WO2021159050A1 - Compositions et procédés de traitement d'infection à coronavirus - Google Patents

Compositions et procédés de traitement d'infection à coronavirus Download PDF

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Publication number
WO2021159050A1
WO2021159050A1 PCT/US2021/017006 US2021017006W WO2021159050A1 WO 2021159050 A1 WO2021159050 A1 WO 2021159050A1 US 2021017006 W US2021017006 W US 2021017006W WO 2021159050 A1 WO2021159050 A1 WO 2021159050A1
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Prior art keywords
coronavirus
heparin
therapeutic agent
enoxaparin
cov
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PCT/US2021/017006
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English (en)
Inventor
Yuenian Shi
Li Li
Jinping LI
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Hepalink Usa Inc.
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Application filed by Hepalink Usa Inc. filed Critical Hepalink Usa Inc.
Publication of WO2021159050A1 publication Critical patent/WO2021159050A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K9/007—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

  • the invention relates generally to compositions and methods for treating coronavirus infections, particularly enoxaparin, a low molecular weight heparin, for treating coronavirus infections.
  • Coronaviruses are enveloped, positive-strand RNA virus, and are members of the Coronavirinae subfamily in the family of Coronaviridae of the order Nidovirales. There are four genera identified in the Coronavirinae subfamily: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus. Theirs genome are approximately 30,000 nucleotides in length with 5’-cap structure and 3’-poly-A tail and contain at least 6 open reading frames (ORFs).
  • the first ORFs occupies the two-third of the whole genome length and encode 16 non-structural proteins(nsp1-16), except Gammacoronavirus lack nspl
  • the remaining ORFs about one-third of whole genome length near the 3’-terminus, encodes four main structural proteins: Spike(S), membrane(M), envelop(E) and nucleocapsid(N).
  • Some coronaviruses carry extraordinary genes encoding special structural and accessory proteins.
  • Coronaviruses are pathogens in humans and animals, which cause acute or chronic symptoms in the host's respiratory system, liver, gastrointestinal tract, and nervous system, such as SARS-CoV, MERS-CoV and 2019-nCoV, leading to the outbreaks of a severe respiratory syndrome in 2003 (China), in 2012 (Middle East) and 2020 (China), each of which belongs to the Betacoronavirus genera.
  • CoVs virion The assembly and infection of CoVs virion are mediated by theirs four structural proteins.
  • the homotrimeric S proteins make up the spike shape on the viral surface and is responsible for adhesion to the cell surface through binding to host cell receptors.
  • Different CoVs-derived S proteins take up the different host molecules as receptors, and so far, the zinc metalloprotease aminopeptidase N (APN,CD13) is identified as the receptor for a number of alpha-CoVs, including human coronavirus 229E, transmissible gastroenteritis virus, porcine respiratory coronavirus and feline infectious peritonitis virus.
  • CEACAMs murine carcinoembryonic antigen-related cell adhesion molecules
  • MHV mouse hepatitis virus
  • Angiotensin-converting enzyme 2 is demonstrated to be the functional receptor for SARS coronavirus.
  • CoVs inject theirs genomic RNA into host cells and immediately function as template to directly produce non- structural proteins(nsps) for assembly of replication-transcription complex (RTC).
  • sgRNAs subgenomic RNAs
  • the S protein mediates virus entry into host cells through its receptor binding domain (RBD). Further analysis of the sequence of RBD structure reveals that the homology of SARS-coV and 2019-nCoV is only 73%. It has been reported that the binding of S protein of SARS-coV to human ACE2 mainly depends on 14 amino acid residues, 8 of which are conserved in 2019- nCoV. (Return of the Coronavirus: 2019-nCoV. Viruses. 2020 Jan 24;12(2))
  • 2019-nCoV also uses ACE2 as a receptor, but its affinity may be weaker than SARS-coV (Evolution of the novel coronavirus from the ongoingWuhan outbreak and modeling of its spike protein for risk of human transmission. Sci. China Life Sci. 2020.). Subsequently, it was reported in the overexpression system in vitro that 2019-nCoV can bind to ACE2 of human, bat, cat and pig, but not to ACE2 of mouse, and S protein of SARS can bind to ACE2 of mouse (A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Feb 3.).
