WO2021224234A1 - Utilisation antivirale de cilengitide - Google Patents

Utilisation antivirale de cilengitide Download PDF

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Publication number
WO2021224234A1
WO2021224234A1 PCT/EP2021/061687 EP2021061687W WO2021224234A1 WO 2021224234 A1 WO2021224234 A1 WO 2021224234A1 EP 2021061687 W EP2021061687 W EP 2021061687W WO 2021224234 A1 WO2021224234 A1 WO 2021224234A1
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WIPO (PCT)
Prior art keywords
compound
viral
post infection
infection
emtricitabine
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PCT/EP2021/061687
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English (en)
Inventor
Luka CICIN-SAIN
Kathrin ESCHKE
Yeonsu KIM
Original Assignee
Helmholtz-Zentrum für Infektionsforschung GmbH
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Publication of WO2021224234A1 publication Critical patent/WO2021224234A1/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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C

Definitions

  • the present invention relates to cilengitide or derivatives thereof, wherein said cilengitide inhibits infections with viruses that utilize an RGD motif on the virus surface to bind to cellular Va integrins, including (but not limited to) SARS-CoV-2 infection, for use in the treatment and prevention of viral disease.
  • Betacoronaviruses are one of four genera of coronaviruses of the subfamily Orthocoronavirinae in the family Coronaviridae, of the order Nidovirales. They are enveloped, single- stranded positive-strand RNA viruses of zoonotic origin.
  • HCoV-229E human coronavirus 229E (HCoV-229E) (classified in the genus Alphacoronavirus) and HCoV-OC43 ( Betacoronavirus lineage 2a member) described in the 1960s, SARS-CoV-1 ( Betacoronavirus lineage 2b member) that emerged in March 2003, HCoV-NL63 (.
  • Betacoronavirus lineage lb member described in 2004, HCoV-HKU 1 ( Betacoronavirus lineage 2a member) discovered in 2005, and finally MERS-CoV that emerged in 2012 (classified in Betacoronavirus lineage 2c), the novel coronavirus is the seventh human coronavirus described to date as being responsible for respiratory infection.
  • 2019-nCoV 2019 novel coronavirus
  • 2019-nCoV now officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • remdesivir and chloroquine and hydrochloroquine have been tested against COVID-19 in vitro, such as, for example remdesivir and chloroquine and hydrochloroquine (Wang et al, 2020), and some showed an activity in a single-digit micromolar concentration.
  • Ribavirin, remdesivir or favipavir exhibit an antiviral activity only in the two- or three-digit range (Wang et al, 2020).
  • the a- ketoamide-Inhibitor 13b was described as an anti-SARS-CoV-2 agent, also showing an antiviral activity in the low micromolar range (Zhang et al., 2020).
  • this object is solved by a compound selected from Formula (I) (cilengitide) both the D and the L forms are also included, and physiologically acceptable salts thereof, for use in the prevention and/or treatment of diseases caused by viral infection in a mammalian subject, such as a human, wherein said viral infection is caused by a virus binding to a mammalian protein of the integrin family through a viral protein comprising an RGD amino acid motif.
  • a mammalian subject such as a human
  • said viral infection is caused by a virus binding to a mammalian protein of the integrin family through a viral protein comprising an RGD amino acid motif.
  • Cilengitide a drug that was already under investigation as a potential anti-cancer agent, showed an antiviral activity in vitro at concentrations starting at about 1 mM, and therefore is an attractive antiviral agent, in particular against SARS-CoV-2 infection.
  • Cilengitide comprises the amino acid sequence R-G-D (herein designated as “RGD amino acid motif’ or “RGD motif’) used for binding to (host) integrins.
  • RGD amino acid motif or “RGD motif’
  • SARS-CoV-2 like a few other viruses, comprises such an RGD motif in its viral spike protein (S), potentially mediating its binding to the host integrins (Sigrist et al., 2020).
