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WO2022093871A1 - Inactivation de sars-cov-2 par l'éthacridine - Google Patents

Inactivation de sars-cov-2 par l'éthacridine Download PDF

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Publication number
WO2022093871A1
WO2022093871A1 PCT/US2021/056717 US2021056717W WO2022093871A1 WO 2022093871 A1 WO2022093871 A1 WO 2022093871A1 US 2021056717 W US2021056717 W US 2021056717W WO 2022093871 A1 WO2022093871 A1 WO 2022093871A1
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Prior art keywords
pubchem
amine
ethoxy
methyl
methylquinolin
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PCT/US2021/056717
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Inventor
Raul Andino-Pavlovsky
Xiaokun Shu
Petr LIDSKIY
Yinghong XIAO
Xiaoquan LI
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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    • 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
    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/345—Nitrofurans
    • 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
    • A61K31/335—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
    • 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
    • A61K31/40—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
    • A61K31/409—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 having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/33—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
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Definitions

  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • SARS-CoV-2 is an RNA betacoronavirus of the family Coronaviridae .
  • SARS-CoV-2 contains a single-stranded positive-sense RNA genome encapsulated within a membrane envelope. Its genomic RNA is approximately 30kb.
  • the genome of SARS-CoV-2 can be split into two main regions that contain as many as 14 open reading frames (ORFs). The first region, containing ORFla/b, makes up about two-thirds of the genome. After coronavirus attachment and entry into the host cell, the viral genomic RNA is released. The first region of the genomic RNA is translated to form polyproteins, which undergo extensive proteolytic processing, resulting in the release of numerous proteins essential for viral propagation.
  • a critical actor in this process is a 3 -chymotrypsin-like protease (3CLpro, referred as the main protease, Mpro).
  • Mpro plays a central and critical role in the lifecycle of the coronavirus and represents a potential drug target. Accordingly, there is a need in the art for new agents that inhibit Mpro and which may be used as antiviral drugs.
  • the inventors of the present disclosure developed a novel screening platform for the identification of Mpro inhibitors.
  • the scope of the invention encompasses novel compositions and associated methods of use for the identification of novel inhibitors of viral proteases such as Mpro.
  • the assay provides the art with a facile detection agent having large dynamic range suitable for the high throughput screening of novel inhibitors of Mpro.
  • Mpro sensor of the invention 1622 FDA-approved drugs were screened, leading to the identification of several existing drugs that inhibit Mpro activity. Among the agents identified as Mpro inhibitors, several were further tested for their anti-SARS-CoV-2 activity and nine showed significant antiviral activity at 5 pM.
  • ethacridine showed outstanding antiviral activity, further validated by studies in ACE2 expressing human lung epithelial cells and human primary nasal epithelial cells, wherein very high antiviral potency was observed. Additional investigation, as disclosed herein, demonstrated that ethacridine inhibits SARS-CoV-2 mainly by inactivating viral particles, including an ability to inactivate the virus before binding to cells and after it has budded from host cells.
  • the surprising and unexpected viral inactivation activity of ethacridine appears to be stronger than its Mpro inhibitory activity alone, and provides the art a powerful agent to inhibit viral spread between cells and between host organisms.
  • ethacridine is a regulatory-approved therapeutic in many jurisdictions, having been long used as an antiseptic and in other treatment contexts, with a good history of safety and tolerance, inexpensive manufacture, and ready availability.
  • the scope of the invention encompasses the novel use of ethacridine as an antiviral agent, for example, for the inactivation of viral particles.
  • the scope of the invention encompasses the novel use of ethacridine as an antiviral agent for the prevention and treatment of CO VID-19.
  • the scope of the invention encompasses the utilization of ethacridine derivatives as antiviral agents, including for the prevention and treatment of COVID-19.
  • the scope of the invention further encompasses the novel use of additional repurposed drugs as inhibitors of viral protease activity, including SARS-CoV-2 Mrpo activity.
  • the repurposed agents may be used in the he prevention and treatment of viral infections such as COVID-19.
  • the repurposed agents include ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfin.
  • Fig. 1 depicts the normalized ratio of Mpro activity in drug (10 pM) vs DMSO-incubated cells.
  • the Mpro activity was determined as FlipGFP fluorescence normalized to mCherry.
  • Fig. 3 A Simeprevir
  • Fig. 3B Cinacalcet
  • Fig. 3C Ethacridine
  • Fig. 3D ABT-199 (Venetoclax)
  • Fig. 3E Hydroxyprogesterone
  • Fig. 3F Remdesivir.
  • Fig. 4A, 4B, and 4C depict Plaque-reduction assay (P value ⁇ 0.0001 ).