  • CoVs inject theirs genomic RNA into host cells and immediately function as template to directly produce non- structural proteins(nsps) for assembly of replication-transcription complex(RTC). Then, a set of subgenomic RNAs(sgRNAs) are synthesized by RTC in a manner of discontinuous transcription, and followed by the production of subgenomic mRNAs under the guidance of these minus-strand sgRNAs templates. In turn, the non-structural as well as the structural proteins can be increasingly produced according to genomic and subgenomic RNAs.
  • Antiviral drugs including interferon, ribavirin, and acyclovir, can achieve viral antiviral effects by inhibiting the synthesis of viral DNA or RNA and preventing viral replication.
  • Remdesivir is a nucleoside analogue developed by Gilead Sciences, which is used to inhibit RNA polymerase and initially amid to deal with Ebola virus. It has been tested against coronaviruses (MERS and SARS) in vitro and in vivo in animal models and shows some antiviral effect.
  • Heparin drugs are mucopolysaccharide drugs, which are composed of glucosamine, L-iduronin, N- acetylglucosamine and D-glucuronic acid alternately, including heparin and low-molecular- weight heparin. Heparin is an anticoagulant that prolongs the clotting time both inside and outside the body.
  • Low-molecular-weight heparin is obtained by degradation of heparin, and its anti-Flla activity is low, and clinical bleeding side effects are small.
  • Low-molecular-weight heparin drugs currently on the market such as enoxaparin sodium, tinzaparin sodium, and dalteparin sodium have weight average molecular weights of 3800 ⁇ 5000, 5500 ⁇ 7500, and 5600 ⁇ 6400, respectively, and anti-Xa / lla ratios of 3.3 ⁇ 5.3, 1.5 ⁇ 2.5 and 1.9 ⁇ 3.2, respectively.
  • Coronavirus infection Provided herein is a method for treating Coronavirus infection, in particular
  • 2019-nCov i.e., SARS-CoV-2, which is used herein interchangeably
  • a method for neutralizing and inhibiting Coronavirus entering and infection into target cells comprising administering low molecular weight heparins, in particular Enoxaparin, either alone or in combination with another antiviral agent such as remdesivir.
  • Enoxaparin in the preparation of a pharmaceutical composition for use in any method as defined above.
  • Enoxaparin in the preparation of a medicament for use in any method as defined above.
  • Enoxaparin in combination with a direct antiviral agent that inhibits Coronavirus growth in the preparation of a medicament for use in any method as defined above.
  • the patent or application file contains at least one drawing executed in color.
  • Figure 1 shows the molecular structure of enoxaparin.
  • Figures 2A-2E show photos of cells that have been treated with no virus, virus, virus + 0.25mg/ml enoxaparin, virus + 2.5mg/ml enoxaparin, and virus + 25mg/ml enoxaparin, respectively, supporting that enoxaparin inhibits CPE induced by SARS-CoV-2.
  • Figures 3A-3E show photos of cells with fluorescence that have been treated with no virus, virus, virus + 0.25mg/ml enoxaparin, virus + 2.5mg/ml enoxaparin, and virus + 25mg/ml enoxaparin, respectively, supporting that enoxaparin inhibits the infection of SARS- CoV-2.
  • Figures 4A and 4B show graphs that depict the abundance of mRNA virus in cells that have been treated with no virus, virus, virus + 0.25mg/ml enoxaparin, virus + 2.5mg/ml enoxaparin, and virus + 25mg/ml enoxaparin, respectively.
  • the graphs support that enoxaparin inhibits the replication of SARS-CoV-2.
  • the present invention provides a method of treating coronavirus infection, neutralization of coronavirus infectivity, reducing viral load, viral clearance time, and/or clinical morbidity or mortality reduction in a patient with coronavirus infection.
  • the present invention also provides a method of reducing the risk of occurrence of individual pathogenic coronavirus infection of the clinical sequelae.