  • S viral spike protein
  • the SARS-CoV-2 spike protein is the main molecule present at the surface of the virion.
  • the spike protein is a multifunctional protein that contributes to host receptor binding, cell tropism and pathogenesis. It acts by binding host receptors on target cells, inducing endocytosis of virion particle, and then catalyzes the fusion between host and viral membranes, allowing penetration of the virus genome into host cytoplasm. It is also the major target for the host immune system, adding selective pressure to this complex machinery.
  • SARS-CoV-2 spike is known to bind to the ACE2 receptor on human cells with higher affinity than SARS spike protein (Lan et al. 2020), and thus it is gebnerally assumed that this interaction is critically important for SARS-CoV-2 infection.
  • RGD motif is the minimal peptide sequence required for binding proteins of the Va integrin family, which are commonly used as receptors by many human viruses, such as human metapneumovirus (HMPV), human Adenovirus type 2/5, human cytomegalovirus (HHV-5), Kaposi's sarcoma-associated virus (HHV-8), Epstein-Barr virus (HHV-4), Rotavirus (RV), and Coxsackievirus A9. Consequently, it is expected that all these viruses can be treated using cilengitide as well.
  • HMPV human metapneumovirus
  • HHV-5 human cytomegalovirus
  • HHV-8 Kaposi's sarcoma-associated virus
  • HHV-4 Epstein-Barr virus
  • RV Rotavirus
  • Coxsackievirus A9 Coxsackievirus A9. Consequently, it is expected that all these viruses can be treated using cilengitide as well.
  • the small molecule cilengitide (EMD 121974) is a molecule based on the cyclic peptide cyclo(-RGDfV-), which is selective for a v integrins, which are important in angiogenesis, and other aspects of tumor biology. Cilengitide is under investigation for the treatment of glioblastoma, and seems to function by inhibiting the FAK/src/AKT pathway and inducing apoptosis in endothelial cells. In a rat xenograft model, combined with radiation, inhibition of integrin expression by cilengitide synergistically improved the cytotoxic effects of ionizing radiation for glioblastoma.
  • cilengitide or “EMD 121974” shall include the compound according to formula I, and its physiologically acceptable salt forms, such as the calcium, potassium, magnesium, or sodium salt.
  • the term shall also include physiologically acceptable solvates, hydrates, crystals and polymorphs.
  • the term also includes derivatives, where, when possible, D and/or L forms of the underlying amino acids are used.
  • the structure of cilengitide is as follows well as methods for making cilengitide are disclosed in EP 0770622 (“Cyclic adhesion inhibitors”), which is hereby incorporated by reference in its entirety.
  • said viral protein comprising an RGD amino acid motif is a viral spike protein (usually abbreviated as “S”).
  • S viral spike protein
  • integrins as cell receptors in one or more host species are the (a) target of binding of said spike protein, and binding to them occurs through a conserved RGD motif (amino acids 403-405: Arg-Gly-Asp of SARS-CoV-2 spike protein) found in the receptor-binding domain of the spike proteins.
  • said virus is selected from the group of human metapneumovirus (HMPV), human adenovirus type 2/5, human cytomegalovirus (HHV-5), Kaposi's sarcoma-associated virus (HHV-8), Epstein- Barr virus (HHV-4), rotavirus (RV), and Coxsackievirus A9, and SARS-CoV-2. Consequently, it is expected that all these viruses can be treated using cilengitide as well, while SARS-CoV-2 is particularly preferred.
  • HMPV human metapneumovirus
  • HHV-5 human cytomegalovirus
  • HHV-8 Kaposi's sarcoma-associated virus
  • HHV-4 Epstein- Barr virus
  • RV rotavirus
  • Coxsackievirus A9 Coxsackievirus A9
  • a mammalian subject can be a patient, and can be preferably selected from a hamster, mouse, rat, cat, dog, rabbit, goat, sheep, horse, camel, lama, cow, monkey, a farm animal, a sport animal, a pet, or a human.
