WO2021214296A1 - Treatment of corona virus infections - Google Patents

Abstract

The invention provides a treatment of viral diseases caused by a virus of the family of Coronaviridae by antagonizing downstream components of growth factor (GFR) receptor signalling. The invention provides certain known compounds that are identified as candidates and are repurposed to be useful in viral treatments of the invention. Disclosed is the medical application of the identified repurposed drugs, therapeutic kits and pharmaceutical compositions comprising the compounds.

Description

TREATMENT OF CORONA VIRUS INFECTIONS

FIELD OF THE INVENTION

[1] The invention provides a treatment of viral diseases caused by a virus of the of the family of Coronaviridae by antagonizing downstream components of growth factor (GFR) receptor signalling. The invention provides certain known compounds that are identified as candidates and are repurposed to be useful in viral treatments of the invention. Disclosed is the medical application of the identified repurposed drugs, therapeutic kits and pharmaceutical compositions comprising the compounds.

DESCRIPTION

[2] Severe acute respiratory syndrome coronavirus 2 (SARS-C0V-2), a novel coronavirus, has been rapidly spreading around the globe since the beginning of 2020. In people, it causes coronavirus disease 2019 (COVID-19) often accompanied by severe respiratory syndrome (Chen et ah, 2020; Zhao et ah, 2020; Zhu et ah, 2020). To conquer the global health crisis triggered by COVID-19, rapidly establishing drugs is required to dampen the disease course and relieve healthcare institutions. However, the development of novel drugs specifically targeting a virus usually takes several years, including clinical trials. Thus, repurposing of already available and (ideally) approved drugs might be essential to rapidly treat COVID-19. Many studies for proposing repurposing of specific drugs have been conducted in the last months, but mostly remain computational without tests in infection models (Smith and Smith, 2020; Wang, 2020). In addition, they are hindered by the lack of knowledge about the molecular mechanisms of SARS-COV-2 infection and the resulting host-cell responses required to allow viral replication. High-content/throughput compound screening would be required to find working inhibitors by chance. However, large screens require well-established cell culture models and readouts for fast analysis. To rationally repurpose drugs, a molecular understanding of the infection and the changes within the host cell pathways is essential. Experimentally identifying viral targets in the cell allows candidate drugs to be selected with high confidence for further testing in the clinics to reduce the risks for patients resulting from tests with drugs lacking in vitro validation.

[3] Growth factor receptor (GFR) signalling plays important roles in cancer pathogenesis and has also been reported to be crucial for infection with some viruses (Beerli et ah, 2019; Eierhoff et ah, 2010; Rung et ah, 2011; Lupberger et ah, 2011; Zhu et ah, 2009). GFR activation leads to the modulation of a wide range of cellular processes, such as proliferation, adhesion or differentiation (Yarden, 2001). Various viruses have been shown to use the epidermal growth factor receptor (EGFR) as an entry receptor to infect the host cell, such as Epstein-Barr virus, influenza or hepatitis C (Eierhoff et ah, 2010; Rung et ah, 2011; Lupberger et ah, 2011). Since GFR regulates various proliferative pathways, activation of GFR signalling might prove beneficial for virus replication and maintenance. Indeed, it was shown that EGFR signalling can suppress interferon signalling and thus the antiviral response elicited in respiratory virus diseases, such as influenza A and rhinovirus (Ueki et ah, 2013). Activation of GFR signalling might play an important role also in other respiratory viruses, such as SARS-C0V-2.

[4] In the last years, it has been shown for many viruses that modulation of host cell signalling is crucial for viral replication and might exhibit strong therapeutic potential (Baturcam et ah, 2019; Beerli et ah, 2019; Pleschka et ah, 2001) and can be studied by proteomics (Weekes et ah, 2014). However, how SARS-C0V-2 infection changes host cell signalling has remained unclear. Recently the inventors established an in vitro cell culture model of SARS-C0V-2 infection using the colon epithelial cell line Caco-2, which is highly permissive for the virus and commonly used for the study of coronaviruses (Herzog et ah, 2008; Morgenstern et ah, 2005; Ren et ah, 2006; Spiegel and Weber, 2006). Monitoring changes in protein translation and abundance, it was shown that infection rearranges the cellular translation network, as well as other important pathways on total protein level. Targeting these pathways in vitro confirmed their importance as inhibition blocking viral replication. However, it was not possible to obtain information into the signalling events brought about by SARS-CoV- 2 infection and responsible for the rapid adaptation or modulation of the host cells.

[5] In view of the prior art knowledge and the lack of effective treatment options of diseases caused or exacerbated by SARS-C0V-2 infection, it is an objective of the present invention to provide novel therapeutics to tackle COVID-19 and related viral diseases.

BRIEF DESCRIPTION OF THE INVENTION

[6] Generally, and by way of brief description, the main aspects of the present invention can be described as follows:

[7] In a first aspect, the invention pertains to a method of treating or preventing a viral infection in a subject, the method comprising administering to the subject an effective amount of a growth factor receptor (GFR) antagonist, preferably an antagonist of a GFR downstream signalling kinase, wherein the viral infection in the subject is caused by a virus of the family of Coronaviridae.

[8] In a second aspect, the invention pertains to a method of treating or preventing respiratory virus-induced exacerbation of a chronic lung disease in a subject, the method comprising administering to the subject an effective amount of a growth factor receptor (GFR) antagonist, preferably an antagonist of a GFR downstream signalling kinase.

[9] In a third aspect, the invention pertains to a growth factor receptor (GFR) antagonist for use in the treatment or prevention of a viral infection in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of the GFR antagonist, and wherein the viral infection in the subject is caused by a virus of the family of Coronaviridae. [IO] In a fourth aspect, the invention pertains to a growth factor receptor (GFR) antagonist for use in the treatment or prevention of respiratory virus-induced exacerbation of a chronic lung disease in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of the GFR antagonist.

[n] In a fifth aspect, the invention pertains to a pharmaceutical composition for use in the treatment or prevention of a viral infection caused by a virus of the family of Coronaviridae in a subject, the pharmaceutical composition comprising (i) a GFR antagonist as recited in any one of the first to the fourth aspect, and (ii) a pharmaceutically acceptable carrier and/or excipient.

DETAILED DESCRIPTION OF THE INVENTION

[12] In the following, the elements of the invention will be described. These elements are listed with specific embodiments; however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine two or more of the explicitly described embodiments or which combine the one or more of the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[13] In a first aspect, the invention pertains to a method of treating or preventing a viral infection in a subject, the method comprising administering to the subject an effective amount of a growth factor receptor (GFR) antagonist, preferably an antagonist of a GFR downstream signalling kinase, wherein the viral infection in the subject is caused by a virus of the family of Coronaviridae.

[14] The term “growth factor receptor”, or “GFR”, as used herein refers to proteins that bind specific signalling molecules. The receptors frequently interact with kinases and other proteins involved in signal transduction pathways. Growth factor receptors include, but are not limited to epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), insulin-like growth factor receptor (IGFR), platelet derived growth factor (PDGF), transforming growth factor (TGF), and nerve growth factor receptor.

[15] The term “GFR antagonist” or “GFR inhibitor” refers to any GFR antagonist that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of any of the GFR signalling components in the patient (in particularly of the MEK/RAF, or Pl3K-AKT-mT0R signalling pathways), including any of the downstream biological effects otherwise resulting from activated GFR signalling. Such GFR antagonist include any agent (small chemical entity, antibody, inhibitory nucleic acid) that may block GFR activation or any of the downstream biological effects of GFR activation. Such an antagonist may act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity. Preferred is however, that the GFR antagonist useful for the present invention is not a direct inhibitor of the receptor, for example is not a compound which directly interacts with a GFR protein or gene of the respective GFR signalling pathway, but is an antagonist of any of the, preferably, intracellular signalling components of the GFR pathway. Such components may be any known GFR signalling proteins, preferably however kinases. Hence, in some preferred embodiments of the invention the GFR antagonist is a GFR downstream signalling antagonist.

[16] The terms “treatment,” “treating,” “treat,” and the like are used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic (also referred to as “prevention” or “preventing”) in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/ or adverse effect attributable to the disease. “Treatment” as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject who may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; (c) relieving the disease symptom, i.e., causing regression of the disease or symptom; (d) limiting spread of a virus from one cell to another within an individual, e.g., limiting spread of a virus from an infected epithelial cell to other, uninfected, epithelial cells within an individual; (e) limiting replication of a virus within an individual; (f) limiting entry of a virus into a cell in an individual; and (g) reducing the number of viruses in an individual or in a target tissue or target biological sample in an individual.

[17] The terms “subject,” “individual,” “host,” and “patient” are used interchangeably herein to refer to a mammal, including, but not limited to, murines (rats, mice), felines, non-human primates (e.g., simians), humans, canines, ungulates, etc. In some embodiments, a “subject” is a human, and can also be referred to as a “patient.”

