caused 774 deaths amongst 8,098 cases
  • MERS-CoV was responsible for the MERS epidemic that started from 2012 with 862 deaths from 2506 infections
  • SARS-CoV-2 is responsible for the ongoing COVID-2019 pandemic resulting in 4,997,967 deaths out of 246,535,404 cases (as of Sunday Oct 31, 2021).
  • SARS-CoV-1 and SARS-CoV-2 are very similar to one another (ca. 80%) but are distinct from most other Coronaviridae members that infect humans. Both viruses have been placed in subgroup B in the Betacoronavirus genus within the Orthocoronavirinae subfamily of the Coronaviridae.
  • coronavirus structural proteins
  • E is the least understood in terms of mechanism of action and structure. Functionally, the E protein has been implicated in viral assembly, release, and pathogenesis. Yet crucially, coronavirus E proteins are important for viral pathogenesis, and attenuated viruses lacking the protein have even been suggested to serve as vaccine candidates.
  • Co V-2 3a protein also known as open reading implicated in assembly of homotetrameric potassium sensitive ion channels (viroporin) and may modulate virus release. Additionally, it is implicated in pathogenesis, including up- regulation of expression of fibrinogen subunits FGA, FGB and FGG in host lung epithelial cells, inducement of apoptosis in cell culture.
  • a pharmaceutical composition comprising a SARS-CoV-23a protein inhibitor and a SARS-CoV-2 E channel blocker.
  • a pharmaceutical composition comprising Flumatinib and Darapladib.
  • a combination of a SARS-CoV-2 3a protein inhibitor and a SARS-CoV-2 E channel blocker for use in the treatment or prevention of SARS-CoV-2 virulence in a subject in need thereof, wherein the SARS-CoV- 2 3a protein inhibitor and a SARS-CoV-2 E channel blocker are provided at a molar per molar ratio ranging from 10:1 to 1:10 to the subject.
  • a method for treating or preventing SARS-CoV-2 virulence in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a SARS-CoV-23a protein inhibitor and a SARS-CoV-2 E channel blocker, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a method for treating or preventing SARS-CoV-2 virulence in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib and Darapladib.
  • the SARS-CoV-2 protein 3a inhibitor is selected from Flumatinib or Darapladib.
  • the SARS-CoV-2 E channel blocker is selected from the group consisting of: Mavorixafor, Saroglitazar, Mebrofenin, Cyclen, Plerixafor, and
  • the SARS-CoV-2 protein 3a inhibitor is Flumatinib and the SARS-CoV-2 E channel blocker is selected from the group consisting of: Mavorixafor, Saroglitazar, Mebrofenin, Cyclen, Plerixafor, and Gliclazide.
  • the SARS-CoV-2 protein 3a inhibitor is Darapladib and the SARS-CoV-2 E channel blocker is selected from the group consisting of: Mavorixafor, Mebrofenin, and Cyclen.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for use in treatment or prevention of SARS-CoV-2 virulence in a subject in need thereof.
  • the SARS-CoV-2 3a protein inhibitor is formulated within a first pharmaceutical composition and the SARS-CoV-2 E channel blocker is formulated within a second pharmaceutical composition.
  • the prevention or preventing comprises prevention or preventing of any one of: SARS-CoV-2 entry to a cell of the subject, uncoating of the SARS- CoV-2, release of the SARS-CoV-2 from a cell of the subject, or any combination thereof.
  • the subject is infected or suspected of being infected by SARS-CoV-2.
  • Fig. 1 includes a graph showing the effect of individual 3 a protein inhibitors on cell survival. Both Flumatinib and Darapladib provided near full protection at a concentration of 3 ⁇ M. include graphs showing the effect of the inhibitor and various E protein inhibitors on cell survival. (2A) Combination of Flumatinib and Mavorixafor; (2B) Combination of Flumatinib and Cyclen; and (2C) Combination of Flumatinib and Sargolitazar.
  • Figs. 3A-3C include graphs showing the effect of a combination of 3a protein inhibitors on cell survival. Combinations of Flumatinib and Darapladib were tested. (3A) Flumatinib (1 ⁇ M) and Darapladib (0.3 ⁇ M); (3B) Flumatinib (0.1 ⁇ M) and Darapladib (1 ⁇ M); and (3C) Flumatinib (0.3 ⁇ M) and Darapladib (1 ⁇ M).
  • Figs. 4A-4C include graphs showing the effect of 3a inhibitors, E protein blockers, or both, on cell survival.
  • the present invention provides compositions comprising a SARS-CoV-2 E protein channel blocker and a SARS-CoV-23a protein inhibitor for treating or preventing SARS-CoV-2 virulence in a subject.
  • the present invention provides compositions comprising a plurality of SARS-CoV-2 3a protein inhibitors for treating or preventing SARS-CoV-2 virulence in a subject.
  • the present invention provides compositions comprising a SARS-CoV-2 E protein channel blocker and a SARS-CoV-23a protein inhibitor, for preventing SARS-CoV- 2 cell entry, uncoating and/or release from a cell.
  • the present invention in some embodiments, provides compositions comprising a plurality of SARS-CoV-2 3a protein inhibitors, for preventing SARS-CoV-2 cell entry, uncoating and/or release from a cell.
  • SARS-CoV-2 E protein is known to one skilled in the art and has a GenBank Accession no: QIH45055.1. According to some embodiments, the SARS-CoV-2 E protein comprises the amino acid sequence as set forth in SEQ ID NO 1: According to some embodiments, comprises an analog of SEQ ID NO: 1, such as an analog having at least 85%, at least 90%, at least 95% identity to SEQ ID NO: 1.