  • Fig. 5A, 5B, 5C, and 5D depict the virucide effect of ethacridine on SARS-CoV-2. Effects of ethacridine on the viral particles of SARS-CoV-2 were examined using plaque-reduction assay at 37C (Fig.
  • Fig. 6A, 6B, and 6C depict ethacridine blocking SARS-CoV-2 in primary human nasal epithelial cells, quantified infection ratio based on anti-Spike protein (S) or anti- Nucleocapsid protein (N) staining. Data are mean (three biological replicates). **: p value ⁇ 0.01.
  • Fig. 6B depicts quantitative analysis of viral titer by plaque assay in the human cells A549 that stably express ACE2, wherein SARS-CoV-2 was pre-incubated with ethacridine (5 uM) for Un, followed by plaque assay on the human A549 cells stably expressing human ACE2.
  • Fig. 6A depicts ethacridine blocking SARS-CoV-2 in primary human nasal epithelial cells, quantified infection ratio based on anti-Spike protein (S) or anti- Nucleocapsid protein (N) staining. Data are mean (three biological replicates). **:
  • the scope of the invention encompasses the novel use of various existing therapeutic compositions discovered by the inventors of the present disclosure to have efficacy against viral pathogens.
  • the invention encompasses a general method of treating viral infection in a subject in need of treatment therefor by the administration of a therapeutically effective amount of a selected repurposed antiviral agent.
  • the antiviral agent is ethacridine.
  • Ethacridine is known as 7-ethoxyacridine-3,9-diamine, CAS Registry Number 442-16-0, Etakridin, or 2-Ethoxy- 6,9-diaminoacridine.
  • the molecular structure of ethacridine is:
  • Ethacridine is known in the art as an antibiotic agent, and is particularly effective against gram-negative bacteria. Commercially, it is often formulated as ethacridine lactate, for example, sold as RIVANOL(TM), and has been used topically as well as in injected and oral forms. Ethacridine is well tolerated and has very low toxicity to mammals, for example, at dosages of up to 20mg/kg.
  • ethacridine is approved for use by the regulatory authorities of various jurisdictions, for example, the United States Food and Drug Administration.
  • an antiviral agent or composition is a composition of matter that effectively inactivates viral particles of one or more types of virus.
  • Ethacridine is an antiviral agent having high efficacy against SARS-CoV-2, inhibiting SARS-CoV-2 with an EC50 of about 0.08 zM.
  • Ethacridine may inactivate viruses by various modes of action: inactivating viral particles prior to cell entry; inhibiting the SARS-CoV-2 3 -chymotrypsin-like protease (3CLpro) which is the main protease (MPro) of the virus; intercalating and binding viral RNA nucleotides, for example, via pi-stacking, hydrogen bonding and electrostatic interactions; and blocking viral binding to host cells by interactions with viral proteins.
  • SARS-CoV-2 3 -chymotrypsin-like protease 3CLpro
  • MPro main protease
  • the methods of the invention further encompass the use of ethacridine derivatives.
  • any therapeutic agent enumerated herein it will be understood that reference to such agent further encompasses derivatives of the enumerated agent.
  • a “derivative” of an enumerated agent comprises a modified form of the agent or a chemically similar composition of matter which retains the therapeutic capabilities of the enumerated composition.
  • Derivatives may comprise one or more modifications and substitutions of the core of the or backbone of the enumerated molecule and modifications or substitutions of the side chains of the enumerated molecule.
  • Derivatives may be designed and selected to optimize any number of factors, for example, chemical modifications that alter the charge, hydrophobicity or hydrophilicity of the molecule, modifications that increase resistance to breakdown in the body, modifications that impart improved bioavailability, modifications that improve solubility, stability, or shelf life, modifications that increase manufacturing convenience, and other modifications, as known in the art.
  • composition e.g., ethacridine
  • ethacridine will encompass its tautomeric forms, its stereoisomers, its enantiomers, and its polymorphs.
  • Certain implementations of the invention encompass the administration of an ethacridine derivative.
  • a derivative of ethacridine may be any composition of matter comprising a modified form of ethacridine, analog of ethacridine, or molecule with chemical similarity to ethacridine which retains some or all antiviral activity of ethacridine, or which has improved antiviral activity, for example, having ethacridine’ s ability to inhibit SARS- CoV-2 viral particles.
  • the ethacridine derivative is a molecule comprising an acridine or substituted derivative thereof.
  • the ethacridine derivative is selected from Table 1.
  • the ethacridine derivative comprises the composition:
  • Ri and R2 may be any of: an amine, hydrogen, or a group selected from acylamino, dialkylamino, cycloalkylamino, azacycloalkyl, alkylcycloalkylamino, aroylamino, diarylamino, arylalkylamino, aralkylamino, alkylaralkylamino, arylaralkylamino, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkoxy, perfluoro alkoxy, mercapto, alkylthio, arylthio, aralkylthio, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, hydroxysulfonyl, amidosulfonyl, dialkyl
  • the scope of the invention encompasses: a pharmaceutical composition comprising ethacridine or a derivative thereof, for use in a method of preventing or treating a viral infection.