[18] Subjects in need of treatment with a GFR antagonist in accordance with the invention include: a) individuals who have been exposed to a virus, but who have not yet been infected; b) individuals who have been infected with a virus, and who have not been treated with any anti viral agent (e.g., infected and treatment naive individuals); c) individuals who have been infected with a virus, who have been treated with an anti-viral agent other than a GFR antagonist, and who have not responded to the anti-viral agent other than a GFR antagonist; d) individuals who have been infected with a virus, who have been treated with an anti-viral agent other than a GFR antagonist, and who have developed resistance to the anti-viral agent other than an a GFR antagonist; and e) individuals who have not yet been infected with a virus, but who are at risk of infection (e.g., due to possible or likely exposure to an infected individual; due to an immunocompromised status; and the like), e.g., individuals who are at greater risk than the general population of becoming infected; and individuals who are at greater risk, if infected, of developing complications or experiencing more severe symptoms,- than the general population.

[19] A “therapeutically effective amount” or “efficacious amount” means the amount of a compound (such as a GFR antagonist) that, when administered to a mammal or other subject for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.

[20] The present disclosure provides methods of treating a viral infection in a subject. The uses and methods generally involve administering to a subject in need thereof an effective amount of a growth factor receptor (GFR) antagonist. The present disclosure further provides methods of treating virus-induced acute exacerbation of a chronic lung disease, the methods generally involving administering to an individual in need thereof (e.g., an individual having a chronic lung disease) an effective amount of an GFR antagonist.

[21] Administration of an effective amount of a GFR antagonist to an individual having a virus infection results in one or more of: 1) a reduction in viral load; 2) a reduction in viral load in a target biological sample; 3) a reduction in the spread of a virus from one epithelial cell to another cell in an individual; 4) a reduction in viral entry into (e.g., reduction of internalization of a virus into) an epithelial cell; 5) a reduction in time to seroconversion (virus undetectable in patient serum); 6) an increase in the rate of sustained viral response to therapy; 7) a reduction of morbidity or mortality in clinical outcomes; and 8) an improvement in an indicator of disease response (e.g., a reduction in one or more symptoms of a viral infection, such as fever, etc.).

[22] In some embodiments, an “effective amount” of a GFR antagonist is an amount that, when administered in one or more doses to an individual having a virus infection, is effective to reduce the number of genome copies of the virus in the individual, e.g., in a target biological sample in the individual. For example, in some embodiments, an “effective amount” of a GFR antagonist is an amount that, when administered in one or more doses to an individual having a virus infection, is effective to reduce the number of genome copies of the virus in the individual by at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the number of genome copies in the individual in the absence of treatment with the antagonist.

[23] The present disclosure provides compounds for use in, and methods for, treating a virus infection, where the virus is a member of the Coronaviridae family, the method involving administering an effective amount of an GFR antagonist to an individual infected with a member of the Coronaviridae family. Coronaviridae includes, e.g., coronaviruses, e.g., human coronavirus 229E (HCoV- 229E), human coronavirus OC43 (HC0V-OC43), and SARS-CoV (the causative agent of severe acute respiratory syndrome (SARS)), which cause upper respiratory tract infection, lower respiratory tract infections, and gastroenteritis.

[24] In some embodiments, a method of treating a virus infection is provided, respectively compounds for use therein, where the virus is a coronavirus, the method involving administering an effective amount of an GFR antagonist to subject infected with a coronavirus, e.g., a coronavirus that infects a human (HCoV). In some embodiments, a method of treating a virus infection is provided, where the virus is a Group 1 coronavirus, the method involving administering an effective amount of a GFR antagonist to an individual infected with a Group 1 coronavirus. In some embodiments, a method of treating a virus infection is provided, where the virus is a Group 2 coronavirus, the method involving administering an effective amount of a GFR antagonist to an individual infected with a Group 2 coronavirus. In some embodiments, a method of treating a virus infection is provided, where the virus is a Group 3 coronavirus, the method involving administering an effective amount of a GFR antagonist to an individual infected with a Group 3 coronavirus. In some embodiments, a method of treating a virus infection is provided, where the virus is HC0V-OC43, the method involving administering an effective amount of a GFR antagonist to an individual infected with HC0V-OC43. In some embodiments, a method of treating a virus infection is provided, where the virus is HC0V-229E, the method involving administering an effective amount of a GFR antagonist to an individual infected with HC0V-229E. In some embodiments, a method of treating a virus infection is provided, where the virus is SARS-CoV, the method involving administering an effective amount of an GFR antagonist to an individual infected with SARS-CoV.

[25] Irrespective of the above, in all of the disclosed aspects and embodiments, the invention is particular useful for the treatment or prevention of a viral infection caused by SARS Cov-2 - thus the invention seeks in particular embodiments to provide a treatment for COVID-19, and any related disorders, the method involving administering an effective amount of an GFR antagonist to an individual infected with SARS-C0V-2. [26] In any one of the above embodiments, the individual is a human of from about one month to about 6 months, from about 6 months to about 1 year, from about 1 year to about 5 years, from about 5 years to about 12 years, from about 13 years to about 18 years, from about 18 years to about 25 years, from about 25 years to about 50 years, from about 50 years to about 75 years of age, or older than 75 years of age. In some embodiments, the individual has a chronic lung disease (e.g., emphysema, chronic bronchitis, asthma, cystic fibrosis, bronchiectasis, COPD, or interstitial lung disease). In some embodiments, the individual has, in addition to a coronavirus infection, pneumonia, where the pneumonia is caused by the coronavirus (preferably SARS-C0V-2) or by a bacterial infection. In some embodiments the human subject is immunecompromised.

[27] In some embodiments of the disclosed invention, the antagonist or inhibitor is a compound of the class of small molecular compounds, or biologies, such as antibodies or nucleic acids. The term "small molecule" or “small molecular compound” refers to a molecule of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macro molecules (e. g. , proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to about 5000 Da, more preferably up to 2000 Da, and most preferably up to about 1000 Da.

[28] In certain preferred embodiments of the invention the GFR antagonist is an inhibitor of the RAF/MEK/ERKMAPK signalling cascade (MEK or RAF inhibitor). Preferably, the MEK or RAF inhibitor is selected from a compound that exhibits an IC50 with respect to RAF/MEK/ERK MAPK signalling, of no more than about too mM or not more than about 50 mM as measurable by a RAF/MEK/ERK MAPK enzyme inhibitory assay.

[29] The term “RAF/MEK/ERK MAPK signalling" refers to the mitogen-activated protein kinase signalling pathway (e.g., the RAF/MEK/ERK MAPK signalling pathway) and encompasses a family of conserved serine/threonine protein kinases (e.g., the mitogen-activated protein kinases (MAPKs)). Abnormal regulation of the MAPK pathway contributes to uncontrolled proliferation, invasion, metastases, angiogenesis, and diminished apoptosis. The RAS family of GTPases includes KRAS, HRAS, and NRAS. The RAF family of serine/threonine protein kinases includes ARAF, BRAF, and CRAF (RAFi ). Exemplary MAPKs include the extracellular signal-regulated kinase 1 and 2 (i.e., ERKi and ERK2), the c- Jun N-terminal kinases 1 -3 (i.e., JNKi , JNK2, and JNK3), the P38 isoforms (i.e., r38a, r38b, r38g, and r38d), and Erk5. Additional MAPKs include Nemo-like kinase (NLK), Erk3/4 (i.e., ERK3 and ERK4), and Erk7/8 (i.e., ERK7 and ERK8).

[30] The term " MEK or RAF inhibitor," " MEK or RAF antagonist," refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction through the MAPK pathway (e.g., the RAF/MEK/ERK MAPK pathway). In some embodiments, a MEK or RAF inhibitor may inhibit the activity of one or more proteins involved in the activation of MEK or RAF signalling. In some embodiments, a MEK or RAF signalling inhibitor may activate the activity of one or more proteins involved in the inhibition of MEK or RAF signalling. MEK or RAF signalling inhibitor include, but are not limited to, MEK inhibitors (e.g., MEKi inhibitors, MEK2 inhibitors, and inhibitors of both MEKi and MEK2), RAF inhibitors (e.g., ARAF inhibitors, BRAF inhibitors, CRAF inhibitors, and pan- RAF inhibitors (i.e., RAF inhibitors that are inhibiting more than one member of the RAF family (i.e., two or all three of ARAF, BRAF, and CRAF)), and ERK inhibitors (e.g., ERKi inhibitors and ERK2 inhibitors).