  • the invention provides a method of treating or preventing SARS-CoV-2 virulence in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SARS-CoV-2 E protein channel blocker and a SARS-CoV-2 3a protein inhibitor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • administering comprises providing a SARS-CoV-2 E protein channel blocker and a SARS-CoV-2 3a protein in a therapeutically effective amount, synergistically effective amount, or both, to the subject.
  • administering comprises providing at least two SARS-CoV- 2 3 a protein inhibitors in a therapeutically effective amount, synergistically effective amount, or both, to the subject.
  • the term “synergistically effective amount” comprises any weight or concentration of a SARS-CoV-2 E protein channel blocker and a SARS-CoV-2 3a protein inhibitor, as long as their molar ratio ranges from: 100: 1 to 1 : 100 (M:M), 50: 1 to 1 :50 (M:M), 30:1 to 1:30 (M:M), 10: lo 1:10 (M:M), 8:1 to 1:8 (M:M), 5:1 to 1:5 (M:M), 4:1 to 1:4 (M:M), 3:1 to 1:3 (M:M), 2:1 to 1:2 (M:M), or is 1:1 (M:M).
  • M:M 100: 1 to 1 : 100
  • M:M 50: 1 to 1 :50
  • M:M 30:1 to 1:30
  • 8:1 to 1:8 (M:M) 5:1 to 1:5 (M:M), 4:1 to 1:4 (M:M), 3:1 to 1:3 (
  • the term “synergistically effective amount” comprises any weight or concentration of a first SARS-CoV-2 3a protein channel inhibitor and a second SARS-CoV- 2 3a protein inhibitor, as long as their molar ratio ranges from: 100:1 to 1:100 (M:M), 50:1 to 1:50 (M:M), 30:1 to 1:30 (M:M), 10:1 to 1:10 (M:M), 8:1 to 1:8 (M:M), 5:1 to 1:5 (M:M), 4:1 to 1:4 (M:M), 3:1 to 1:3 (M:M), 2:1 to 1:2 (M:M), or is 1:1 (M:M).
  • M:M 100:1 to 1:100
  • M:M 50:1 to 1:50
  • 8:1 to 1:8 (M:M) 10:1 to 1:10 (M:M), 8:1 to 1:8 (M:M), 5:1 to 1:5 (M:
  • the first 3a protein inhibitor comprises any one of Flumatinib and Darapladib.
  • the second 3a protein inhibitor comprises any one of Flumatinib and Darapladib.
  • the invention provides a method of treating or preventing SARS-CoV-2 virulence in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of at least 2 SARS-CoV-2 3a protein inhibitors, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the invention provides a method Coronavirus disease 2019 (COVID-19) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SARS-CoV-2 E protein channel blocker and a SARS-CoV-2 3a protein inhibitor, thereby treating or preventing COVID-19.
  • the invention provides a method of treating or preventing Coronavirus disease 2019 (COVID-19) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of at least two SARS-CoV-2 3a protein inhibitors, thereby treating or preventing COVID-19.
  • the invention provides a method of preventing SARS-CoV-2 release from a cell.
  • the method comprises contacting a cell with a SARS-CoV-2 E protein channel blocker and a SARS-CoV-2 3a protein inhibitor, thereby preventing SARS-CoV-2 release from the cell.
  • the method comprises contacting a cell with at least 2 SARS-CoV-2 3a protein inhibitors, thereby preventing SARS-CoV-2 release from the cell.
  • the invention provides a method of preventing SARS-CoV-2 cell entry.
  • the method comprises contacting a cell with a SARS-CoV-2 E protein channel blocker and a SARS-CoV-2 3a protein inhibitor, thereby preventing SARS-CoV-2 cell entry.
  • the method comprises contacting a cell with at least 2 SARS-CoV-2 3a protein inhibitors, thereby preventing SARS-CoV-2 cell entry.
  • the invention provides a method of preventing SARS-CoV-2 uncoating.
  • the method comprises contacting a cell with a SARS-CoV-2 E protein channel blocker and a SARS-CoV-2 3a protein inhibitor, thereby preventing SARS-CoV-2 uncoating.
  • the method comprises contacting a cell with at least 2 SARS-CoV-2 3a protein inhibitors, thereby preventing SARS-CoV-2 uncoating.
  • a cell is a cell of a subject.
  • contacting comprises administering to the subject.
  • the subject is a subject infected or suspected as being infected by SARS-CoV-
  • a method for treating or preventing SARS-CoV-2 virulence in a subject in need thereof comprising to the subject a therapeutically effective amount composition comprising a SARS-CoV-2 3a protein inhibitor and a SARS-CoV-2 E channel blocker in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 10:1 to 1:10, 8:1 to 1:8, 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a therapeutically effective amount composition comprising a SARS-CoV-2 3a protein inhibitor and a SARS-CoV-2 E channel blocker in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 10:1 to 1:10, 8:1 to 1:8, 5:1 to 1:5, 4:1 to
  • the SARS-CoV-2 protein 3a inhibitor is Flumatinib or Darapladib.
  • the SARS-CoV-2 E channel blocker is selected: Mavorixafor, Saroglitazar, Mebrofenin, Cyclen, Plerixafor, and Gliclazide.
  • the SARS-CoV-2 protein 3a inhibitor is Flumatinib and the SARS-CoV-2 E channel blocker is selected from: Mavorixafor, Saroglitazar, Mebrofenin, Cyclen, Plerixafor, and Gliclazide.