  • the scope of the invention encompasses a method of preventing or treating a viral infection in a subject in need of treatment, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising ethacridine or a derivative thereof.
  • the scope of the invention encompasses the use of ethacridine or a derivative thereof in the manufacture of a medicament for the prevention or treatment of a viral infection.
  • the scope of the invention encompasses: a pharmaceutical composition comprising ethacridine or a derivative thereof, for use in a method of preventing or treating coronavirus infection.
  • the scope of the invention encompasses a method of preventing or treating a coronavirus infection in a subject in need of treatment, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising ethacridine or a derivative thereof.
  • the scope of the invention encompasses the use of ethacridine or a derivative thereof in the manufacture of a medicament for the prevention or treatment of coronavirus infection.
  • the scope of the invention encompasses: a pharmaceutical composition comprising ethacridine or a derivative thereof, for use in a method of preventing or treating CO VID-19.
  • the scope of the invention encompasses a method of preventing or treating COVID-19 in a subject in a subject in need of treatment, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising ethacridine or a derivative thereof.
  • the scope of the invention encompasses the use of ethacridine or a derivative thereof in the manufacture of a medicament for the prevention or treatment of COVID-19.
  • the scope of the invention further encompasses methods of preventing or treating a viral infection by the administration of one or more selected agents discovered by the inventors of the present disclosure to have antiviral activity.
  • the inventors of the present disclosure have discovered that certain existing therapeutic molecules have an inhibitory effect on the activity of viral proteases necessary for viral propagation, such as the Mpro protease of SARS-CoV-2.
  • the repurposed antiviral agents include: ABT- 199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfin, and therapeutically effective derivatives of the foregoing.
  • the scope of the invention encompasses: a pharmaceutical composition comprising an agent selected from the group consisting of: ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, verteporfin, and a derivative of any of the foregoing, for use in a method of inhibiting the activity of a viral protease, e.g. SARS-CoV-2 Main viral protease.
  • a viral protease e.g. SARS-CoV-2 Main viral protease.
  • the scope of the invention encompasses a method of inhibiting the activity of a viral protease, e.g. SARS-CoV-2 Main viral protease, in a subject at risk of or suffering from a viral infection, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising an agent selected from the group consisting of ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, verteporfin, and a derivative of the foregoing.
  • a viral protease e.g. SARS-CoV-2 Main viral protease
  • a pharmaceutical composition comprising an agent selected from the group consisting of ABT-199, artesunate, bexarotene, butoconazole
  • the scope of the invention encompasses the use of an agent selected from the group consisting of ABT- 199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfin, or a derivative of the foregoing, in the manufacture of a medicament for inhibiting the activity of a viral protease, e.g. the SARS-CoV-2 Main viral protease (Mpro).
  • Mpro SARS-CoV-2 Main viral protease
  • the scope of the invention encompasses: a pharmaceutical composition comprising an agent selected from the group consisting of: ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfin, or a derivative of the foregoing, for use in a method of preventing or treating a viral infection, e.g. a coronavirus infection, e.g., CO VID-19.
  • a viral infection e.g. a coronavirus infection, e.g., CO VID-19.
  • the scope of the invention encompasses a method of preventing or treating a viral infection, e.g. a coronavirus infection, e.g., COVID-19, in a subject, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising an agent selected from the group consisting of ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfm, or a derivative of the foregoing.
  • a viral infection e.g. a coronavirus infection, e.g., COVID-19
  • a pharmaceutical composition comprising an agent selected from the group consisting of ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet,
  • the scope of the invention encompasses the use of an agent selected from the group consisting of ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfm, or a derivative of the foregoing, in the manufacture of a medicament for preventing or treating a viral infection, e.g. a coronavirus infection, e.g., COVID-19.
  • a viral infection e.g. a coronavirus infection, e.g., COVID-19.
  • a “subject” may comprise any animal.
  • the subject is a human, for example, a human patient.
  • the subject is a subject having a viral infection or in need or treatment for a viral infection, for example, a coronavirus infection, for example, COVID-19.
  • the subject is a subject having symptoms of a viral infection, for example, a coronavirus infection, e.g., COVID-19.
  • the subject is a subject at risk of a viral infection, for example, COVID- 19, for example, by suspected or actual exposure to viruses.
  • the subject is a medical practitioner or other medical staff at risk of viral infection, such as COVID-19 by virtue of sustained exposure to infected persons.
  • the subject may comprise a test animal, veterinary subject, or other non-human animal, for example, a mouse, rat, dog, cat, cow, horse, pig, or non-human primate.