[31] Most preferably the MEK or RAF inhibitor is a compound selected from a (i) MEK inhibitor of the group: AZD8330 (ARRY-424704), Refametinib (BAY 86- 9766, RDEAl 19), Cobimetinib (GDC-0973, XL-518, RG7421 ); E6201 ; Binimetinib (MEK162, ARRY-162); PD0325901; Pimasertib (AS703026, MSC1936369B); R04987655 (CH4987655), R05126766 (CH5126766), Selumetinib (AZD6244, ARRY- 142,886), Trametinib (GSKi 120212), GDC-0623, PD035901 , PD184352 (CI-1040), WX- 554, Uoi26-EtOH, PD98059, BIX 02189, BIX 02188, PD318088, Honokiol, SL-327, GDC-0623, APS-2-79 HCI, Cobimetinib, XL518, PD325901 , TAK-733, R05126766, or HL-085; or (ii) a RAF inhibitor selected from(PLX4032, RG7204), Sorafenib Tosylate, PLX-4720, Dabrafenib (GSK21 18436), GDC-0879, CCT196969, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372, GW5074, TAK-632, CEP- 32496, Encorafenib (LGX818), Regorafenib, R05126766 (CH5126766), MLN2480, PLX7904, CCT196969, Lonafarnib, Tipifarnib, PLX-4720, Lifirafenib, BMS-214662 LY3009120, and BAY 43-9006 (sorafenib).

[32] In other embodiments of the invention the GFR antagonist is an inhibitor of signalling via phosphoinositide 3 kinase [PI3K] and protein kinase B (AKT) and mTORCi (PI3K-AKT- mTOR inhibitor). The Pl3K-AKT-mTOR inhibitor is preferably selected from a compound that exhibits an IC50 with respect to Pl3K-AKT-mTOR signalling, of no more than about 100 mM or not more than about 50 pM as measurable by preferably a Pl3K-AKT-mTOR enzyme inhibitory assay.

[33] Most preferably the Pl3K-AKT-mTOR inhibitor is an PI3K inhibitor and is a small molecule which is an isoform-selective inhibitor of PI3K selected among the following compounds: BYL719 (Alpelisib, Novartis), GDC-0032 (Taselisib, Genentech/Roche), BKM120 (Buparlisib), Dactolisib (BEZ235), INK1117 (Millenium), A66 (University of Auckland), GSK260301 (Glaxosmithkline), KGN- 193 (Astra-Zeneca), TGX221 (Monash University), TG1202, CAL101 (Idelalisib, Gilead Sciences), GS-9820 (Gilead Sciences), AMG319 (Amgen), SF-1126, IC87114 (Icos Corporation), Fimepinostat (CUDC-907), BAY80-6946 (Copanlisib, Bayer Healthcare), VS-5584, GDC0941 (Pictlisib, Genentech), IPI145 (Duvelisib, Infinity), SAR405 (Sanofi), PX-866 (Oncothyreon), MEN1611, ZSTK474, WX-037; GS-1101 or is GSK 2126458 (omipalisib, GSK).

[34] In other embodiments of the invention the GFR antagonist is an inhibitor of Epidermal Growth Factor Receptor (EGFR) antagonist. The EGFR antagonist is selected from a compound that exhibits an IC50 with respect to EGFR signalling, of no more than about 100 mM or not more than about 50 mM as measurable by a EGFR signalling inhibitory assay. Preferably the EGFR antagonist is a compound selected from Gefitinib, Erlotionib, Dacomitinib, Lapatinib (GW-572016), Neratinib, Canertinib, Sapitinib, Pelitinib, AC480, AEE788, and Varlitinib.

[35] For the herein disclosed invention the GFR antagonist is most preferably a compound selected from the group consisting of pictilisib, omipalisib, RO5126766, lonafarnib and sorafenib; or is combination of any of the aforementioned compounds.

[36] In a second aspect, the invention pertains to a method of treating or preventing respiratory virus-induced exacerbation of a chronic lung disease in a subject, the method comprising administering to the subject an effective amount of a growth factor receptor (GFR) antagonist, preferably an antagonist of a GFR downstream signalling kinase.

[37] In some embodiments, a respiratory virus (e.g., a coronavirus) causes exacerbation of a chronic lung disease (e.g., asthma, COPD, cystic fibrosis, emphysema, chronic bronchitis, interstitial lung disease, bronchitis; sarcoidosis, idiopathic pulmonary fibrosis, bronchiectasis, bronchiolitis, etc.). Thus, the present disclosure provides methods for treating respiratory virus- induced exacerbation of a chronic lung disease, where the methods involve administering an effective amount of an GFR antagonist in monotherapy, or administering, in combined effective amounts, an GFR antagonist and at least one additional therapeutic agent.

[38] In a third aspect, the invention pertains to a growth factor receptor (GFR) antagonist for use in the treatment or prevention of a viral infection in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of the GFR antagonist, and wherein the viral infection in the subject is caused by a virus of the family of Coronaviridae.

[39] In a fourth aspect, the invention pertains to a growth factor receptor (GFR) antagonist for use in the treatment or prevention of respiratoiy virus-induced exacerbation of a chronic lung disease in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of the GFR antagonist.

[40] In alternative aspects the invention provides a use of GFR antagonists for the preparation of a medicament for the treatment of a viral disease or of respiratoiy virus-induced exacerbation of a chronic lung disease in a subject. [41] In a fifth aspect, the invention pertains to a pharmaceutical composition for use in the treatment or prevention of a viral infection caused by a virus of the family of Coronaviridae in a subject, the pharmaceutical composition comprising (i) a GFR antagonist as recited in any one of the first to the fourth aspect, and (ii) a pharmaceutically acceptable carrier and/ or excipient. In any of the herein disclosed methods and aspects in all of the disclosed embodiments, the antagonists may be formulated alone or together with additional active ingredients in such a pharmaceutical composition.

[42] A “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” means an excipient, diluent, carrier, and adjuvant that are useful in preparing a pharmaceutical composition that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that are acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable excipient, diluent, carrier and adjuvant” as used in the specification and claims includes one and more than one such excipient, diluent, carrier, and adjuvant.

[43] A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et ah, eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A. H. Kibbe et ah, eds., 3rd ed. Amer. Pharmaceutical Assoc.

[44] As used herein, a “pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human. In general, a “pharmaceutical composition” is sterile, and generally free of contaminants that are capable of eliciting an undesirable response within the subject (e.g., the compound(s) in the pharmaceutical composition is pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal and the like. In some embodiments the composition is suitable for administration by an oral route of administration. In some embodiments the composition is suitable for administration by an inhalation route of administration. In some embodiments the composition is suitable for administration by a transdermal route, e.g., using a penetration enhancer. In other embodiments, the pharmaceutical compositions are suitable for administration by a route other than transdermal administration. [45] As used herein, “pharmaceutically acceptable derivatives” of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and are either pharmaceutically active or are prodrugs.

[46] A “pharmaceutically acceptable salt” of a compound, such as an GFR antagonist of the invention, means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1 ) acid addition salts, formed with inorganic acids such as hydrochloric acid,-hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like.

[47] In the subject methods, an active agent maybe administered to the subject in need of a treatment using any convenient means capable of resulting in the desired reduction in viral titers, symptoms of viral infection, etc. Thus, the active agent can be incorporated into a variety of formulations for therapeutic administration. More particularly, an active agent can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

[48] In pharmaceutical dosage forms, an active agent may be administered in the form of their pharmaceutically acceptable salts, or an active agent may be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting. [49] In some embodiments, an active agent is administered in an amount of from about 10 pg to about 500 mg per dose. In some embodiments, an active agent is administered in an amount of from about 10 mg/m2 per dose to about 150 mg/m2 per dose. In some embodiments, an active agent is administered in an amount of from about 10 mg/m per week to about 200 mg/m per week.

[50] The present invention in addition pertains to the following preferred itemized embodiments:

Item l: A method of treating or preventing a viral infection in a subject, the method comprising administering to the subject an effective amount of a growth factor receptor (GFR) antagonist, wherein the viral infection in the subject is caused by a virus of the family of Coronaviridae.

Item 2:The method of item l, wherein the subject is a human.

Item 3:The method of item l or 2, wherein the subject is immunocompromised.

Item 4:The method of any one of items 1 to 3, wherein the subject has a chronic lung disease.

Item 5: The method of any one of items 1 to 4, wherein the chronic lung disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial lung disease, bronchitis, sarcoidosis, idiopathic pulmonary fibrosis, bronchiectasis, acute respiratory distress syndrome, or acute lung injury.

Item 6:The method of any one of items 1 to 5, wherein the subject:

(i) is from about l month to about 6 months of age, or from about 6 months to about i year of age;

(ii) is from about i year to about 5 years of age, or from about 5 years to about 12 years of age;

(iii) is from about 13 years to about 19 years of age;

(iv) is from about 20 years to about 30 years of age;

(v) is from about 30 years to about 50 years of age;

(vi) is from about 50 years to about 75 years of age;

(vii) is about 75 years of age or older. Item 7: The method of any one of items 1 to 6, wherein the virus infection is caused by HCoV- 229E, HC0V-OC43 (HC0V-OC43), or severe acute respiratory syndrome coronavirus (SARS- CoV), and preferably is caused by SARS Cov-2.