  • the SARS-CoV-2 protein 3a inhibitor is in some embodiments, the SARS-CoV-2 protein 3a inhibitor is Flumatinib or Darapladib and the SARS-CoV-2 E channel blocker is selected from: Mavorixafor, Cyclen, or Mebrofenin.
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib and Mavorixafor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Mavorixafor
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Mavorixafor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Mavorixafor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising Flumatinib and Mavorixafor in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Mavorixafor in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Mavorixafor in
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib treating or preventing SARS-CoV-2 possibility represents a separate embodiment of the invention.
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Cyclen, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Cyclen, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising Flumatinib and Cyclen in a molar per molar ratio ranging from100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Cyclen in a molar per molar ratio ranging from100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Cyclen in a molar per molar ratio
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib and Mebrofenin, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Mebrofenin
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Mebrofenin, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Mebrofenin, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising Flumatinib and Mebrofenin in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Mebrofenin in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Mebrofenin in
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib and Saroglitazar, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Saroglitazar
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Saroglitazar, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Saroglitazar in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib and Plerixafor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Plerixafor
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Plerixafor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Plerixafor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising Flumatinib and Plerixafor in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Plerixafor in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Plerixafor in a
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib and Gliclazide, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Gliclazide
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Gliclazide, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a synergistically effective amount of a pharmaceutical composition comprising Flumatinib and Gliclazide, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising Flumatinib and Gliclazide in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Gliclazide in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Flumatinib and Gliclazide in a
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Darapladib thereby treating or preventing SARS-CoV-2 possibility represents a separate embodiment of the invention.
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Darapladib and Mavorixafor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a synergistically effective amount of a pharmaceutical composition comprising Darapladib and Mavorixafor, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising Darapladib and Mavorixafor in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • a pharmaceutical composition comprising Darapladib and Mavorixafor in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • Each possibility represents a separate embodiment of the invention.
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Darapladib and Cyclen, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Darapladib and Cyclen
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Darapladib and Cyclen, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a synergistically effective amount of a pharmaceutical composition comprising Darapladib and Cyclen, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising Darapladib and Cyclen in a molar per molar ratio ranging froml00:l to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Darapladib and Cyclen in a molar per molar ratio ranging froml00:l to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Darapladib and Cyclen in a molar per
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Darapladib and Mebrofenin, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a pharmaceutical composition comprising Darapladib and Mebrofenin
  • the method comprises administering to the subject a synergistically effective amount of a pharmaceutical composition comprising Darapladib and Mebrofenin, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • a synergistically effective amount of a pharmaceutical composition comprising Darapladib and Mebrofenin, thereby treating or preventing SARS-CoV-2 virulence in the subject.
  • the method comprises pharmaceutical composition comprising Darapladib and Mebrofenin in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1, thereby treating or preventing SARS-CoV- 2 virulence in the subject.
  • a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10
  • a method for treating or preventing SARS-CoV-2 virulence in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib and Darapladib.
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising Flumatinib and Darapladib in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1.
  • a pharmaceutical composition comprising Flumatinib and Darapladib in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to 1:30, 15:1 to 1:15, 10:1 to 1:10, 8:1 to 1:8, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or is 1:1.
  • a pharmaceutical composition comprising Flumatinib and Darapladib in a molar per molar ratio ranging from 100:1 to 1:100, 50:1 to 1:50, 30:1 to
  • the SARS-CoV-2 E protein channel blocker is Azacytidine, an analog or a salt thereof. According to some embodiments, the SARS-CoV- 2 E protein channel blocker is 5 -Azacytidine.
  • Azacytidine includes Azacytidine (CAS: 320-67-2; 4-Amino-1- ⁇ -D- ribofuranosyl-s-triazin-2(1H)-one), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof. Azacytidine is described, for example in WO2012135405AE The terms “5- Azacytidine” and “Azacytidine” are used herein interchangeably.
  • the invention provides a pharmaceutical composition comprising Memantine, an analog or a salt thereof, for use in the treatment of a viral infection.
  • the viral infection comprises a coronaviruses infection.
  • the viral infection comprises an infection by virus having an E protein being an ion channel.
  • the viral infection is a coronaviruses infection.
  • the SARS-CoV-2 E protein channel blocker is Memantine, an analog or a salt thereof. According to some embodiments, the SARS-CoV-2 E protein channel blocker is memantine hydrochloride.
  • Memantine as used herein, includes memantine (CAS: 19982-08-2; 1-amino-3,5- dimethyladamantane), as well as pharmaceutically acceptable salts, solvates, hydrates, or Memantine is described, for example, in 5,891,885, 5,919,826, and 6,187,338.
  • the invention provides a pharmaceutical composition comprising Gliclazide, an analog or a salt thereof, for treating a viral infection.
  • the viral infection is an infection by virus having an E protein being an ion channel.
  • the SARS-CoV-2 E protein channel blocker is Gliclazide an analog or a salt thereof.
  • Gliclazide as used herein, includes gliclazide (CAS: 21187-98-4; 1-(3- azabicyclo(3.3.0)oct-3-yl)-3-(p-tolylsulfonyl)urea) as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the SARS-CoV-2 E protein channel blocker is selected from a group including Ginsenoside.
  • the invention provides a pharmaceutical composition comprising Mavorixafor, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 E protein channel blocker is Mavorixafor, an analog or a salt thereof. According to some embodiments, the SARS-CoV- 2 E protein channel blocker is Mavorixafor.