  • the subject comprises cultured cells, as in an experimental or drug screening process.
  • Viruses are directed to the treatment of viral infections.
  • the methods are applied in the treatment of an infection caused by a non-viral pathogen such as a bacteria, protozoan, or other infectious agent.
  • the virus is a coronavirus, i.e. a virus of the family Coronaviridae .
  • the virus is SARS-CoV-2.
  • Reference to SARS- CoV-2 made herein encompasses all known and future variants of SARS-CoV-2, including, for example, any of: alpha, beta, gamma, delta, epsilon, eta, zeta, iota, theta, and kappa variants; variants comprising the B.1.427, B.1.429, B.1.1.7., and B.1.617.2 lineages; and variants comprising the D614G, N501 Y, E484K, or L452R mutants.
  • the virus may comprise another coronaviruses, including for example, 229E, NL63 (alpha), OC43 (beta), HKU1 (beta), MERS-CoV (the causative agent of Middle East respiratory syndrome (MERS)) or SARS-CoV (the causative agent of severe acute respiratory syndrome (SARS)).
  • coronaviruses including for example, 229E, NL63 (alpha), OC43 (beta), HKU1 (beta), MERS-CoV (the causative agent of Middle East respiratory syndrome (MERS)) or SARS-CoV (the causative agent of severe acute respiratory syndrome (SARS)).
  • the virus may be selected from the group consisting of: adeno-associated virus, BK polyomavirus, cowpox virus, coxsackievirus, eastern equine encephalitis virus, Ebolavirus, encephalomyocarditis virus, Epstein-Barr virus, Hanta virus, a hepatitis virus (for example, hepatitis A virus, hepatitis B virus , or hepatitis C virus), a herpes virus, Human immunodeficiency virus (HIV), papillomavirus, a rhinovirus, an influenza virus (including, for example, influenza A virus, influenza B virus, and influenza C virus), Marburg virus, measles virus, poliovirus, a rotavirus (including rotavirus A, rotavirus B, and rotavirus C), a rhinovirus, rubella virus, a vaccinia virus, varicella-zoster virus, West Nile virus, yellow fever
  • Treatment encompasses achieving any therapeutic effect with regards to a viral infection.
  • Treatment may encompass ameliorating, reducing, curing or otherwise therapeutically intervening against the symptoms, morbidity, infectivity, and risk of mortality associated with the infection of a subject by the selected pathogen.
  • treatment may encompass prevention of infection by a selected pathogen, reducing the severity of symptoms, reducing the duration of the infection, etc.
  • treatment encompasses the inactivation of viral particles, wherein the agent inhibits one or more viral processes which underlie infection, viral propagation, and spread.
  • viral inactivation may encompass the inhibition of one or more processes selected from the group consisting of: docking of the virus to target extracellular moieties, membrane fusion, endocytosis of viral particle contents, viral replication, post-translational processing of viral transcripts, packaging of virions, lysis of the host cell, transmission of virions to other cells, viral shedding, or the spread of virions to other subjects.
  • Administration of Antiviral Agents encompass the administration of a selected antiviral agent, e.g., ethacridine, to a subject. Administration may be by any selected route.
  • the antiviral agent e.g., ethacridine
  • the agent is delivered by intravenous injection.
  • the antiviral agent is delivered by any of intravenous, intraperitoneal, intramuscular, or subcutaneous injection.
  • the selected route of administration is aerosol administration, e.g. wherein the therapeutic agent is delivered to the airway of the subject.
  • the selected antiviral agent e.g. ethacridine
  • Aerosol delivery advantageously enables delivery of therapeutic agents directly to cells of the airway wherein many viruses, for example, SARS-CoV-2, infect cells of the respiratory tract.
  • the “airway” may encompass any one or more of the following: the nasal cavity; sinuses; the nasopharynx; the oropharynx; the larynx; the trachea; the lungs or portions thereof, including the bronchi; the bronchioles, the alveolar ducts, and the alveolar sacs; and airway cells such as epithelial cells, goblet cells, ciliated cells, basal cells, and secretory cells.
  • compositions of the invention are administered by other modes of delivery, for example, oral, transmucosal, transdermal, or topical delivery.
  • the therapeutic agents of the invention will be administered in therapeutically effective amounts comprising one or more administered doses.
  • One of skill in the art may determine the dosage by taking into account the physical, chemical, and pharmacological (e.g. ADMET) properties of the pharmaceutical composition comprising the selected antiviral agent, the route of administration, and the therapeutic need.