Item 8: The method of any one of items 1 to 7, wherein the GFR antagonist is a small molecule inhibitor or is a biologic.

Item 9:The method of any one of the preceding items, wherein the GFR antagonist is small molecule kinase inhibitor.

Item 10: The method of any one of the preceding items, wherein the GFR antagonist is an antagonist of a downstream component, preferably of a kinase, of a GFR receptor signalling pathway.

Item 11: The method of any one of items 1 to 10, wherein the GFR antagonist is an inhibitor of the RAF/MEK/ERK MAPK signalling cascade (MEK or RAF inhibitor).

Item 12: The method of item 11, wherein the MEK or RAF inhibitor is selected from a compound that exhibits an IC50 with respect to RAF/MEK/ERK MAPK signalling, of no more than about 100 mM or not more than about 50 pM as measurable by a RAF/MEK/ERK MAPK enzyme inhibitory assay.

Item 13: The method of item 11 or 12, wherein the MEK or RAF inhibitor is a compound selected from a (i) MEK inhibitor of the group: AZD8330 (ARRY-424704), Refametinib (BAY 86- 9766, RDEAi 19), Cobimetinib (GDC-0973, XL-518, RG7421 ); E6201 ; Binimetinib (MEK162, ARRY-162); PD0325901; Pimasertib (AS703026, MSC1936369B); R04987655 (CH4987655), R05126766 (CH5126766), Selumetinib (AZD6244, ARRY- 142,886), Trametinib (GSKi 120212), GDC-0623, PD035901 , PD184352 (CI-1040), WX- 554, Uoi26-EtOH, PD98059, BIX 02189, BIX 02188, PD318088, Honokiol, SL-327, GDC-0623, APS-2-79 HCI, Cobimetinib, XL518, PD325901 , TAK-733, R05126766, or HL-085; or (ii) a RAF inhibitor selected from(PLX4032, RG7204), Sorafenib Tosylate, PLX-4720, Dabrafenib (GSK21 18436), GDC-0879, CCT196969, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372, GW5074, TAK-632, CEP- 32496, Encorafenib (LGX818), Regorafenib, R05126766 (CH5126766), MLN2480, PLX7904, CCT196969, Lonafarnib, Tipifarnib, PLX-4720, Lifirafenib, BMS-214662 LY3009120, and BAY 43-9006 (sorafenib).

Item 14: The method of any one of items 1 to 10, wherein the GFR antagonist is an inhibitor of via phosphoinositide 3 kinase [PI3K] and protein kinase B (AKT) mTORCi signalling (Pl3K-AKT-mT0R inhibitor). Item 15: The method of item 14, wherein the Pl3K-AKT-mT0R inhibitor is preferably selected from a compound that exhibits an IC50 with respect to Pl3K-AKT-mT0R signalling, of no more than about 100 mM or not more than about 50 pM as measurable by preferably a PI3K- AKT-mTOR enzyme inhibitory assay.

Item 16: The method of item 15, wherein the Pl3K-AKT-mT0R inhibitor is an PI3K inhibitor and is a small molecule which is an isoform-selective inhibitor of PI3K selected among the following compounds: BYL719 (Alpelisib, Novartis), GDC-0032 (Taselisib, Genentech/Roche), BKM120 (Buparlisib), Dactolisib (BEZ235), INK1117 (Millenium), A66 (University of Auckland), GSK260301 (Glaxosmithkline), KGN- 193 (Astra-Zeneca), TGX221 (Monash University), TG1202, CAL101 (Idelalisib, Gilead Sciences), GS-9820 (Gilead Sciences), AMG319 (Amgen), SF-1126, IC87114 (Icos Corporation), Fimepinostat (CUDC-907), BAY80- 6946 (Copanlisib, Bayer Healthcare), VS-5584, GDC0941 (Pictlisib, Genentech), IPI145 (Duvelisib, Infinity), SAR405 (Sanofi), PX-866 (Oncothyreon), MEN 1611, ZSTK474, WX-037; GS-1101 or is GSK 2126458 (omipalisib, GSK).

Item 17: The method of any one of items 1 to 10, wherein the GFR antagonist is an inhibitor of Epidermal Growth Factor Receptor (EGFR) antagonist.

Item 18: The method of item 17, wherein the EGFR antagonist is selected from a compound that exhibits an IC50 with respect to EGFR signalling, of no more than about 100 pM or not more than about 50 pM as measurable by a EGFR signalling inhibitory assay.

Item 19: The method of item 17 or 18, wherein the EGFR antagonist is a compound selected from Gefitinib, Erlotionib, Dacomitinib, Lapatinib (GW-572016), Neratinib, Canertinib, Sapitinib, Pelitinib, AC480, AEE788, and Varlitinib.

Item 20: The method of any one of the preceding items, wherein the GFR antagonist is a multi-kinase inhibitor.

Item 21: The method of any one of items 1 to 12, or 14 or 15, wherein the GFR antagonist is a bicyclic heterocyclic compound.

Item 22: The method of any one of items 1 to 12, or 14 or 15, wherein the GFR antagonist is an antibody specific for GFR.

Item 23: The method of any one of items 1 to 12, or 14 or 15, wherein the GFR antagonist is an inhibitoiy nucleic acid that reduces the level of GFR, or a downstream component of GFR signalling, produced in a cell. Item 24: The method of any one of items 1 to 10, wherein the GFR antagonist is selected from the group consisting of pictilisib, omipalisib, RO5126766, lonafarnib and sorafenib; or is combination of any of the aforementioned compounds.

Item 25: The method of any one of items 1 to 24, wherein the GFR antagonist is administered to the subject via a systemic route, preferably intravenously.

Item 26: The method of any one of items 1 to 24, wherein the GFR antagonist is administered to the respiratory system of the subject, such as via oral inhalation or intranasally.

Item 27: The method of any one of items 1 to 26, wherein the GFR antagonist is administered after the subject has been exposed to the virus. Item 28: The method of any one of items 1 to 27, wherein the GFR antagonist is administered in an amount effective to reduce viral replication in the subject.

Item 29: The method of any one of items 1 to 28, wherein the GFR antagonist is administered in an amount effective to reduce viral load in the subject.

Item 30: The method of any one of items 1 to 29, wherein said administration is effective to ameliorate at least one symptom of viral infection in the subject, such as fever, diarrhoea, cough, shortness of breath, or vomiting.

Item 31: The method of any one of items 1 to 30, further comprising administering at least one additional therapeutic agent to the subject.

Item 32: The method of any one of the preceding items, wherein the GFR antagonist is administered to the subject in the form of a pharmaceutical composition comprising the GFR antagonist and a pharmaceutically acceptable carrier and/or excipient.

Item 33: A method of treating or preventing respiratory virus-induced exacerbation of a chronic lung disease in a subject, the method comprising administering to the subject an effective amount of a growth factor receptor (GFR) antagonist. Item 34: The method of item 33, wherein the chronic lung disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial lung disease, bronchitis, sarcoidosis, idiopathic pulmonary fibrosis, bronchiectasis, or bronchiolitis. Item 35: The method of any one of the preceding items, wherein the subject receives lung supporting therapy, such as active respiratory assistance, and/or wherein the subject is intubated with a tracheal canula suitable for active respiratory assistance.

Item 36: A growth factor receptor (GFR) antagonist for use in the treatment or prevention of a viral infection in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of the GFR antagonist, and wherein the viral infection in the subject is caused by a virus of the family of Coronaviridae.

Item 37: A growth factor receptor (GFR) antagonist for use in the treatment or prevention of respiratory virus-induced exacerbation of a chronic lung disease in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of the GFR antagonist.

Item 38: A pharmaceutical composition for use in the treatment or prevention of a viral infection caused by a virus of the family of Coronaviridae in a subject, the pharmaceutical composition comprising (i) a GFR antagonist as recited in any one of items 1 to 35, and (ii) a pharmaceutically acceptable carrier and/or excipient.

Item 39: The pharmaceutical composition for use of item 38, wherein the treatment or prevention comprises the administration of a therapeutically effective amount of the pharmaceutical composition to the subject.

[51] The terms “of the [present] invention”, “in accordance with the invention”, “according to the invention” and the like, as used herein are intended to refer to all aspects and embodiments of the invention described and/ or claimed herein.

[52] As used herein, the term “comprising” is to be construed as encompassing both “including” and “consisting of’, both meanings being specifically intended, and hence individually disclosed embodiments in accordance with the present invention. Where used herein, “and/or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and/or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein. In the context of the present invention, the terms “about” and “approximately” denote an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±20%, ±15%, ±10%, and for example ±5%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect. Where an indefinite or definite article is used when referring to a singular noun, e.g. "a", "an" or "the", this includes a plural of that noun unless something else is specifically stated.

[53] It is to be understood that application of the teachings of the present invention to a specific problem or environment, and the inclusion of variations of the present invention or additional features thereto (such as further aspects and embodiments), will be within the capabilities of one having ordinary skill in the art in light of the teachings contained herein.