  • Mavorixafor includes Mavorixafor (CAS: 558447-26-0; N-(1H- benzimidazol-2-ylmethyl)-N-[(8S)-5,6,7,8-tetrahydroquinolin-8-yl]butane- 1,4-diamine), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • Mavorixafor is described, for example, in U.S. Patent US7332605, and as compound 89 from a series of 169 analogues in W02003055876.
  • the invention provides a pharmaceutical composition comprising Saroglitazar, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 E protein channel blocker is Saroglitazar, an analog or a salt thereof. According to some embodiments, the SARS-CoV- 2 E protein channel blocker is Saroglitazar Magnesium.
  • Saroglitazar includes Saroglitazar (CAS: 495399-09-2; (aS)-a- Ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-lH-pyrrol-l-yl]ethoxy]benzenepropanoic pharmaceutically acceptable salts, solvates, Saroglitazar is described, for example, in W02016181409.
  • the invention provides a pharmaceutical composition comprising Mebrofenin, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 E protein channel blocker is Mebrofenin, an analog or a salt thereof. According to some embodiments, the SARS-CoV- 2 E protein channel blocker is Mebrofenin.
  • Mebrofenin includes Mebrofenin (CAS: 78266-06-5; 2-[[2-(3- bromo-2,4,6-trimethylanilino)-2-oxoethyl]-(carboxymethyl)amino]acetic acid), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof. Mebrofenin is described, for example, in US9,878,984.
  • the invention provides a pharmaceutical composition comprising Cyclen, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 E protein channel blocker is Cyclen, an analog or a salt thereof. According to some embodiments, the SARS-CoV-2 E protein channel blocker is Cyclen.
  • Cyclen includes Cyclen (CAS: 294-90-6; 1,4,7,10-
  • Tetraazacyclododecane as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof. Cyclen is described, for example in US9421223B2.
  • the invention provides a pharmaceutical composition comprising Kasugamycin, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 E protein channel blocker is Kasugamycin, an analog or a salt thereof.
  • the SARS-CoV- 2 E protein channel blocker is Kasugamycin hydrochloride hydrate (CAS: 19408-46-9).
  • Kasugamycin includes Kasugamycin (CAS: 6980-18-3; 2-amino-2- [(2R,3S,5S,6R)-5-amino-2-methyl-6-[(2R,3S,5S,6S)-2,3,4,5,6- pentahydroxycyclohexyl]oxyoxan-3-yl]iminoacetic acid), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof. Kasugamycin is described, for example in US3358001A.
  • the invention provides a pharmaceutical composition comprising Plerixafor, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 E Plerixafor an analog or a salt thereof.
  • the SARS-CoV-2 E protein channel blocker is Plerixafor octahydrochloride.
  • Plerixafor includes Plerixafor (CAS: 155148-31-5; 1-[[4-(1,4,8,11- tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,l 1-tetrazacyclotetradecane), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • Plerixafor is described, for example in WO2014125499A1.
  • SARS-CoV-2 3a protein also known as open reading frame 3a (ORF3a)
  • ORF3a open reading frame 3a
  • P0DTC3 UniProt Accession no: P0DTC3.
  • the SARS-CoV-2 3a protein comprises the amino acid sequence as set forth in SEQ ID NO 2: MDLFMRIFTIGTVTLKQGEIKDATPSDFVRATATIPIQASLPFGWLIVGVALLAVFQ S AS KIITFKKRW QF ALS KG VHFVCNFFFFFVT V Y S HFFF V A AGLE APFFYF Y AFV Y FFQS INFVRIIMRFWFC WKCRS KNPFF YD AN YFFC WHTNC YD Y CIP YN S VT S S IVIT S GDGTTS PIS EHD Y QIGG YTEKWES G VKDC V VFHS YFTS D Y Y QF Y S TQFS TDTG VE H VTFFIYNKIVDEPEEH V QIHTIDGS S G VVNP VMEPIYDEPTTTT S VPF According to some embodiments, the SARS-CoV-2 3a protein
  • the invention provides a pharmaceutical composition comprising Capreomycin, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 3a protein inhibitor is Capreomycin, an analog or a salt thereof. According to some embodiments, the SARS-CoV- 2 3a protein inhibitor is Capreomycin sulfate.
  • Capreomycin includes Capreomycin (CAS: 11003-38-6; IUPAC: (3S)-3,6-diamino-N-[[(2S,5S,8E,11S, 15S)-15-amino-11-[(4R)-2-amino-3, 4,5,6- tetrahydropyrimidin-4-yl]-8-[(carbamoylamino)methylidene]-2-(hydroxymethyl)- 3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide; (3S)-3,6- diamino-N-[[(2S,5S,8E,11S,15S)-15-amino-11-[(4R)-2-amino-3,4,5,6- tetrahydropyrimidin-4-yl]-8-[(carbamoylamino)
  • the SARS-CoV-2 E protein channel blocker is Pentamidine, an analog or a salt thereof.
  • the SARS-CoV- 23a protein inhibitor is Pentamidine isethionate.
  • Pentamidine as used herein, includes Pentamidine (CAS: 100-33-4; IUPAC: 4,4'- [pentane-l,5-diylbis(oxy)]dibenzenecarboximidamide), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the invention provides a pharmaceutical composition comprising Spectinomycin, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 E protein channel blocker is Spectinomycin, an analog or a salt thereof.
  • the SARS- CoV-23a protein inhibitor is Spectinomycin dihydrochloride.