  • ADMET pharmacological
  • Exemplary dosages may include, for example, cumulative daily dosages of 10 ng to 50 mg/kg body weight per day, for example: 10 ng, 50 ng, 100 ng, 200 ng, 500 ng, 1 pg 5 pg, 10 pg, 15 pg, 20 pg, 25 pg, 30 pg, 40 pg, 50 pg, 60 pg, 70 pg, 80 pg, 90 pg, 100 pg, 200 pg, 300 pg, 400 pg, or 500 pg, 1 mg, 5 mg, 10, mg, or more mg per kg body weight per day.
  • Administration may be daily, including multiple daily administrations (e.g. 2, 3, 4, 5, or more), or multiple times per week.
  • the dose is an amount sufficient to induce a concentration of the selected antiviral agent in target cells (or in the extracellular area of such cells) of at least 0.01 pM, 0.05 pM, 0.08 pM, 0.10 pM, 0.20 pM, or 0.50 pM.
  • compositions comprising treatment of a subject by administration of a therapeutically effective amount of a pharmaceutical composition comprising a selected antiviral agent, e.g., ethacridine.
  • a selected antiviral agent e.g., ethacridine.
  • отноотнотели отное о ⁇ оло ⁇ октивное отное о ⁇ оло ⁇ о ⁇ о ⁇ о ⁇ оло ⁇ о ⁇ о ⁇ о ⁇ оло ⁇ о ⁇ о ⁇ о ⁇ оло ⁇ о ⁇ о ⁇ о ⁇ олово ⁇ о ⁇ оло ⁇ о ⁇ о ⁇ о ⁇ олово ⁇ о ⁇ оло ⁇ о ⁇ о ⁇ о ⁇ олово ⁇ о ⁇ олово ⁇ о ⁇ оло ⁇ о ⁇ ⁇ ани ⁇ ани ⁇ еским ионент ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇ о ⁇
  • Exemplary salts of ethacridine, or other antiviral agents enumerated herein, and their derivatives include, for example, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, sodium, stearate, succinate,
  • compositions of the invention may further encompass conjugates between the selected antiviral agent and one or more functional moieties, for example, a moiety selected to facilitate drug delivery and retention, targeting to specific tissues or cell types, and conjugates with additional therapeutic agents.
  • one or more functional moieties for example, a moiety selected to facilitate drug delivery and retention, targeting to specific tissues or cell types, and conjugates with additional therapeutic agents.
  • the pharmaceutical compositions of the invention may further encompass the selected antiviral agent in combination with one or more additional compositions.
  • the formulations of the pharmaceutical composition may facilitate storage, administration, and efficient delivery to target cells or tissues of the body.
  • the pharmaceutical compositions of the invention may comprise any number of pharmacologically compatible carriers, excipients, diluents, buffers, preservatives, colorants, flavoring agents, or release formulations.
  • the pharmaceutical compositions of the invention may be formulated in particular dosage forms compatible with the selected route of administration. In one embodiment, the selected route of administration is aerosol administration.
  • compositions for aerosol delivery may include solutions or dry powders, for example, wherein the antiviral agent is dissolved in a solvent or present in or on particles comprising a carrier material, for example, particles in the range of 1-10 pm.
  • exemplary carriers include carbohydrates, lipids, polymeric materials, and other aerosol delivery carriers known in the art.
  • the pharmaceutical compositions of the invention are formulated for other routes of administration.
  • the pharmaceutical compositions of the invention comprise liquid solutions, such as for oral ingestion or injection; suspensions and emulsions; granules, tablets, or capsules; gels, creams, and other dosage forms known in the art.
  • the pharmaceutical compositions of the invention may be formulated as nanoparticles containing or functionalized with the selected therapeutic agent, for delivery by nanoparticle-based delivery methods.
  • the pharmaceutical compositions comprises the selected therapeutic agent admixed with a polymeric material for timed release elution of the therapeutic agent in the body, for example, drug eluting hydrogels.
  • the therapeutic agent is coated onto an implant or drug-eluting device.
  • the pharmaceutical compositions of the invention comprise combination products, wherein a selected antiviral agent of the invention, e.g. ethacridine, is administered in combination with one or more additional therapeutic agents.
  • a selected antiviral agent of the invention e.g. ethacridine
  • the one or more additional active agents comprises an antiviral agent.
  • the one or more additional active agents comprises an agent administered to subjects being treated for a respiratory disease, such as COVID-19.
  • Exemplary additional agents include, for example, remdesivir, dexamethasone, favilavir, ebselen, therapeutic antibodies, such as anti-SARS-CoV-2 antibodies, peramivir, zanamivir, oseltamivir phosphate, baloxavir marboxil, interferon-a, cidofovir, ribavirin, fomivirsen, protease inhibitors, nucleoside analogs, nucleotide analogs, drugs that serve as competitive substrates for viral DNA polymerases, and inhibitors of viral ion channel M2 protein or neuraminidase.