[54] Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described.

[55] All references, patents, and publications cited herein are hereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE FIGURES

The figures show:

[56] Figure 1: Phospho proteomic profiling of SARS-C0V-2 infected cells. (A) experimental scheme. Caco-2 cells were infected with SARS-C0V-2 for one hour, washed and incubated for additional 24 hours. Proteins were extracted and prepared for bottom-up proteomics. All ten conditions were multiplexed using TMTio reagents. 250 pg of pooled samples were used for whole cell proteomics (24 Fractions) and the remainder (~i mg) enriched for phosphopeptides by Fe-NTA. Phosphopeptides were fractionated into 8 fractions and concatenated into 4 fractions. All samples were measured on an Orbitrap Fusion Lumos. (B) Volcano plot showing fold changes of infected versus mock cells for all 15,392 quantified phosphopeptides. P values were calculated using an unpaired, two-sided student’s t-test with equal variance assumed and adjusted using the Benjamini Hochberg FDR method (N = 5). Orange or blue points indicate significantly increased or decreased phosphopeptides, respectively. (C) Volcano plot showing differences between SARS-C0V-2 and mock infected cells in total protein levels for all 7,150 quantified proteins. P values were calculated using an unpaired, two-sided student’s t-test with equal variance assumed and adjusted using the Benjamini Hochberg FDR method (N = 5). Orange or blue points indicate significantly increased or decreased phosphopeptides, respectively. (D) Distribution of phosphorylation sites identified across modified amino acids.

[57] Figure 2: (A - F) Domain structures of SARS-C0V-2 proteins predicted by InterPro. Identified phosphorylation sites are indicated. Protein 3a (A), Membrane Protein M (B), Non- structural protein 6 (C), Protein 9b (D), Replicase Polyprotein lb (E) and Nucleoprotein N (F). (G) X-ray structure of the RNA binding domain (PDB: 6yyo, residues 47-173) with identified phosphorylation sites marked in red.

[58] Figure 3: Correlation map of all detected phospho-proteins indicating Euclidean distance between proteins. To determine correlation, Z-scores of phospho-peptides and total protein levels were added and all peptide values for one protein collapsed into an average Z score. Correlation clustering was performed by Euclidean distance on combined Z scores for all conditions. Red dashed line indicates main clusters found and identified. (B) Reactome pathway enrichment of proteins found in Cluster I in (A). Shown are the number of proteins identified in the respective cluster versus statistical significance of enrichment.Circles are increasingly sized according to the number of proteins found in the pathway. (C) Scatter plot showing fold changes of phospho-peptides compared to fold changes of total protein levels. The yellow oval indicates peptides for which phosphorylation is not driven by changes in protein abundance. (D) Reactome pathways found enriched in Cluster II in (A). Analyses and presentation as in (B). (E) Scatter plot showing correlation between fold changes of phosphopeptides compared to fold changes of total proteins levels. Two subsets of phosphopeptides were detected: one was mainly regulated by differential modification (indicated in yellow), the second by changes in protein abundance. (F) STRING network analysis of proteins decreased in total protein levels (Figure lC). Inserts indicate pathways found in the network.

[59] Figure 4: Reprogramming of carbon metabolism upon SARS-C0V-2 infection. Representation of carbon metabolism pathways. All proteins, for which changes in phosphorylation upon SARS-C0V-2 infection could be quantified, were indicated.. Pie charts show fold changes in individual phosphosites, color coded according to the extent to which individual phosphorylation site increased or decreased

[60] Figure 5: Drug-target phosphoprotein network analysis identifies growth factor signaling as central hub for possible intervention by repurposed drugs. (A) Proteins significantly increased in phosphorylation (FC > 1, FDR < 0.05) were subjected to ReactomeFI pathway analysis and overlaid with a network of FDA-approved drugs. The network was filtered for drugs and drug targets only, to identify pathways that could be modulated by drug repurposing. Red lines indicate drug-target interactions, grey lines protein-protein interactions. Identified drugs are represented with yellow rectangles, while proteins are represented by blue circles. (B) Search across all proteins with significant phosphorylation changes upon SARS-CoV- 2 infection for proteins related to the EGFR pathway. STRING network highlighting all proteins annotated for EGFR signaling and their direct interaction neighbors. Red lines indicate direct EGFR interactions, black lines indicate interactions between pathway members. Grey lines represent filtered interactions to represent the whole network. (C) Pathway representation of proteins identified in (B) to be direct interactors of EGFR, according to the STRING interaction database (confidencecutoff 0.9). Phosphorylation changes of all significantly regulated sites are indicated by color-coded pie charts. Red indicates upregulation and blue indicates down- regulation

[61] Figure 6: Inhibition of growth factor receptor downstream signaling prevents SARS- C0V-2 replication. (A) Schematic representation of growth factor signaling pathways activated upon SARS-COV-2 infection. Inhibitors tested are indicated and their targets shown. (B) Viral replication assay. Percentage inhibition of cytopathic effects (CPE) is plotted versus compound concentration (n = 3 for all compounds). Grey dots indicate replicate measurements, red lines dose-response curve fits. (C) Microscopy pictures showing staining for dsRNA to determine viral dsRNA production and CPE. Mock or SARS-C0V-2 infected cells are shown on the left. SARS- C0V-2 infected cells were treated with different concentrations of inhibitors (as indicated) and imaged after 24 hours. Pictilibsib: 0.625 mM, 2.5 pM, 10 pM; omipalisib: 0.01 pM, 0.625 pM, 2.5 pM; sorafenib: 2.5 pM, 5pM, 10 pM; RO5126766: 2.5 pM, 5 pM, 10 pM; lonafarnib: 0.6 pM, 2.5 pM, 10 pM. N = 3, one representative pictures are shown, two more replicates are shown in Figure S4. Scale bar represents too pm.

[62] Figure 7: Inhibition of growth factor signaling prevents SARS-C0V-2 replication and is cytoprotective. Scheme showing inhibition of growth factor receptor (GFR) signaling by repurposed drugs preventing SARS-C0V-2 replication. Upon SARSC0V-2 infection, GFR signaling is activated and regulates downstream PI3K and MAPK axes. Inhibition of either PI3K or MAPK axes prevents SARS-C0V-2 replication (right), in contrast to the normal infection course (left).

[63] Figure 8: Cytotoxicity data for all tested inhibitors overlaid with CPE data from Figure 6B. Cells were plated and incubated with dose series of different inhibitors. Cytotoxicity was assessed by rotitest vital (n = 3). Red points/axis indicate inhibition of CPE through different inhibitor concentrations. Blue points/axis represent percentage of dead cells compared to control.

EXAMPLES

[64] Certain aspects and embodiments of the invention will now be illustrated by way of example and with reference to the description, figures and tables set out herein. Such examples of the methods, uses and other aspects of the present invention are representative only, and should not be taken to limit the scope of the present invention to only such representative examples.

[65] The examples show:

[66] Example 1: Phospho-proteomics of cells infected with SARS-C0V-2

[67] To evaluate the changes in intracellular signaling networks brought about by SARS-CoV- 2 infection, the inventors quantified phospho-proteome changes 24 hours after infection (Figure lA). Caco-2 cells were mock-infected or infected with SARS-C0V-2 patient isolates (in biological quintruplicates) for one hour, washed, and incubated for 24 hours before cell harvest. Extracted proteins were digested and split to 1) carry out whole-cell proteomics of a tandem mass tag (TMT) 10-plex samples using liquid chromatography synchronous precursor selection mass spectromety (LC-SPS-MS3), or 2) use Fe-NTA phosphopeptide enrichment (achieving 98% enrichment) for phospho proteome analyses of a TMT 10-plex analyzed by LC-MS2. The inventors identified and quantified 7,150 proteins and 15,392 different phosphopeptides for a total of 15,040 different modification sites (Figure lB, C). The main fraction of phosphopeptides were modified serines (86.4%), followed by threonine (13.4%), and tyrosine (0.2%) (Figure lD). Upon infection, 2,197 and 799 phosphopeptides significantly increased or decreased respectively, with a log2FC > 1 and p value < 0.05.