  • the invention is directed to a method for treating coronavirus infection in a subject in need thereof by administering a therapeutically effective amount of heparin or a pharmaceutically acceptable salt or ester thereof to the subject.
  • Heparin may be any heparin currently used in medical treatment.
  • heparin is a low molecular weight heparin as known in the medical field. The low molecular weight heparin may be enoxaparin.
  • the invention is directed to a method for treating coronavirus infection in a subject in need thereof by administering a therapeutically effective amount of heparin or a pharmaceutically acceptable salt or ester thereof in combination with a therapeutically effective amount of at least one other therapeutic agent.
  • Other therapeutic agent may be a corticosteroid, an anti-inflammatory signal transduction modulator, a 132- adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline, imatinib mesylate, nilotinib hydrochlorine, dasatinib, interferon, ribavirin, adefovir, tenofovir, acyclovir, brivudine, cidofovir, fomivirsen, foscarnet, ganciclovir, penciclovir, amantadine, rimantadine, zanamivir and remdesivir.
  • the administration of therapeutic agents may be by intravenous injection, intramuscular injection, inhalation, or nebulization depending on the nature of the therapeutic agent.
  • the method may be used for treating SARS infection in a subject. In other embodiments, the method may be used for treating MERS (Middle East respiratory syndrome) infection. In still other embodiments, the method may be used for treating 2019-nCov infection.
  • MERS Middle East respiratory syndrome
  • the invention is directed to a method for neutralizing coronavirus in a subject in need thereof by administering a therapeutically effective amount of heparin or a pharmaceutically acceptable salt or ester thereof to the subject.
  • Neutralization of coronavirus may be achieved as heparin competes for binding to coronavirus so that less coronavirus may binds to ACE2 receptor and enter host cells in a subject.
  • heparin may be any heparin currently used in medical treatment.
  • heparin is a low molecular weight heparin as known in the medical field. The low molecular weight heparin may be enoxaparin.
  • the invention is directed to a method for treating coronavirus infection in a subject in need thereof by administering a therapeutically effective amount of heparin or a pharmaceutically acceptable salt or ester thereof in combination with a therapeutically effective amount of at least one other therapeutic agent.
  • Other therapeutic agent may be a corticosteroid, an anti-inflammatory signal transduction modulator, a 132- adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline, imatinib mesylate, nilotinib hydrochlorine, dasatinib, interferon, ribavirin, adefovir, tenofovir, acyclovir, brivudine, cidofovir, fomivirsen, foscarnet, ganciclovir, penciclovir, amantadine, rimantadine, zanamivir and remdesivir.
  • the administration of therapeutic agents may be by intravenous injection, intramuscular injection, inhalation, or nebulization depending on the nature of the therapeutic agent.
  • the method may be used for treating SARS infection in a subject. In other embodiments, the method may be used for treating MERS (Middle East respiratory syndrome) infection. In still other embodiments, the method may be used for treating 2019-nCov infection.
  • MERS Middle East respiratory syndrome
  • the methods described herein can be used for reducing viral load, viral clearance time, and/or clinical morbidity or mortality in a subject with coronavirus infection. In still further embodiments, the methods described herein can be used for reducing the risk of occurrence of individual pathogenic coronavirus infection of the clinical sequelae.
  • the method comprises the step of administering a therapeutically effective amount of heparin or a pharmaceutically acceptable salt or ester thereof to the subject.
  • the method comprises the step of administering a therapeutically effective amount of heparin or a pharmaceutically acceptable salt or ester thereof in combination with a therapeutically effective amount of at least one other therapeutic agent.
  • Other therapeutic agent may be a corticosteroid, an anti inflammatory signal transduction modulator, a B2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline, imatinib mesylate, nilotinib hydrochlorine, dasatinib, interferon, ribavirin, adefovir, tenofovir, acyclovir, brivudine, cidofovir, fomivirsen, foscarnet, ganciclovir, penciclovir, amantadine, rimantadine, zanamivir and remdesivir.
  • the term "therapeutically effective amount”, as used herein, is the amount of compound of enoxaparin present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by the chosen route of administration.