  • therapeutic antibodies such as anti-SARS-CoV-2 antibodies, peramivir, zanamivir, oseltamivir phosphate, baloxavir marboxil, interferon-a, cidofovir, ribavirin, fomivirsen, protease inhibitors, nucleoside analogs, nucleotide analogs
  • the selected therapeutic agent and the one or more additional active agents are admixed in a single formulation.
  • the combination products of the invention comprise a kit, wherein the kit comprises separate dosage forms of the selected antiviral agent, e.g. ethacridine, and the one or more additional active agents, packaged or sold together.
  • the scope of the invention encompasses aerosol delivery devices comprising an apparatus which holds and facilitates delivery of a pharmaceutical composition of the invention.
  • the devices may further comprise mechanical components capable of delivering a controlled dosage of such pharmaceutical composition to the airway of the subject.
  • the delivery may be accomplished by pumps, vaporizing elements such as heaters or vibrational energy sources, or by the use of compressed gases and propellants, as known in the art.
  • the device comprises a dry powder inhaler.
  • the device comprises a metered-dose inhaler.
  • the device comprises a nebulizer.
  • the device comprises a device for delivering agents via a mechanical ventilator, such as a pressurized metered dose inhaler, adaptive aerosol device, or vibrating mesh nebulizer configured for use with a mechanical ventilator.
  • the drug delivery devices of the invention are constituted for delivery of pharmaceutical compositions comprising ethacridine or derivatives thereof.
  • the drug delivery device may comprise any of: a dry powder inhaler loaded with a pharmaceutical compositions comprising ethacridine or a derivative thereof; a metered-dose inhaler loaded with a pharmaceutical compositions comprising ethacridine or a derivative thereof; a nebulizer loaded with a pharmaceutical compositions comprising ethacridine or a derivative thereof; or an adaptive aerosol device loaded with a pharmaceutical compositions comprising ethacridine or a derivative thereof.
  • the scope of the invention encompasses an article of manufacture functionalized with one or more selected antiviral agents enumerated herein, for example, ethacridine.
  • selected antiviral agents enumerated herein, for example, ethacridine.
  • such items may be used for the prevention of viral infection, for example, to prevent SARS-CoV-2 infection.
  • coatings on textiles, for example wherein the therapeutic agent is incorporated into a carrier material e.g.
  • textiles may be components of items such as face masks, gloves, gowns, or other items of Personal Protective Equipment (PPE), such as used by medical personnel or for general use. Similar coatings may be applied to medical equipment, such as ventilator components, treatment surfaces, and other items wherein viral spread is a threat.
  • PPE Personal Protective Equipment
  • the scope of the invention encompasses novel tools and associated methods for the assessment of viral RNA processing protease activity, such as SARS-CoV-2 Mpro activity.
  • SARS-CoV-2 the main protease Mpro is 3 -chymotrypsin-like protease (3CLpro) , which processes the ppla and pplab polyproteins at 11 conserved sites comprising a conserved cleavage sequence.
  • This processing of the polypeptides ppla and pplab is essential to viroid formation and spread and is a major target in the search for COVID-19 therapeutics. Accordingly, there is a need in the art for screening tools that enable the facile identification of viral protease inhibitors, such as SARS-CoV-2 Mpro inhibitors.
  • the inventors of the present disclosure have developed a novel viral protease reporter that may be used screening for viral protease inhibitors such as Mpro inhibitors.
  • the protease reporter is a fusion protein comprising the domains of a fluorescent reporter proteins, wherein one or more domains of the fluorescent protein is configured in a position such that it is not active and protein fluorescence is absent, wherein the inactive domain is configured with a protease cleavage site, such that viral protease activity, e.g. SARS-CoV-2 Mpro activity, if present, liberates the domain to assume an active form, creating a fluorescent signal.
  • the screening tool is a FlipGFP construct, for example, as described in Zhang et al., 2019. Designing a Green Fluorogenic Protease Reporter by Flipping a Beta Strand of GFP for Imaging Apoptosis in Animals, Am. Chem. Soc. 141 : 4526-4530.
  • the viral protease reporter may comprises a fusion protein FlipGFP, wherein one of the eleven beta-strands of a split GFP is flipped.
  • the split GFP contains two parts: one part contains beta-strands 10 and 11 (i.e. GFP10 and 11), and the other part contains nine other beta-strands and the central alpha helix (i.e. GFP1-9).
  • GFP10-11 contains the highly conserved Glu222 that is essential in catalyzing the chromophore maturation.
  • GFP 1-9 contains the three amino acids that form the chromophore via cyclization, dehydration and oxidation.
  • GFP 10-11 spontaneously binds GFP 1-9 and catalyzes the chromophore maturation, leading to a green fluorescent GFP.
  • GFP 10- 11 is “flipped” using heterodimeric coiled coils (for example, E5 and K5) so that the “flipped” GFP10-11 cannot bind GFP1-9 when viral protease activity is absent, and thus little or no fluorescence is generated.