[68] Example 2: Phosphorylation of SARS-C0V-2 viral proteins in the host cell

[69] Viral proteins are produced in the host cell and underlie (and often require) post- translational modification (PTM) by host cell enzymes (Wu et ah, 2009). Accordingly, it was first assessed whether viral proteins are phosphorylated in the host cell. The inventors identified 33 modification sites on 6 different viral proteins (Figure 2A-F). SARS-C0V-2 protein 3a was phosphorylated on a cluster of serine residues close to the C-terminal part of the protein (Figure 2A), which constitutes the luminal side of this transmembrane protein. In SARS-C0V-1, protein 3a mediates virus release and is localized to different membrane compartments, such as the endoplasmic reticulum (ER) and Golgi, where it is glycosylated (Lu et ah, 2006; Yuan et ah, 2005). However, no phosphorylation sites had been described so far and the function of PTMs remain unclear. Membrane protein M was phosphorylated at three serines in close proximity, at the C-terminal, cytoplasmic region of the protein (Figure 2B), suggesting a high-activity modification surface. SARS-C0V-1 protein 6 was described as a non-structural and possible determinant of virulence, since it accelerates infections in murine systems (Tangudu et ah, 2007). It was found that a single phosphorylation of the SARS-C0V-2 protein homologue non- structural protein 6 in host cells (Figure 2C), possibly influencing its trafficking or interaction profile. Protein 9b was also found to be modified at two sites (Figure 2D), however the function of protein 9b in SARS-C0V-1 or SARS-C0V-2 remains unknown. Polyprotein lb is a large 7,096 amino acid protein with various functional domains. Its SARS-C0V-1 homologue has been shown to be heavily processed to generate multiple different proteins with various functions in the cell (Tangudu et al., 2007). Whether similar processes occur for the SARS-C0V-2 protein remains likely albeit unknown. It was found that polyprotein lb modified at two residues, one in a region of unknown function and one in the non-structural protein 11 (NSP11) part of the protein (Figure 2E). The shown data cannot distinguish whether phosphorylation occurred before or after cleavage and whether phosphorylation may affect processing. In line with the current knowledge about SARS-C0V-1, the inventors found the nucleoprotein of SARS-C0V-2 to be heavily modified by phosphorylation (Figure 2F). The crystal structure of residues 47 to 173 was recently described (PDB: 6vyo). The modified phosphosites identified in this domain were mapped to its structure (Figure lG). This showed a small surface region to be phosphorylated, suggesting similar regulation of these sites and specific interaction changes driven by that surface.

[70] In SARS-CoV-i, nucleoprotein N was described to be modified by the host glycogen synthase kinase 3 (GSK3) with phosphorylation regulating RNA binding and localization behavior (Chen et al., 2005; Peng et al., 2008; Surjit et al., 2005; Wu et al., 2009). Likely, similar regulatory patterns also occur in SARS-C0V-2, suggesting inhibition of GSK3 as a possible treatment strategy to test for COVID-19. To bioinformatically predict possible additional host kinases, NetPhos 3.1 and GPS5 was used to predict kinases for the different identified motifs in the viral proteins. Interestingly, among the motifs present in the heavily modified nucleoprotein, the inventors could find many motifs predicted to be modified by CMGC kinases. Among several others, casein kinase II (CK2) kinases are part of the CMGC family and have been independently identified as interaction partners of the nucleoprotein, when expressed in cells (Gordon et al., 2020). Inhibition of CK2 kinases, as achieved by ellagic acid (Cozza et al., 2006), could be employed to study possible functional interactions between kinase and viral protein.

[71] This demonstrates that SARS-C0V-2 proteins are modified by yet unknown host kinases. The role of these modifications remain unclear. However, targeting host kinases required may offer new treatment strategies.

[72] Example 3: Signaling pathways modulated upon infection

[73] To identify the key host signaling pathway networks modulated by infection, the inevntors carried out protein-protein co-regulation analysis on all proteins quantified in phosphorylation and total protein level. First phosphorylation and total protein levels were standardized by individual Z-scoring to compare the different datasets. Subsequently, to merge phosphorylation and proteome data, the inventors collapsed all phospho-sites for each protein into one average profile and calculated combined Z-scores. Patterns of co-regulation were identified using protein-protein correlation and hierarchical clustering (Figure 3A). The dynamic landscape of the proteome revealed three main clusters of co-regulated proteins, each one representing different sets of pathways (discussed in detail below):

[74] The first cluster was mainly comprised of receptor signalling and endocytic pathways (Figure 3B). Prominent among these pathways were platelet derived growth factor receptor (PDGFR), ErbBi (EGFR) signalling, metabolism, and various pathways associated with vesicle trafficking. As changes in phospho-peptide abundance can represent different ratios in phosphorylated versus non-phosphorylated peptide or a change in protein abundance (with the same ratio of protein being phosphorylated), the inventors integrated our phospho-proteome dataset with total proteome data (Figure 3C). In contrast to the extensive changes observed in the phospho-proteome, no general changes were observed for the total proteome (Figure 1C). Thus, phosphorylation changes were induced by signalling activity alteration resulting in increased phosphorylation and not due to protein abundance differences. This strongly suggests that those pathways are indeed activated during infection and might provide candidates for modulation of host-pathogen interaction for therapy.

[75] The second cluster was mainly comprised of proteins decreased in phosphorylation and was highly connected to cell cycle and translation initiation (Figure 3D). It was recently reported that inhibition of cellular translation prevented SARS-C0V-2 replication in cells (Bojkova et ah, 2020), consistent with regulation of translation by altering phosphorylation patterns. To further distinguish the regulations within this cluster, the inventors correlated protein levels with differential phosphorylation abundance (Figure 3E) and found two groups of proteins: The first was contained translation related pathways (identified in Figure 3E) and was predominantly regulated by decreased modification. The second set of proteins was decreased in phosphorylation and on total protein level. The majority of proteins found in the second cluster belonged to diverse cell cycle pathways. Consistent with these findings, cell cycle pathways were also enriched in the set of proteins significantly decreased on protein level (Figure 3F). Translation pathways were not regulated on protein level to this extent.

[76] Analysis of the third cluster revealed signalling events of the splicing machinery possibly explaining previously observed changes in splicing machinery abundance upon SARS-C0V-2 infection (Bojkova et ah, 2020). Consistent with previous literature (Grimmler et ah, 2005; Ilan et ah, 2017; Mathew et ah, 2008; Mermoud et ah, 1994), it was therefore hypothesized that the host splicing machinery is extensively reshaped during viral infection. This finding further supports splicing as a potential therapeutic target, in agreement with decreased SARS-C0V-2 pathogenic effects when inhibiting splicing by pladeinolide B. [77] Taken together, the data show that, during SARS-C0V-2 infection, specific rearrangements of signalling pathways were elicited in the cellular proteome. Regulation was mainly comprised of cellular signalling and translational pathways as well as proteins regulated not only by phosphorylation, but also in total protein abundance. Proteins exhibiting decreased protein levels were significantly enriched in cell cycle proteins.

[78] Example 4: Carbon metabolism modulation in response to SARS-C0V-2 infection

[79] The inventors found carbon metabolism among the pathways showing significantly increased phosphorylation upon SARS-C0V-2 infection in addition to previously described changes of total protein levels of enzymes part of glycolysis and carbon metabolism (Bojkova et ah, 2020). This supports a scenario in which metabolic pathways are controlled both on protein abundance levels and by post-translational modifications (Hitosugi et ah, 2009, 2011; Pozuelo Rubio et ah, 2003; Tripodi et ah, 2015; Zhang et ah, 2015). Strikingly, it was recently shown that inhibition of glycolysis showed cytoprotective activity upon SARS-C0V-2 infection in vitro (Bojkova et al. 2020).

[80] To gain a broader understanding of the host cell changing in carbon metabolism upon SARS-COV-2 infection, the pathway was mapped and overlaid with differential phosphorylation information (Figure 4). The phospho-proteome was sufficiently deep to cover most of the enzymatic steps. Most steps of glucose metabolism as well as pentose phosphate and tricarboxylic acid (TCA) cycle enzymes were found to be highly regulated by phosphorylation (Figure 4). This revealed that the host cell metabolism was highly modified upon SARS-C0V-2 infection. While it remains unclear whether this effect is driven by the virus reshaping cellular behaviour to support replication, or as part of the host cell response, modulation of these pathways by small molecule inhibitors could provide potential therapy options. Carbon metabolism is being tested for cancer therapy, with a number of compounds in various phases of clinical trials (Xintaropoulou et al., 2015), suggesting carbon metabolism as a potential clinical target.

[81] Example 4: Drug-target network reveals growth factor signalling as potent therapy candidate

[82] The inventors observed over 2,000 phospho-peptides to be increased in abundance while their protein levels stay constant upon infection (Figure 3C). This reveals differential modification activity (e.g. signalling events) for these phospho-proteins. For many kinases in cellular signalling pathways there are already approved drugs available. Thus, modulation of signalling and repurposing of available drugs represents a fast option for targeting SARS-C0V-2 infection. Hence, the inventors investigated the potential to repurpose drugs to treat COVID-19 by mapping already available drugs via ReactomeFI to the set of proteins increased in phosphorylation. The inventors filtered the network for drugs and direct targets and found EGFR as one of the central hits, including a number of regulated proteins in the downstream signalling pathway of EGFR (Figure 5A). These downstream targets are also regulated by other GFRs and could thus also be explained by their observed activation upon SARS-C0V-2 infection (Figure 3). 28 clinically approved drugs (largely used in cancer therapy) are already available to target EGFR or downstream targets. The inventors built a stringently filtered interaction network with STRING, taking all proteins significantly altered in their phosphorylation in any direction, and searched for components of the EGFR pathway (Figure 5B). This showed a subnetwork of growth factor signalling components remodelled. The inventors mapped identified members of growth factor signalling and their respective phosphorylation differences upon SARS-COV-2 infection (Figure 5C) revealing an extensive overall increase in phosphorylation of the whole pathway, including related components for cytoskeleton remodelling and receptor endocytosis. How GFR signalling might regulate SARS-C0V-2 infection is still matter for speculation. EGFR activation can suppress apoptosis, which would result in maintenance of viral replication, even under cellular stress conditions (Venkataraman and Frieman, 2017). Taken together, GFR signalling inhibition provides a useful approach already implicated in SARS-CoV induced fibrosis therapy (Venkataraman and Frieman, 2017) and might be a viable strategy to treat COVID-19.