  • Spectinomycin includes Spectinomycin (CAS: 1695-77-8; IUPAC: lR,3S,5R,8R,10S,llS,12S,13R,14S)-8,12,14-trihydroxy-5-methyl-ll,13- bis(methylamino)-2,4,9-trioxatricyclo[8.4.0.03,8]tetradecan-7-one), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the invention provides a pharmaceutical composition comprising Kasugamycin, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 3a protein inhibitor is N-(2-aminoethyl)-2-a protein inhibitor
  • the SARS-CoV- 23a protein inhibitor is Kasugamycin hydrochloride hydrate.
  • Kasugamycin includes Kasugamycin (CAS :6980- 18-3; IUPAC: 2- amino-2-[(2R,3S,5S,6R)-5-amino-2-methyl-6-[(2R,3S,5S,6S)-2,3,4,5,6- pentahydroxycyclohexyl]oxyoxan-3-yl]iminoacetic acid), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the invention provides a pharmaceutical composition comprising Plerixafor, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-23a an analog or a salt thereof.
  • the SARS-CoV-2 3a protein inhibitor is Plerixafor.
  • Plerixafor includes Plerixafor (CAS: 155148-31-5; IUPAC: 1,1’- (1,4-phenylenebismethylene)bis(1,4,8,ll- tetraazacyclotetradecane)), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the invention provides a pharmaceutical composition comprising Flumatinib, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 3a protein inhibitor is Flumatinib, an analog or a salt thereof. According to some embodiments, the SARS-CoV-2 3a protein inhibitor is Flumatinib.
  • Flumatinib includes Flumatinib (CAS: 895519-90-1; IUPAC: 4-[(4- methylpiperazin-l-yl)methyl]-N-[6-methyl-5-[(4-pyridin-3-ylpyrimidin-2- yl)amino]pyridin-3-yl]-3-(trifluoromethyl)benzamide), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the invention provides a pharmaceutical composition comprising Litronesib, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 3a protein inhibitor is N-(2-aminoethyl)-2-a protein inhibitor
  • the SARS-CoV-2 3a protein inhibitor is Litronesib.
  • Litronesib includes Litronesib (CAS: 910634-41-2; IUPAC: N- [(5R)-4-(2,2-dimethylpropanoyl)-5-[[2-(ethylamino)ethylsulfonylamino]methyl]-5-phenyl- 1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the invention provides a pharmaceutical composition comprising Darapladib, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 3a protein inhibitor is N-(2-aminoethyl)-2-a protein inhibitor
  • the SARS-CoV-2 3a protein inhibitor is Darapladib.
  • Darapladib includes Darapladib (CAS: 356057-34-6; IUPAC: N-(2- Diethylaminoethyl)-2-[2-[(4-fluorophenyl)methylsulfanyl]-4-oxo-6,7-dihydro-5H- as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the invention provides a pharmaceutical composition comprising Floxuridine, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 3a protein inhibitor is N-(2-aminoethyl)-2-a protein inhibitor
  • the SARS-CoV- 2 3a protein inhibitor is Floxuridine.
  • Floxuridine includes Floxuridine (CAS: 50-91-9; IUPAC: 5-Fluoro- 1-[4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-lH-pyrimidine-2,4-dione), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the invention provides a pharmaceutical composition comprising Fludarabine, an analog or a salt thereof, for treating a viral infection.
  • the SARS-CoV-2 3a protein inhibitor is N-(2-aminoethyl)-2-a protein inhibitor
  • the SARS-CoV- 2 3a protein inhibitor is Fludarabine.
  • Fludarabine includes Fludarabine (CAS: 21679-14-1; IUPAC: [(2R,3S,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2- yl]methoxyphosphonic acid), as well as pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.
  • the subject is a subject infected or suspected as being infected by SARS-CoV-2.
  • the subject is a human subject.
  • the invention provides at least two SARS-CoV-2 3a protein inhibitors for use in the treatment or prevention of SARS-CoV-2 virulence, in a subject in need thereof.
  • the invention provides at least two SARS-CoV-2 3a protein inhibitors for use in the prevention of SARS-CoV-2 release from a cell.
  • the at least two SARS-CoV-23a protein inhibitors are within a pharmaceutical composition.
  • the viral infection is an infection by virus having a 3a protein.
  • a method for increasing or enhancing the anti-viral activity of Mavorixafor in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Flumatinib.
  • a enhancing the anti-viral activity of Cyclen in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Flumatinib.
  • a method for increasing or enhancing the anti-viral activity of Mebrofenin in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Flumatinib.
  • a method for increasing or enhancing the anti-viral activity of Saroglitazar in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Flumatinib.
  • a method for increasing or enhancing the anti-viral activity of Plerixafor in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Flumatinib.
  • a method for increasing or enhancing the anti-viral activity of Gliclazide in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Flumatinib.
  • a method for increasing or enhancing the anti-viral activity of Flumatinib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Saroglitazar.
  • a method for increasing or enhancing the anti-viral activity of Flumatinib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Plerixafor.
  • a method for increasing or enhancing the anti-viral activity of Flumatinib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Gliclazide.
  • a method for increasing or enhancing the anti-viral activity of Flumatinib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Mavorixafor.
  • a method for increasing or enhancing the anti-viral activity of Flumatinib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Cyclen.
  • enhancing the anti-viral activity of Flumatinib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Mebrofenin.
  • a method for increasing or enhancing the anti-viral activity of Mavorixafor in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Darapladib.
  • a method for increasing or enhancing the anti-viral activity of Cyclen in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Darapladib.
  • a method for increasing or enhancing the anti-viral activity of Mebrofenin in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Darapladib.
  • a method for increasing or enhancing the anti-viral activity of Darapladib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Mavorixafor.
  • a method for increasing or enhancing the anti-viral activity of Darapladib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Cyclen.