  • the E5 coiled coil may inserted between GFP10 and GFP11, and GFP11 is followed by the K5 coiled coil.
  • a viral protease cleavage sequence for example, a SARS-CoV-2 Mpro-specific cleavage sequence AVLQSGFR, is inserted between GFP11 and K5.
  • the protease e.g., Mpro
  • the two parts (flipped GFP10-11 and GFP1-9) are linked by a “selfcleaving” peptide, such as 2A.
  • the construct further comprises a secondary fluorescent protein, such as red mCherry.
  • compositions may be screened to identify inhibitors of viral protease activity, such as SARS-CoV-2 Mpro activity.
  • cells are engineered to express the selected viral protease, e.g., SARS-CoV- 2 Mpro, and the protease reporter construct of the invention. The cells are then cultured and exposed to a putative viral protease inhibitor, wherein protease activity results in cleavage and activation of the fluorescent protein and wherein inhibited protease activity results in reduced activation of the fluorescent signal.
  • Example 1 Ethacridine inhibits SARS-CoV-2 by inactivating viral particles
  • Rational design of a Anorogenic Mpro activity reporter To develop an activity reporter of Mpro with a large dynamic range suitable for high-throughput screening (HTS), a GFP -based protease reporter was developed. The FlipGFP reported, as described in Zhang et al. Designing a Green Fluorogenic Protease Reporter by Flipping a Beta Strand of GFP for Imaging Apoptosis in Animals. J Am Chem Soc. American Chemical Society; 2019; 141 : 4526-4530, was adapted, which was designed by flipping one of the 11 beta-strands of a split GFP.
  • the split GFP contains two parts: one part contains beta-strands 10 and 11 (i.e., GFP10 and 11), and the other contains nine other beta-strands and the central alpha helix (i.e., GFP1-9).
  • GFP10-11 contains the highly conserved Glu222 that is essential for catalyzing chromophore maturation.
  • GFP 1-9 contains the three amino acids that form the chromophore via cyclization, dehydration and oxidation.
  • GFP 10-11 spontaneously binds GFP 1-9 and catalyzes the chromophore maturation, leading to green fluorescence.
  • GFP10-11 was “flipped” using heterodimeric coiled coils (E5 and K5) so that the flipped GFP10-11 cannot bind GFP1-9 when Mpro is inactive, and thus, no or little fluorescence is detected.
  • An Mpro-specific cleavage sequence was used between GFP11 and K5. In this way, when Mpro cleaves the proteolytic site, GFP11 is flipped back, allowing GFP10-11 to bind GFP1-9, resulting in bright fluorescence
  • the reporter was named FlipGFP Mpro .
  • a red fluorescent protein mCherry was added within the construct via a “self-cleaving” 2A peptide.
  • ACE2 a SARS-CoV2 receptor
  • dsRNA double-stranded RNA
  • FlipGFP Mpro green fluorescence The green fluorescence of the sensor, normalized by the co-expressed mCherry, was 63% greater in the coronavirus- infected cells than in mock-infected cells.
  • Infected cells also showed dsRNA fluorescence compared to non-infected (mock) cells without dsRNA staining.
  • the FlipGFP Mpro sensor was not responsive to the TEV protease, and the FlipGFP- based TEV reporter (FlipGFP TEV ) was only activated by TEV but not by Mpro.
  • FlipGFP Mpro specifically detects Mpro activity with a large dynamic range, establishing a robust HTS system for screening Mpro inhibitors at a BSL2 level with 60-fold fluorescence change and a robust z’ -factor.
  • HTS high throughput screen
  • -1600 FDA-approved drugs (20 pM final concentration) was performed.
  • the reporter construct (FlipGFP Mpro and mCherry) was transfected into HEK293 cells, followed by addition and incubation of the drugs. Green fluorescence normalized to red fluorescence were then calculated.
  • a volcano plot revealed -120 drugs that showed > 50% reduction of Mpro activity with a p-value ⁇ 0.001.
  • the identified -120 drugs were re-screened under similar conditions, the top 15 drugs were surveyed at a lower concentration (10 pM) and it was found that 12 drugs showed >50% reduction of FlipGFP Mpro fluorescence (normalized by mCherry) at 10 pM concentration (Fig. 1). An IC50 was calculated for each of the 12 drugs. IC50 of six drugs were at 2-6 pM, and the rest were above 6 pM. Lastly, determined cellular viability of these identified drugs in HEK293T cells was determined, which showed that they are not toxic at the concentrations that inhibit Mpro activity.
  • Antiviral activity of identified drugs Next was investigated antiviral activity of selected drugs in Vero E6 cells.