[83] Example 5: Inhibition of growth factor signalling prevents viral replication

[84] Since GFR signalling seemed to be central during SARS-C0V-2 infection, the inventors examined the use of inhibitors as antiviral agents. Since there are several GFRs integrating their signalling and regulating a number of processes inside the cell, directly targeting downstream signalling components is likely to be more successful to prevent signalling of different GFRs and to avoid mixed effects of multiple pathways. GFR signalling, amongst others, results in activation of 1) the RAF/MEK/ERK MAPK signalling cascade and 2) integrates (via phosphoinositide 3 kinase [PI3K] and protein kinase B [AKT]) into mTORCi signalling to regulating proliferation (Figure 6A). To explore the antiviral efficiency of targeting proteins downstream of GFRs, the inventors first tested the PI3K inhibitors pictilisib and omipalisib (Ippolito et al., 2016; Sarker et ah, 2015; Schmid et ah, 2016). Both compounds inhibited viral replication, based on their propensity to prevent cytopathogenic effect (CPE) and viral RNA production in cells (Figure 6B-D, and Figure 8).

[85] Our drug-target analyses identified mitogen activated protein kinase kinase (MAP2K2, better known as MEK) and the RAF inhibitor sorafenib (Wilhelm et ah, 2006) as promising targets inhibiting downstream signalling of GFRs (Figure 5A). Thus, sorafenib and the dual RAF/MEK inhibitor RO5126766 was tested in the viral replication assays. Both compounds inhibited cytopathic effects during infection and the viral replication (Figure 6B, C, and Figure 8). Overall, five compounds, inhibiting downstream signalling of GFRs, prevented SARS-C0V-2 replication at clinically achievable concentrations (Figure 6B) (Eskens et ah, 2001; Fucile et ah, 2014; Martinez-Garcia et al., 2012; Munster et al., 2016; Sarker et al., 2015), emphasizing the importance of GFR signalling during SARS-C0V-2 infection and revealing clinically available treatment options as drug candidates for COVID-19 (Figure 7).

[86] Cell culture

[87] Human Caco-2 (Caucasian male) cells, derived from colon carcinoma, was obtained from the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ; Braunschweig, Germany). Cells were grown at 37°C in Minimal Essential Medium (MEM) supplemented with 10% fetal bovine serum (FBS) and containing 100 IU/ml penicillin and 100 pg/ml streptomycin. All culture reagents were purchased from Sigma.

[88] Virus preparation

[89] SARS-COV-2 was isolated from samples of travelers returning from Wuhan (China) to Frankfurt (Germany) using human colon carcinoma cell line CaCo-2 as described previously¹². SARS-COV-2 stocks used in the experiments had undergone one passage on CaCo-2 cells and were stored at -8o° C. Virus titers were determined as TCID50/ml in confluent cells in 96-well microtiter plates.

[90] Antiviral and cell viability assays

[91] Confluent layers of CaCo-2 cells in 96-well plates were infected with SARS-C0V-2 at MOI 0.01. Virus was added together with drugs and incubated in MEM supplemented with 2% FBS with different drug dilutions. Cytopathogenic effect (CPE) was assessed visually 48 h after infection. To assess effects of drugs on Caco-2 cell viability, confluent cell layers were treated with different drug concentration in 96-well plates. The viability was measured using the Rotitest Vital (Roth) according to manufacturer’s instructions. Data for each condition was collected for at least three biological replicates. For dose response curves, data was fitted with all replicates using OriginPro 2020 with the following equation:

IC50 values were generated by OriginPro 2020 together with metrics for curve fits.

[92] Detection of viral replication

[93] Effect of selected compounds on viral replication was assessed by staining of double- stranded RNA, which has been shown to be sufficient for measurement of SARS-C0V-1 replication(Weber et ah, 2006). Briefly, cells were fixed with acetone/methanol (40:60) solution 48 h post infection. Immunostaining was performed using a monoclonal antibody directed against dsRNA (1:150 dilution, SCI CONS J2, mouse, IgG2a, kappa chain, English & Scientific Consulting Kft., Szirak, Hungary), which was detected with biotin-conjugated secondary antibody (i:iooo dilution, Jackson ImmunoResearch) followed by application streptavidin, peroxidase conjugate (1:3000 dilution, Sigma Aldrich). Lastly, the dsRNA positive cells were visualized by addition of AEC substrate.

[94] Sample preparation for mass spectrometry

[95] The sample preparation was performed as described previously(Klann et al., 2020). Briefly, lysates were precipitated by methanol/chloroform and proteins resuspended in 8 M Urea/10 mM EPPS pH 8.2. Concentration of proteins was determined by Bradford assay and 300 pg of protein per samples was used for digestion. For digestion, the samples were diluted to 1 M Urea with lomM EPPS pH 8.2 and incubated overnight with 1:50 LysC (Wako Chemicals) and 1:100 Sequencing grade trypsin (Pro mega). Digests were acidified using TFA and tryptic peptideswere purified by tCi8 SepPak (50 mg, Waters). 125 pg peptides per sample were TMT labelled and the mixing was normalized after a single injection measurement by LC-MS/MS to equimolar ratios for each channel. 250 pg of pooled peptides were dried for offline High pH Reverse phase fractionation by HPLC (whole cell proteome) and remaining 1 mg of multiplexed peptides were used for phospho-peptide enrichment by High-Select Fe-NTA Phosphopeptide enrichment kit (Thermo Fisher) after manufacturer's instructions. After enrichment, peptides were dried and resuspended in 70% acetonitrile/0.1% TFA and filtered through a C8 stage tip to remove contaminating Fe-NTA particles. Dried phospho-peptides then were fractionated on C18 (Empore) stage-tip. For fractionation C18 stagetips were washed with 100% acetonitrile twice, followed by equilibration with 0.1% TFA solution. Peptides were loaded in 0.1% TFA solution and washed with water. Elution was performed stepwise with different acetonitrile concentrations in 0.1% Triethylamine solution (5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 50%). The eight fractions were concatenated into four fractions and dried for LC-MS.

[96] Offline high pH reverse phase fractionation

[97] Peptides were fractionated using a Dionex Ultimate 3000 analytical HPLC. 250 pg of pooled and purified TMT-labeled samples were resuspended in 10 mM ammonium-bicarbonate (ABC), 5% ACN, and separated on a 250 mm long C18 column (X-Bridge, 4.6 mm ID, 3.5 pm particle size; Waters) using a multistep gradient from 100% Solvent A (5% ACN, 10 mM ABC in water) to 60% Solvent B (90% ACN, 10 mM ABC in water) over 70 min. Eluting peptides were collected every 45 s into a total of 96 fractions, which were cross-concatenated into 24 fractions and dried for further processing.

[98] Liquid chromatography mass spectrometry

[99] All mass spectrometry data was acquired in centroid mode on an Orbitrap Fusion Lumos mass spectrometer hyphenated to an easy-nLC 1200 nano HPLC system using a nanoFlex ion source (ThermoFisher Scientific) applying a spray voltage of 2.6 kV with the transfer tube heated to 300°C and a funnel RF of 30%. Internal mass calibration was enabled (lock mass 445.12003 m/z). Peptides were separated on a self-made, 32 cm long, 75pm ID fused-silica column, packed in house with 1.9 pm C18 particles (ReproSil-Pur, Dr. Maisch) and heated to 50°C using an integrated column oven (Sonation). HPLC solvents consisted of 0.1% Formic acid in water (Buffer A) and 0.1% Formic acid, 80% acetonitrile in water (Buffer B).