  • the precise amount will depend upon numerous factors, for example the particular compound of enoxaparin, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.
  • Example 1 Low-molecular weight heparin enoxaparin
  • Enoxaparin is a low-molecular-weight heparin (LMWH) widely used in clinical practice for the prevention and treatment of thromboembolism.
  • Enoxaparin is obtained from benzyl heparin through a basic b-elimination reaction. It is a highly sulfated, acidic linear polysaccharides having closely related structures and consist of alternating 1 ,4-linked hexuronic acid and D-glucosamine residues with mass-average relative molecular mass ranges between 3800 and 5000 Da.
  • the hexuronic acid can be either D-glucuronic acid (GlcA) or L-iduronic acid (IdoA), both of which can be modified with 2-O-sulfo groups.
  • the glucosamine residue can be modified with N-acetyl (GlcNAc) or N-sulfo (GlcNS) groups and can be substituted with 3- and/or 6-O-sulfo groups.
  • Most of its oligosaccharide chains contain 4,5-unsaturated uronic acid structure at the non-reducing end, 15%- 25% of the oligosaccharide chain contains the unique structure of 1,6-anhydride at its reducing end.
  • Example 2 Enoxaparin sodium SARS- and 2019-nCoV infectivity in human airway epithelial cells
  • the anti-virus activity of low molecular weight heparin, in particular enoxaparin can be observed by any method including direct and indirect methods of detecting Such activity.
  • the antiviral activity of enoxaparin of the invention can be measured using standard Screening protocols that are known.
  • the antiviral activity of a compound can be measured using the following general protocols: Coronavirus Antiviral Activity and Cytotoxicity Assays
  • HAE Human airway epithelial
  • Antiviral activity against SARS- AND 2019-NCOV is determined using an in vitro cytoprotection assay in HAE cells.
  • compounds inhibiting the virus infection exhibit cytoprotective effect against the virus-induced cell killing that can be quantified using a cell viability reagent.
  • the method used is similar to methods previously described in published literature (Chapman et al., Antimicrob Agents Chemother: 2007,51 (9):3346-53.).
  • Such assays may demonstrate antiOviral infection activity of enoxaparin.
  • HAE cells are seeded into 96-well plates 24 hours before the assay at a density of 3,000 cells/well.
  • compounds to be tested are serially diluted in cell culture media. Eight concentrations in 3-fold serial dilution increments are prepared for each tested compound and 100 uL/well of each dilution is transferred in duplicate onto plates with seeded HAE cells.
  • virus Stock previously determined by titration is prepared in cell culture media and 100 u/well is added to test plates containing cells and serially diluted compounds. Each plate includes three wells of infected untreated cells and three wells of uninfected cells that served as 0% and 100% virus inhibition control, respectively.
  • testing plates are incubated for 4 days in a tissue culture incubator. After the incubation, SARS- AND 2019-NCOV-induced cytopathic effect is determined using a Cell TiterGlo reagent (Promega, Madison, Wis.) followed by a luminescence read-out. The percentage inhibition is calculated for each tested concentration relative to the 0% and 100% inhibition controls and the EC50 value for each compound is determined by non-linear regression as a concentration inhibiting the SARS- AND 2019-NCOV-induced cytopathic effect by 50%.
  • Example 4 Therapeutic post-exposure administration of enoxaparin mitigates
  • 2019-nCov disease 2019-nCov disease [0053] In December 2019, viral pneumonia caused by a novel beta-coronavirus (2019- nCoV) outbroke in Wuhan, China. Part of patients rapidly progress severe acute respiratory failure with substantial mortality, making it imperative to develop an efficient treatment for severe 2019-nCoV pneumonia besides the supportive care.
  • 2019- nCoV novel beta-coronavirus
  • Age 18-55 years old, unlimited gender.
  • RT-PCR Laboratory (RT-PCR) confirmed infection with 2019-nCoV and accompanied with clinical manifestations.
  • Time to Clinical Recovery [0060] [ Time Frame: up to 30 days]
  • TTCR is defined as the time (in hours) from initiation of study treatment until normalisation of fever, respiratory rate, and oxygen saturation, and alleviation of cough, sustained for at least 72 hours.