  • the compound is for use in viral infection, and therefore treats and/or prevents the related diseases or syndromes, such as, for example, cancer, bronchitis, diarrhea, gastroenteritis, conjunctivitis, herpes, viral flu, respiratory disease, acute respiratory disease, sepsis, acute respiratory distress syndrome, and adverse immune reactions, in particular moderate to severe cases of said diseases, and wherein said disease preferably is selected from diseases causes by SARS-CoV-2, in particular COVID-19, such as acute respiratory disease, sepsis, acute respiratory distress syndrome, and adverse immune reactions, such as a cytokine storm.
  • diseases or syndromes such as, for example, cancer, bronchitis, diarrhea, gastroenteritis, conjunctivitis, herpes, viral flu, respiratory disease, acute respiratory disease, sepsis, acute respiratory distress syndrome, and adverse immune reactions, in particular moderate to severe cases of said diseases
  • said disease preferably is selected from diseases causes by SARS-CoV-2, in particular COVID-19, such as acute respiratory disease, se
  • treatment or “treating” is meant any treatment of a disease or disorder, in a mammal, including: preventing or protecting against the disease or disorder, that is, causing, the clinical symptoms of the disease not to develop; inhibiting the disease, that is, arresting or suppressing the development of clinical symptoms; and/or relieving the disease, that is, causing the regression of clinical symptoms.
  • amelioration is meant the prevention, reduction or palliation of a state, or improvement of the state of a subject; the amelioration of a stress is the counteracting of the negative aspects of a stress. Amelioration includes, but does not require complete recovery or complete prevention of a stress.
  • said prevention and/or treatment is in combination with standard antiviral therapy, for example selected from at least one of neuraminidase inhibitors (e.g., oseltamivir, zanamivir), favipiravir, remdesivir, ribavirin (tribavirin), interferon alfa-2b/ribavirin systemic, interferon alpha 2a or 2b, inclusive any pegylated versions, chloroquine or hydroxychloroquine (given in combination with azithromycin), dolutegravir + rilpivirine (JULUCA®), dolutegravir + lamivudine (DOVATO®), ritonavir + lopinavir (Kaletra®), bictegravir + tenofovir alafenamide + emtricitabine (BIKTARVY®), dolutegravir + abacavir + lamiv
  • neuraminidase inhibitors e.
  • the present compound and/or a pharmaceutical composition comprising the present compound is for use to be administered to a human patient.
  • the term "administering" means administration of a sole therapeutic agent or in combination with another therapeutic agent.
  • the pharmaceutical composition of the present invention are employed in co-therapy approaches, i.e. in co-administration with other medicaments or drugs and/or any other therapeutic agent which might be beneficial in the context of the methods of the present invention.
  • the other medicaments or drugs and/or any other therapeutic agent can be administered separately from the compound for use, if required, as long as they act in combination (i.e. directly and/or indirectly, preferably synergistically) with the present compound for use.
  • the compounds for use of the invention can be used alone or in combination with other active compounds - for example with medicaments already known for the treatment of the aforementioned diseases, whereby in the latter case a favorable additive, amplifying or preferably synergistically effect is noticed.
  • Suitable amounts to be administered to humans range from 5 to 500 mg, in particular 10 mg to 100 mg.
  • the compound for use can be provided and/or is administered as a suitable pharmaceutical composition, such as a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler and/or chewable.
  • a suitable pharmaceutical composition such as a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler and/or chewable.
  • Such solid formulations may comprise excipients and other ingredients in suitable amounts.
  • Such solid formulations may contain e.g. cellulose, cellulose microcrystalline, polyvidone, in particular FB polyvidone, magnesium stearate and the like.
  • Preferred is a pharmaceutical composition for inhalation, preferably in COVID-19.
  • the dosage can preferably be reduced because of the application of the drug directly to the site of action, i.e. the respiratory tract.