  • a method for increasing or enhancing the anti-viral activity of Darapladib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Mebrofenin.
  • a method for increasing or enhancing the anti- viral activity of Flumatinib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Darapladib.
  • a method for increasing or enhancing the anti-viral activity of Darapladib in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising Flumatinib.
  • increase, increasing, enhance, or enhancing is at least 5%, 10%, 35%, 50%, 80%, 100%, 150%, 270%, 400%, 650%, 800%, or 1,000% increase compared to a control, or any value and range therebetween.
  • anti-viral activity encompasses hampering, inhibiting, any equivalent thereof, or any combination thereof, of viral: genome replication, mRNA synthesis, budding, internalization, entry to a cell, uncoating, release from a cell, or any combination thereof.
  • the cell is a host cell.
  • the host is a mammal host. In some embodiments, the host is a human host or a subject, as disclosed herein.
  • treatment encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured.
  • a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, or provide improvement to a patient or subject’s quality of life.
  • prevention of a disease, disorder, or condition encompasses the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition.
  • prevention relates to a process of prophylaxis in which a subject is exposed to the presently described compositions or formulations prior to the induction or onset of the disease/disorder process.
  • suppression is used to describe a condition wherein the disease/disorder process has already begun but obvious symptoms of the condition have yet to be realized.
  • the cells of an individual may have the disease/disorder, but no outside signs of the disease/disorder have yet been clinically recognized.
  • the term prophylaxis can be applied to encompass both prevention and suppression.
  • treatment refers to the clinical application of active agents to combat an already existing condition whose clinical presentation has already been realized in a patient.
  • preventing comprises reducing the disease severity, delaying the disease onset, reducing the disease cumulative incidence, or any combination thereof.
  • administering refers to any method which, in sound medical practice, delivers a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect.
  • subject or “individual” or “mammal,” refers to any subject, particularly a mammalian subject, for whom therapy is desired, for example, a human.
  • a therapeutically effective dose of the composition of the invention is administered.
  • therapeutically effective amount refers to an amount of a drug effective to treat a disease or disorder in a mammal.
  • a therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. The exact dosage form and regimen would be determined by the physician according to the patient's condition.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the route of administration of the pharmaceutical compositions will depend on the disease or condition to be treated. Suitable routes of administration include, but are not limited to, parenteral injections, e.g., intradermal, intravenous, intramuscular, intralesional, subcutaneous, intrathecal, and any other mode of injection as known in the art.
  • compositions of the invention can be lower than when administered via parenteral injection, by using appropriate compositions it is envisaged that it will be possible to administer the compositions of the invention via transdermal, oral, rectal, vaginal, topical, nasal, inhalation and ocular modes of treatment.
  • a pharmaceutical composition comprising a SARS-CoV-2 3a protein and a SARS-CoV-2 E channel blocker.
  • the pharmaceutical composition comprises a SARS-CoV-2 E channel blocker being selected from: Mavorixafor, Cyclen, or Mebrofenin, or any combination thereof.
  • a pharmaceutical composition comprising Flumatinib and Darapladib.
  • the pharmaceutical composition is for use in treatment or prevention of SARS-CoV-2 virulence in a subject in need thereof.
  • a 2 3a protein inhibitor and a SARS-CoV-2 E channel blocker for use in the treatment or prevention of SARS-CoV-2 virulence in a subject in need thereof.
  • the SARS CoV-2 3a protein inhibitor is formulated within a first pharmaceutical composition and the SARS-CoV-2 E channel blocker, as disclosed herein, is formulated within a second pharmaceutical composition.
  • a combination of Flumatinib and Darapladib for use in the treatment or prevention of SARS-CoV-2 virulence in a subject in need thereof.
  • prevention as disclosed herein for the pharmaceutical composition of the invention or the combination of the invention comprises prevention of: SARS-CoV-2 entry to a cell of a subject, uncoating of a SARS-CoV-2, release of A SARS- CoV-2 from a cell of a subject, or any combination thereof.
  • the composition of the invention is delivered orally.
  • the composition of the invention is an oral composition.
  • the composition of the invention further comprises orally acceptable carrier, excipient, or a diluent.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant or excipient.
  • carrier refers to any component of a pharmaceutical composition that is not the active agent.
  • pharmaceutically acceptable carrier refers to non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline.
  • sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; and phosphate
  • sugars such as lactose, glucose and suc
  • substances which can serve as a carrier herein include sugar, starch, cellulose and its derivatives, powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier as well as other non-toxic pharmaceutically compatible substances used in other pharmaceutical formulations.
  • Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, stabilizers, antioxidants, and preservatives may also be present.
  • any nontoxic, inert, and effective carrier may be used to formulate the compositions contemplated herein.
  • Suitable pharmaceutically acceptable carriers, excipients, and diluents in this regard are well known to those of skill in the art, such as those described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the “Inactive Ingredient Guide,” U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, the contents of all of which are hereby incorporated by reference in their entirety.
  • Examples of pharmaceutically acceptable excipients, carriers and diluents useful in the present compositions include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO. These additional inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as Goodman and Gillman’s: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990); Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.
  • compositions may also be contained in artificially created structures such as liposomes, ISCOMS, slow-releasing particles, and other vehicles which increase the half-life of the peptides or polypeptides in serum.
  • liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.
  • Liposomes for use with the presently described peptides are formed from standard vesicle-forming lipids which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol.
  • the selection of lipids is generally determined by considerations such as liposome size and stability in the of methods are available for preparing liposomes a by Coligan, J. E. et al, Current Protocols in Protein Science, 1999, John Wiley & Sons, Inc., New York, and see also U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.