  • the cell monolayers were pretreated with the 12 selected drugs for 3 hours, and then infected with SARS-CoV-2.
  • the cells were further cultivated in the presence of each respective compound at a concentration of 5 pM. After 16 hours of incubation, the culture media samples were collected, and the amount of infectious particles were estimated by plaque assay revealing that 9 of the 12 drugs showed significant antiviral activity at 5 pM.
  • Ethacridine inhibits SARS-CoV-2 by inactivating viral particles.
  • infectivity of the virus particles after ethacridine treatment was tested with plaque assay, and viral RNA levels using qRT-PCR was also measured.
  • the antiviral effect of ethacridine on different stages of the lifecycle of SARS- CoV-2 was examined, including virus-cell binding, RNA replication, and budding.
  • SARS-CoV-2 particles were pre-incubated with ethacridine (5 pM) or DMSO control for 1 hour.
  • the mixture was then added to Vero E6 cells for viral adsorption at a multiplicity of infection (MOI) at 0.5.
  • MOI multiplicity of infection
  • the solution was removed and fresh medium added containing ethacridine (5 pM) or DMSO control.
  • ethacridine 5 pM
  • DMSO DMSO control.
  • supernatant was collected and a plaque assay with overlaid agar without ethacridine or DMSO was conducted to measure viral titer.
  • qRT-PCR was used to measured viral RNA levels in the supernatant and within cells.
  • Control DMSO + DMSO
  • the virus and cells were exposed to the drug at all stages, including 1 hour before infection, during replication, and after viral budding (i.e. Eth. + Eth.); 3) The virus and cells were exposed to the drug only after viral entry, during replication, and after budding (i.e. DMSO + Eth.).
  • a fourth condition was devloped: a plaque assay was conducted right after pretreatment of SARS-CoV-2 with ethacridine for 1 hr (i.e. Eth. [1 hr]), which determines direct effect of the drug on viral particles.
  • RNA accumulation in infected cells was investigated next.
  • qRT-PCR measurement revealed no change of viral RNA (vRNA) levels when the drug was added after viral binding and cell entry (DMSO + Eth.) in both the supernatant and the cells. This indicates that the drug had no effect on vRNA replication.
  • vRNA viral RNA
  • DMSO + Eth cell entry
  • these data suggests that ethacridine inhibits SARS-CoV-2 by inactivating the viral particles without effect on vRNA replication. This is consistent with the results of plaque assays for the supernatant samples with 3 different treatments in that showed 3 ⁇ 4 log reduction in infectivity after virions in the supernatant were exposed to the drug before plaque assay.
  • plaque assay and qRT-PCR data show that ethacridine inhibits SARS-CoV- 2 mainly by inactivating viral particles, including the virus before binding to cells and in the supernatant after budding from host cells, with no or little effect on vRNA replication.
  • a human lung epithelial A549 cell line stably expressing human ACE2 (A549 ACE2 ) and human primary nasal epithelial (HNE) cells were used.
  • a plaque assay in A549 ACE2 cells revealed that ethacridine-treated virus showed a dramatic decrease in infectivity when applied to A549 ACE2 cells (Fig. 6B), indicating that the effect of virus inactivation of ethacridine is not specific to Vero E6 cells.
  • Ethacridine (PubChem ID number: 2017), Acridine, 9-amino-2-methoxy- (PubChem ID number: 18867), 7-Methoxy-l, 2,3,4- tetrahydroacridin-9-amine (PubChem ID number: 119053), 6-Ethoxy-2-methylquinoline (PubChem ID number: 81118), ACRIDINE, 9-(p-ANISIDINO)- (PubChem ID number: 43640), 2-Ethoxy-6-nitroacridin-9-amine (PubChem ID number: 30102), 4-[6-(2- Fluoroethoxy)-2-quinolinyl]benzenamine (PubChem ID number: 76023983), 6-Methoxy-2- methylquinolin-4-amine (PubChem ID number: 774820), Acridin-9-yl(4-

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Abstract

La présente invention concerne des médicaments existants et approuvés qui n'ont pas été utilisés auparavant en tant qu'agents antiviraux qui peuvent être facilement reconvertis pour traiter des infections virales, y compris COVID-19. Dans un mode de réalisation principal, l'éthacridine et ses dérivés sont utilisés dans des méthodes de traitement d'infections virales, y compris COVID -19. L'invention concerne également des dispositifs d'administration de médicament pour l'administration d'éthacridine. L'invention concerne également de nouveaux rapporteurs de l'activité de SARS-CoV-2 Mpro qui peuvent être utilisés pour identifier de nouveaux agents pour le traitement d'infections virales telles que COVID-19.
PCT/US2021/056717 2020-10-26 2021-10-26 Inactivation de sars-cov-2 par l'éthacridine Ceased WO2022093871A1 (fr)

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