  • Example 5 In vitro study of enoxaparin against SARS-CoV-2 infection
  • Vero E6 an African green monkey kidney derived cell line Vero E6 was used to assay the effect of enoxaparin against SARS-Cov-2 infection.
  • Vero E6 cells were inoculated into 96-well plate for overnight culture.
  • Enoxaparin (0,0.25,2.5,25mg / ml, Prolongin®, Techdow, Lot#AD03391 B) was added for pretreatment for 1 hour.
  • SARS- CoV-2 viruses 2019-nCov was extracted and added into the culture for 1.5 hours at MOI 0.05.
  • the experiment was conducted without adding enoxaparin and without viruses as negative control, without heparin sodium but with viruses as the positive control.
  • RNA of virus was extracted by RNA Extraction Kit (Takara, cat. 9766), and the expression of N protein and ORF1 gene in the supernatant was quantitatively detected by reverse transcription (Takara cat. Rr047a) and real-time quantitative PCR (Takara cat. Rr820a).
  • CPE cytopathic effect
  • SARS-CoV-2 by means of cytopathic effect (CPE) observation, virus fluorescence staining and real-time quantitative PCR detection.
  • CPE cytopathic effect

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Abstract

Des héparines de faible poids moléculaire, en particulier de l'énoxaparine et leur utilisation dans le traitement d'une infection à coronavirus, en particulier 2019-nCov, chez un sujet sont divulguées. Ces héparines de faible poids moléculaire peuvent être administrées au sujet conjointement à un autre agent thérapeutique tel qu'un corticostéroïde, un modulateur de transduction de signal anti-inflammatoire, un bronchodilatateur agoniste des récepteurs bêta-2 adrénergiques, un anticholinergique, un agent mucolytique, une solution saline hypertonique, du mésylate d'imatinib, du chlorhydrate de nilotinib, du dasatinib, un interféron, de la ribavirine, de l'adéfovir, du ténofovir, de l'acyclovir, de la brivudine, du cidofovir, du fomivirsen, du foscarnet, du ganciclovir, du penciclovir, de l'amantadine, de la rimantadine, du zanamivir et du remdesivir.
PCT/US2021/017006 2020-02-09 2021-02-08 Compositions et procédés de traitement d'infection à coronavirus WO2021159050A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2794315C1 (ru) * 2022-07-28 2023-04-14 Борис Игоревич Круглый Способ профилактики или лечения коронавирусной и других острых респираторных вирусных инфекций

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US20090054374A1 (en) * 2007-02-28 2009-02-26 Paringenix, Inc. Methods of treating acute exacerbations of chronic obstructive pulmonary disease
WO2012073025A1 (fr) * 2010-11-30 2012-06-07 Vectura Limited Glucosaminoglucanes, tels que l'héparine, en vue d'une utilisation dans le traitement d'une inflammation pulmonaire, telle que la maladie pulmonaire obstructive chronique (mpoc)
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US20090054374A1 (en) * 2007-02-28 2009-02-26 Paringenix, Inc. Methods of treating acute exacerbations of chronic obstructive pulmonary disease
WO2012073025A1 (fr) * 2010-11-30 2012-06-07 Vectura Limited Glucosaminoglucanes, tels que l'héparine, en vue d'une utilisation dans le traitement d'une inflammation pulmonaire, telle que la maladie pulmonaire obstructive chronique (mpoc)
US20170136043A1 (en) * 2014-04-11 2017-05-18 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrrolopyrimidine compounds with anti-mer tyrosine kinase activity

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ANONYMOUS: "Coronavirus- Wikipedia, the free encyclopedia", 8 February 2020 (2020-02-08), pages 1 - 15, XP055848828, Retrieved from the Internet <URL:https://en.wikipedia.org/w/index.php?titte=Coronavirus&oldid=939693562> [retrieved on 20210407] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2794315C1 (ru) * 2022-07-28 2023-04-14 Борис Игоревич Круглый Способ профилактики или лечения коронавирусной и других острых респираторных вирусных инфекций

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