  • the carrier may comprise, in total, from about 0.1% to about 99.99999% by weight of the pharmaceutical compositions presented herein.
  • a length of about 1,000 nanometers (nm) refers to a length of 1,000 nm ⁇ 100 nm.
  • Vero E6 cells in the presence of SARS-CoV-2 grown in 96-well plates with a culture density of 10,000 cells per well.
  • the culture media contained 10% FCS. After 24 hours, the culture media was replaced to media with 2% FCS and appropriate drugs with a final DMSO concentration of 0.1%. After one hour the cells were infected with virus at an multiplicity of infection (MOI) of 0.01. After 48 hours cell viability was monitored by MTS according to standard protocol from the manufacturer (Promega, USA).
  • Results were normalized relative to uninfected cells. Further comparisons may be gained by comparing the data to untreated cells and to cells that received only 0.1% DMSO. All infection experiments were performed in a BSF-3 facility.
  • the screen was at high concentration (100 ⁇ M)
  • the inventors examined the activity of each of the chemicals in vitro by testing their ability to protect cells against viral death.
  • Results were compared relative to uninfected cells (100%), and to cells that received a drug “placebo” (0.1% DMSO).
  • the results show that in the presence of Flumatinib at concentrations of 0.1 to 3 ⁇ M, approximately 60% or more cells have survived. In particular, Flumatinib at 3 ⁇ M, provided near full survival (Fig. 1). Further, in the presence of Darapladib at concentrations of 1 to 3 ⁇ M, approximately 60% or more cells have survived. In particular, Darapladib at 3 ⁇ M, provided full survival (Fig. 1).
  • the inventors further sought to examin whether a combination of E inhibitors and 3 a inhibitors would provide a better protection against viral-induced cell death.
  • Flumatinib and Mavorixafor at concentrations of either 0.1 ⁇ M and 0.3 ⁇ M or 0.3 ⁇ M and 0.1 ⁇ M provided the synergitic and increased cell viability effect (Fig. 2A).
  • Flumatinib and Cyclen at concentrations of 1 ⁇ M and 1 ⁇ M provided a synergitic effect, resulting with more than 90% cell viability (Fig. 2B).
  • the inventors have shown that at a signet E inhibitors positively reacted to a combination with Flumatinib (Fig. 4B).
  • the inventors showed that Darapladib exhibited a synergistic effect on the cell survival when provided along with Mavorixafor, Cyclen, and Plerixafor (Fig. 4C).
  • the inventors further sought to examine whether a particular combination of 3a inhibitors would provide a better protection against viral-induced cell death.

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant un bloqueur de canal de la protéine E du SARS-CoV-2 et un inhibiteur d'ORF3, ainsi que des méthodes d'utilisation de celles-ci, telles que pour le traitement ou la prévention de la virulence du SARS-CoV-2 chez un sujet le nécessitant.
PCT/IL2021/051396 2020-05-01 2021-11-24 Bloqueurs de canal de la protéine e et inhibiteurs de l'orf3 utilisés en tant qu'agents anti-covid-19 WO2022113069A1 (fr)

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Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3358001A (en) 1963-12-28 1967-12-12 Umezawa Hamao Antibiotic kasugamycin
US3391142A (en) 1966-02-09 1968-07-02 Lilly Co Eli Adamantyl secondary amines
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4666828A (en) 1984-08-15 1987-05-19 The General Hospital Corporation Test for Huntington's disease
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4801531A (en) 1985-04-17 1989-01-31 Biotechnology Research Partners, Ltd. Apo AI/CIII genomic polymorphisms predictive of atherosclerosis
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5019369A (en) 1984-10-22 1991-05-28 Vestar, Inc. Method of targeting tumors in humans
US5192659A (en) 1989-08-25 1993-03-09 Genetype Ag Intron sequence analysis method for detection of adjacent and remote locus alleles as haplotypes
US5272057A (en) 1988-10-14 1993-12-21 Georgetown University Method of detecting a predisposition to cancer by the use of restriction fragment length polymorphism of the gene for human poly (ADP-ribose) polymerase
US5891885A (en) 1996-10-09 1999-04-06 Algos Pharmaceutical Corporation Method for treating migraine
US5919826A (en) 1996-10-24 1999-07-06 Algos Pharmaceutical Corporation Method of alleviating pain
US6187338B1 (en) 1996-08-23 2001-02-13 Algos Pharmaceutical Corporation Anticonvulsant containing composition for treating neuropathic pain
WO2003055876A1 (fr) 2001-12-21 2003-07-10 Anormed Inc. Composes heterocycliques a efficacite accrue se fixant sur les recepteurs de la chimiokine
US7332605B2 (en) 2004-03-15 2008-02-19 Anormed, Inc. Process for the synthesis of CXCR4 antagonist
WO2012135405A1 (fr) 2011-03-31 2012-10-04 Pharmion Llc Synthèse de la 5-azacytidine
WO2014125499A1 (fr) 2013-02-13 2014-08-21 Natco Pharma Limited Procédé amélioré et commercialement viable pour la préparation de plérixafor base de haute pureté