  • Pharmaceutical compositions as used may optionally comprise a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers or excipients include diluents (fillers, bulking agents, e.g. lactose, microcrystalline cellulose), disintegrants (e.g. sodium starch glycolate, croscarmellose sodium), binders (e.g. PVP, HPMC), lubricants (e.g. magnesium stearate), glidants (e.g. colloidal S1O2), solvents/co-solvents (e.g. aqueous vehicle, Propylene glycol, glycerol), buffering agents (e.g. citrate, gluconates, lactates), preservatives (e.g.
  • diluents fillers, bulking agents, e.g. lactose, microcrystalline cellulose
  • disintegrants e.g. sodium starch glycolate, croscarmellose sodium
  • binders e.g. PVP, HPMC
  • lubricants e.g. magnesium stearate
  • BHT anti oxidants
  • BHA Ascorbic acid
  • wetting agents e.g. polysorbates, sorbitan esters
  • thickening agents e.g. methylcellulose or hydroxyethylcellulose
  • sweetening agents e.g. sorbitol, saccharin, aspartame, acesulf
  • the therapeutics can be administered orally, e.g. in the form of pills, tablets, coated tablets, sugar coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or as aerosol mixtures. Administration, however, can also be carried out rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injections or infusions, or percutaneously, e.g. in the form of ointments, creams or tinctures.
  • the pharmaceutical composition can contain further customary, usually inert carrier materials or excipients.
  • the pharmaceutical preparations can also contain additives, such as, for example, fillers, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, colorants, flavorings or aromatizers, buffer substances, and furthermore solvents or solubilizers or agents for achieving a depot effect, as well as salts for changing the osmotic pressure, coating agents or antioxidants. They can also contain the aforementioned salts of two or more compounds for use of the invention and also other therapeutically active substances as described above.
  • the compound for use according to the present invention wherein said compound is administered to said subject in an effective dosage, for example at a dosage to reach a concentration of about 1 mM, preferably about 0.3 to about 10 mM at the site of treatment (e.g. the respiratory tract).
  • this exemplary dose can vary within wide limits and is to be suited to the individual conditions in each individual case.
  • the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results are achieved at dosage rates of about 1 to 100 mg/kg animal body weight particularly 1 to 50 mg/kg.
  • Suitable dosage rates for larger mammals are of the order of from about 10 mg to 3 g/day, conveniently administered once or in divided doses, e.g. 2 to 4 times a day, or in sustained release form.
  • a daily dose of approximately 10 mg to 100 mg, particularly 10 to 50 mg, per human individual is appropriate in the case of the oral administration. In the case of other administration forms too, the daily dose is found within similar ranges.
  • the compound for use according to the present invention can be administered to a subject at between 8 to 24 hours post infection, preferably at between 10 to 20 hours post infection, more preferably at 12 to 16 hours post infection.
  • This regimen still provides a surprisingly low viral load.
  • the compound for use according to the present invention can be administered to a subject, in particular as a (synergistic) combination therapy, e.g. when administered at between 5 to 14 days post infection, preferably at between 5 to 11 days post infection, more preferably at 7 to 11 days post infection.
  • This regimen provides a surprisingly effective treatment effect, and furthermore helps to control excessive spread of the virus and immune reactions, like cytokine storms.
  • the present invention provides methods for preventing and/or treating viral infection in a mammalian subject, such as a human, comprising administering to said mammal an effective amount of a compound selected from Formula (I) (cilengitide) both the D and the L forms are also included, and physiologically acceptable salts thereof, wherein said viral infection is caused by a virus binding to a mammalian protein of the integrin family through a viral protein comprising an RGD amino acid motif.
  • Formula (I) cilengitide
  • cilengitide a drug that was already under investigation as a potential anti-cancer agent, showed an antiviral activity in vitro at concentrations starting at about 1 mM, and therefore is an attractive antiviral agent, in particular against SARS-CoV-2 infection.