US9421223B2 (en) 2006-02-17 2016-08-23 Abbott Cardiovascular Systems Inc. Nitric oxide generating medical devices
WO2016181409A1 (fr) 2015-05-11 2016-11-17 Cadila Healthcare Limited Magnésium saroglitazar pour le traitement du syndrome chylomicronémie
US9878984B2 (en) 2008-01-11 2018-01-30 Northwestern University Anti-cancer compounds
CN111773282A (zh) * 2020-06-09 2020-10-16 广东金骏康生物技术有限公司 一种药食两用的中药制剂及其应用

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3358001A (en) 1963-12-28 1967-12-12 Umezawa Hamao Antibiotic kasugamycin
US3391142A (en) 1966-02-09 1968-07-02 Lilly Co Eli Adamantyl secondary amines
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4666828A (en) 1984-08-15 1987-05-19 The General Hospital Corporation Test for Huntington's disease
US5019369A (en) 1984-10-22 1991-05-28 Vestar, Inc. Method of targeting tumors in humans
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4683202B1 (fr) 1985-03-28 1990-11-27 Cetus Corp
US4801531A (en) 1985-04-17 1989-01-31 Biotechnology Research Partners, Ltd. Apo AI/CIII genomic polymorphisms predictive of atherosclerosis
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5272057A (en) 1988-10-14 1993-12-21 Georgetown University Method of detecting a predisposition to cancer by the use of restriction fragment length polymorphism of the gene for human poly (ADP-ribose) polymerase
US5192659A (en) 1989-08-25 1993-03-09 Genetype Ag Intron sequence analysis method for detection of adjacent and remote locus alleles as haplotypes
US6187338B1 (en) 1996-08-23 2001-02-13 Algos Pharmaceutical Corporation Anticonvulsant containing composition for treating neuropathic pain
US5891885A (en) 1996-10-09 1999-04-06 Algos Pharmaceutical Corporation Method for treating migraine
US5919826A (en) 1996-10-24 1999-07-06 Algos Pharmaceutical Corporation Method of alleviating pain
WO2003055876A1 (fr) 2001-12-21 2003-07-10 Anormed Inc. Composes heterocycliques a efficacite accrue se fixant sur les recepteurs de la chimiokine
US7332605B2 (en) 2004-03-15 2008-02-19 Anormed, Inc. Process for the synthesis of CXCR4 antagonist
US9421223B2 (en) 2006-02-17 2016-08-23 Abbott Cardiovascular Systems Inc. Nitric oxide generating medical devices
US9878984B2 (en) 2008-01-11 2018-01-30 Northwestern University Anti-cancer compounds
WO2012135405A1 (fr) 2011-03-31 2012-10-04 Pharmion Llc Synthèse de la 5-azacytidine
WO2014125499A1 (fr) 2013-02-13 2014-08-21 Natco Pharma Limited Procédé amélioré et commercialement viable pour la préparation de plérixafor base de haute pureté
WO2016181409A1 (fr) 2015-05-11 2016-11-17 Cadila Healthcare Limited Magnésium saroglitazar pour le traitement du syndrome chylomicronémie
CN111773282A (zh) * 2020-06-09 2020-10-16 广东金骏康生物技术有限公司 一种药食两用的中药制剂及其应用

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Goodman and Gillman's: The Pharmacological Bases of Therapeutics", 1990, PERGAMON PRESS
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
"Strategies for Protein Purification and Characterization - A Laboratory Course Manual", 1996, CSHL PRESS
"The Merck Index", 2001, MERCK & CO., INC.
AUSUBEL ET AL.: "A Practical Guide to Molecular Cloning", 1988, JOHN WILEY AND SONS
COLIGAN, J. E. ET AL.: "Current Protocols in Protein Science", 1999, JOHN WILEY & SONS, INC.
CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, 1994
FRESHNEY: "Culture of Animal Cells - A Manual of Basic Technique", 1994, APPLETON & LANGE
JIMÉNEZ-JIMÉNEZ FÉLIX JAVIER ET AL: "Anti-Inflammatory Effects of Amantadine and Memantine: Possible Therapeutics for the Treatment of Covid-19?", JOURNAL OF PERSONALIZED MEDICINE, vol. 10, no. 4, 9 December 2020 (2020-12-09), pages 217, XP055797833, ISSN: 2075-4426, DOI: 10.3390/jpm10040217 *
SAMBROOK ET AL.: "Molecular Cloning: A laboratory Manual", 1989
SINGH TOMAR PRABHAT PRATAP ET AL: "SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 530, no. 1, 1 September 2020 (2020-09-01), Amsterdam NL, pages 10 - 14, XP055797629, ISSN: 0006-291X, DOI: 10.1016/j.bbrc.2020.05.206 *
TOMAR PRABHAT PRATAP SINGH ET AL: "Blockers of the SARS-CoV-2 3a Channel Identified by Targeted Drug Repurposing", vol. 13, no. 3, 23 March 2021 (2021-03-23), pages 532, XP055822458, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004704/pdf/viruses-13-00532.pdf> DOI: 10.3390/v13030532 *
TOMAR PRABHAT PRATAP SINGH ET AL: "Significance Statement", BIORXIV, 24 February 2021 (2021-02-24), pages 1 - 6, XP055830277, Retrieved from the Internet <URL:https://www.biorxiv.org/content/10.1101/2021.02.24.432490v1.full.pdf> [retrieved on 20210805], DOI: 10.1101/2021.02.24.432490 *
UGUREL OSMAN MUTLUHAN ET AL: "Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13)", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, ELSEVIER BV, NL, vol. 163, 24 September 2020 (2020-09-24), pages 1687 - 1696, XP086300468, ISSN: 0141-8130, [retrieved on 20200924], DOI: 10.1016/J.IJBIOMAC.2020.09.138 *
WATSON ET AL.: "Genome Analysis: A Laboratory Manual Series", 1998, COLD SPRING HARBOR LABORATORY PRESS

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