  • the method comprises treating and/or ameliorating symptoms associated with viral infection in a mammalian subject, comprising administering to the subject cilengitide in a pharmaceutically effective amount, and by said administering, reducing symptoms associated with said viral infection, such as, for example, bronchitis, diarrhea, gastroenteritis, conjunctivitis, pneumonia, respiratory disease, acute respiratory disease, sepsis, acute respiratory distress syndrome, and adverse immune reactions, in particular moderate to severe cases of said diseases, and wherein said disease preferably is selected from diseases causes by SARS-CoV-2, in particular COVID-19, such as acute respiratory disease, sepsis, acute respiratory distress syndrome, and adverse immune reactions, such as a cytokine storm.
  • diseases causes by SARS-CoV-2 in particular COVID-19, such as acute respiratory disease, sepsis, acute respiratory distress syndrome, and adverse immune reactions, such as a cytokine storm.
  • said viral infection is by a virus binding to a mammalian protein of the integrin family through a viral protein comprising an RGD amino acid motif, such as human metapneumovirus (HMPV), human Adenovirus type 2/5, human cytomegalovirus (HHV-5), Kaposi's sarcoma-associated virus (HHV-8), Epstein-Barr virus (HHV-4), Rotavirus (RV), and Coxsackievirus A9. Consequently, it is expected that all these viruses can be treated using cilengitide as well.
  • HMPV human metapneumovirus
  • HMPV-5 human Adenovirus type 2/5
  • human cytomegalovirus HHV-5
  • HHV-8 Kaposi's sarcoma-associated virus
  • HHV-4 Epstein-Barr virus
  • Rotavirus RV
  • Coxsackievirus A9 Coxsackievirus A9. Consequently, it is expected that all these viruses can be treated using cilengitide as
  • said prevention and/or treatment is in combination with standard antiviral therapy, for example selected from at least one of neuraminidase inhibitors (e.g., oseltamivir, zanamivir), favipiravir, remdesivir, ribavirin (tribavirin), interferon alfa-2b/ribavirin systemic, interferon alpha 2a or 2b, inclusive any pegylated versions, chloroquine or hydroxychloroquine (given in combination with azithromycin), dolutegravir + rilpivirine (JULUCA®), dolutegravir + lamivudine (DOVATO®), ritonavir + lopinavir (Kaletra®), bictegravir + tenofovir alafenamide + emtricitabine (BIKTARVY®), dolutegravir + abacavir + lami
  • neuraminidase inhibitors e.g
  • the compound for use can be provided and/or is administered as a suitable pharmaceutical composition as discussed above.
  • the compounds can be administered alone or in combination with other active compounds - for example with medicaments already known for the treatment of the aforementioned diseases, whereby in the latter case a favorable additive, amplifying or preferably synergistically effect is noticed.
  • Suitable amounts and dosages to be administered to mammals, in particular humans, are as above, and can range from 5 to 500 mg, in particular 10 mg to 100 mg.
  • the compound cilengitide shows particular advantages both in the prevention of viral infection as well as in the treatment of all stages of the diseases, particularly as a combination treatment.
  • the compound in the preventive approach of the method according to the present invention, can be administered to a subject at between 8 to 24 hours post infection, preferably at between 10 to 20 hours post infection, more preferably at 12 to 16 hours post infection.
  • This regimen provides a surprisingly low viral load.
  • the compound in the treatment approach of the method according to the present invention, can be administered to a subject as a (synergistic) combination therapy, e.g. when administered at between 5 to 14 days post infection, preferably at between 5 to 11 days post infection.
  • This regimen provides a surprisingly effective treatment effect, and furthermore helps to control excessive immune reactions, like cytokine storms.
  • Figure 1 shows the results of a WST-1 toxicity assay over a potential therapeutic range of cilengitide.
  • VeroE6 cells were infected with SARS-CoV-2 virus, strain SARS-CoV2/ZG/297-20 in the presence of ImM or IOmM of cilengitide, and overlayed with Avicel (Matrosovich et al, 2006). The number of viral plaques was counted 4- 5 days later.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne le cilengitide ou ses dérivés, ledit cilengitide inhibant de manière compétitive la liaison d'une protéine d'enveloppe virale à des intégrines, pour une utilisation dans le traitement et la prévention d'une infection virale dans des virus comprenant de tels motifs RGD, comprenant, mais sans s'y limiter, une infection virale provoquée par le SARS-CoV-2 et en particulier le COVID-19.
PCT/EP2021/061687 2020-05-04 2021-05-04 Utilisation antivirale de cilengitide WO2021224234A1 (fr)

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US63/019,641 2020-05-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0770622A2 (fr) 1995-09-15 1997-05-02 MERCK PATENT GmbH Inhibiteurs cycliques de l'adhésion
WO2017140862A1 (fr) * 2016-02-17 2017-08-24 Royal College Of Surgeons In Ireland Méthode de traitement ou de prévention de la septicémie

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0770622A2 (fr) 1995-09-15 1997-05-02 MERCK PATENT GmbH Inhibiteurs cycliques de l'adhésion
WO2017140862A1 (fr) * 2016-02-17 2017-08-24 Royal College Of Surgeons In Ireland Méthode de traitement ou de prévention de la septicémie

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BÁLINT MÉSZÁROS ET AL: "Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications", ARXIV.ORG, CORNELL UNIVERSITY LIBRARY, 201 OLIN LIBRARY CORNELL UNIVERSITY ITHACA, NY 14853, 21 April 2020 (2020-04-21), XP081650097 *
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BORBA, M.G.S.VAL, F.F.A.SAMPAIO, V.S.ALEXANDRE, M.A.A.MELO, G.C.BRITO, M.MOURAO, M.P.G.BRITO-SOUSA, J.D.BAIA-DA-SILVA, D.GUERRA, M: "Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial", JAMA NETW OPEN, vol. 3, 2020, pages e208857
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GARCIARENA C ET AL: "Inhibition of integrin AVB3 with cilengitide prevents endothelial injury induced by neutrophil extracellular traps in response to staphylococcus aureus infection in a 3D ex vivo model of sepsis", RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS 20180701 WILEY-BLACKWELL PUBLISHING LTD NLD, vol. 2, no. Supplement 1, 1 July 2018 (2018-07-01), XP002803835, ISSN: 2475-0379 *
LAN, J.GE, J.YU, J.SHAN, S.ZHOU, H.FAN, S.ZHANG, Q.SHI, X.WANG, Q.ZHANG, L. ET AL.: "Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor", NATURE, 2020
MATROSOVICH, M.MATROSOVICH, T.GARTEN, W.KLENK, H.-D.: "New low-viscosity overlay medium for viral plaque assays", VIROLOGY JOURNAL, vol. 3, 2006, pages 63, XP021019369, DOI: 10.1186/1743-422X-3-63
MILLAN-ONATE, J.MILLAN, W.MENDOZA, L.A.SANCHEZ, C.G.FERNANDEZ-SUAREZ, H.BONILLA-ALDANA, D.K.RODRIGUEZ-MORALES, A.J.2020: "Successful recovery of COVID-19 pneumonia in a patient from Colombia after receiving chloroquine and clarithromycin", ANN CLIN MICROBIOL ANTIMICROB, vol. 19, pages 16
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WANG, M.CAO, R.ZHANG, L.YANG, X.LIU, J.XU, M.SHI, Z.HU, Z.ZHONG, W.XIAO, G.: "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus 2019-nCoV) in vitro", CELL RESEARCH, vol. 30, 2020, pages 269 - 271, XP037049320, DOI: 10.1038/s41422-020-0282-0
ZHANG, L.LIN, D.SUN, X.CURTH, U.DROSTEN, C.SAUERHERING, L.BECKER, S.ROX, K.HILGENFELD, R.: "Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors", SCIENCE, vol. 368, 2020, pages 409 - 412, XP055795759, DOI: 10.1126/science.abb3405

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