[100] For total proteome analysis, a synchronous precursor selection (SPS) multi-notch MS3 method was used in order to minimize ratio compression as previously described (McAlister et ah, 2014). Individual peptide fractions were eluted by a non-linear gradient from 7 to 40% B over 90 minutes followed by a step-wise increase to 95% B in 6 minutes which was held for another 9 minutes. Full scan MS spectra (350-1400 m/z) were acquired with a resolution of 120,000 at m/z 200, maximum injection time of 100 ms and AGC target value of 4 x 10⁵. The 20 most intense precursors with a charge state between 2 and 6 per full scan were selected for fragmentation (“Top 20”) and isolated with a quadrupole isolation window of 0.7 Th. MS2 scans were performed in the Ion trap (Turbo) using a maximum injection time of 50ms, AGC target value of 1.5 x 10⁴ and fragmented using CID with a normalized collision energy (NCE) of 35%. SPS-MS3 scans for quantification were performed on the 10 most intense MS2 fragment ions with an isolation window of 0.7 Th (MS) and 2 m/z (MS2). Ions were fragmented using HCD with an NCE of 65% and analyzed in the Orbitrap with a resolution of 50,000 at m/z 200, scan range of 110-500 m/z, AGC target value of 1.5 xio⁵ and a maximum injection time of 120ms. Repeated sequencing of already acquired precursors was limited by setting a dynamic exclusion of 45 seconds and 7 ppm and advanced peak determination was deactivated.

[101] For phosphopeptide analysis, each peptide fraction was eluted by a linear gradient from 5 to 32% B over 120 minutes followed by a step-wise increase to 95% B in 8 minutes which was held for another 7 minutes. Full scan MS spectra (350-1400 m/z) were acquired with a resolution of 120,000 at m/z 200, maximum injection time of 100 ms and AGC target value of 4 x 10⁵. The 20 most intense precursors per full scan with a charge state between 2 and 5 were selected for fragmentation (“Top 20”), isolated with a quadrupole isolation window of 0.7 Th and fragmented via HCD applying an NCE of 38%. MS2 scans were performed in the Orbitrap using a resolution of 50,000 at m/z 200, maximum injection time of 86ms and AGC target value of 1 x 10⁵. Repeated sequencing of already acquired precursors was limited by setting a dynamic exclusion of 60 seconds and 7 ppm and advanced peak determination was deactivated.

[102] Mass spectrometry data analysis

[103] Raw files were analyzed using Proteome Discoverer (PD) 2.4 software (ThermoFisher Scientific). Spectra were selected using default settings and database searches performed using SequestHT node in PD. Database searches were performed against trypsin digested Homo Sapiens SwissProt database, SARS-C0V-2 database (Uniprot pre-release). Static modifications were set as TMT6 at the N-terminus and lysines and carbamidomethyl at cysteine residues. Search was performed using Sequest HT taking the following dynamic modifications into account: Oxidation (M), Phospho (S,T,Y), Met-loss (Protein N-terminus), Acetyl (Protein N- terminus) and Met-loss acetyl (Protein N-terminus). For whole cell proteomics, the same settings were used except phosphorylation was not allowed as dynamic modification. For phospho-proteomics all peptide groups were normalized by summed intensity normalization and then analyzed on peptide level. For whole cell proteomics normalized PSMs were summed for each accession and data exported for further use.

[104] Significance testing

[105] Unless otherwise stated significance was tested by unpaired, two-sided students t-tests with equal variance assumed. Resulting P values were corrected using the Benjamini-Hochberg FDR procedure. Adjusted P values smaller/equal 0.05 were considered significant. For phospho-proteomics an additional fold change cutoff was applied (log2 > |i|), while for total protein levels, due to different dynamic range, a fold change cutoff of log 2 > 10.51 was applied.

[106] Prediction of kinase motifs

[107] Kinase motifs of phosphopeptides from SARS-C0V-2 proteins were predicted using NetPhos 3.1 (Blom et ah, 1999) and GPS 5.0 (stand-alone version) using the fasta-file of the Uniprot pre-release which was also used for the proteomics data analysis. (Blom et ah, 2004; Wang et ah, 2020). For NetPhos, only Kinases with a score above 0.5 were considered as positive hits. For GPS 5.0, sequences were submitted separately for S/T- and Y-kinases and the score threshold was set to “high”. For the final list in Supplementary Table 3, only the top hits with the highest scores were considered.

[108] Protein co-regulation analysis

[109] Z-scores were calculated for each phospho-site and the total protein levels individually. Phosphosites were collapsed by average. For merging phosphorylation and total protein levels Z-scores for collapsed phosphorylation and protein level were added for each condition and replicate. Thus, both negative Z-scores (downregulation) will produce a lower combined Z-score and vice versa two positive Z-scores will produce a larger combined Z-score. Next, Euclidean distance correlation for all possible protein-protein pairs were calculated, taking all conditions and replicates individually into account. Heatmap was then build by Euclidean distance hierarchical clustering of correlation matrix.

[110] Pathway enrichment analysis

[111] Pathway enrichment analysis was performed by ReactomeFI cytoscape plugin or by STRING functional enrichment analysis. Both analysis used Reactome database for pathway annotations.

[112] Drug-target network analysis [113] All proteins were loaded into ReactomeFI cytoscape plugin to visualize protein-protein functional interaction network. Next, drugs were overlaid by ReactomeFI and network was filtered for the drugs and the first interacting partners. Layout was calculated by yFilesLayout algorithm. [114] Interaction network analysis

[115] All proteins showing significant regulation were loaded by OmicsVisualizer cytoscape plugin and STRING interaction network was retrieved with a confidence cutoff of 0.9. For EGFR subnetwork, EGFR was selected with first interacting neighbors.

[116] Data and Code Availability [117] The mass spectrometry proteomics data have been deposited to the ProteomeXchange

Consortium via the PRIDE (Perez-Riverol et ak, 2019) partner repositoiy with the dataset identifiers PXD018357.

Claims

1. A growth factor receptor (GFR) antagonist for use in the treatment or prevention of a viral infection in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of the GFR antagonist, and wherein the viral infection in the subject is caused by a virus of the family of Coronaviridae.

2. The GFR antagonist for use of claim l, wherein the virus infection is caused by HCoV- 229E, HC0V-OC43 (HC0V-OC43), or severe acute respiratory syndrome coronavirus (SARS-CoV), and preferably is caused by SARS Cov-2.

3. The GFR antagonist for use of claim 1 or 2, wherein the GFR antagonist is an antagonist of a downstream component, preferably of a kinase, of a GFR receptor signalling pathway, and wherein the GFR antagonist does not directly interact with a GFR protein.

4. The GFR antagonist for use of any one of claims 1 to 3, wherein the GFR antagonist is an inhibitor of the RAF/MEK/ERK MAPK signalling cascade (MEK or RAF inhibitor).

5. The GFR antagonist for use of claim 4, wherein the MEK or RAF inhibitor is a compound selected from a (i) MEK inhibitor of the group: AZD8330 (ARRY-424704), Refametinib (BAY 86- 9766, RDEAl 19), Cobimetinib (GDC-0973, XL-518, RG7421 ); E6201 ; Binimetinib (MEK162, ARRY-162); PD0325901; Pimasertib (AS703026, MSC1936369B); R04987655 (CH4987655), R05126766 (CH5126766), Selumetinib (AZD6244, ARRY- 142,886), Trametinib (GSKi 120212), GDC-0623, PD035901 , PD184352 (CI-1040), WX- 554, Uoi26-EtOH, PD98059, BIX 02189, BIX 02188, PD318088, Honokiol, SL-327, GDC-0623, APS-2-79 HCI, Cobimetinib, XL518, PD325901 , TAK-733, R05126766, or HL-085; or (ii) a RAF inhibitor selected from(PLX4032, RG7204), Sorafenib Tosylate, PLX-4720, Dabrafenib (GSK21 18436), GDC-0879, CCT196969, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372, GW5074, TAK-632, CEP- 32496, Encorafenib (LGX818), Regorafenib, R05126766 (CH5126766), MLN2480, PLX7904, CCT196969, Lonafarnib, Tipifarnib, PLX-4720, Lifirafenib, BMS-214662 LY3009120, and BAY 43-9006 (sorafenib).

6. The GFR antagonist for use of any one of claims 1 to 3, wherein the GFR antagonist is an inhibitor of via phosphoinositide 3 kinase [PI3K] and protein kinase B (AKT) mTORCi signalling (Pl3K-AKT-mTOR inhibitor).

7. The GFR antagonist for use of claim 6, wherein the Pl3K-AKT-mT0R inhibitor is an PI3K inhibitor and is a small molecule which is an isoform-selective inhibitor of PI3K selected among the following compounds: BYL719 (Alpelisib, Novartis), GDC-0032 (Taselisib, Genentech/Roche), BKM120 (Buparlisib), Dactolisib (BEZ235), INK1117 (Millenium), A66 (University of Auckland), GSK260301 (Glaxosmithkline), KGN- 193 (Astra-Zeneca), TGX221 (Monash University), TG1202, CAL101 (Idelalisib, Gilead Sciences), GS-9820 (Gilead Sciences), AMG319 (Amgen), SF-1126, IC87114 (Icos Corporation), Fimepinostat (CUDC-907), BAY80-6946 (Copanlisib, Bayer Healthcare), VS-5584, GDC0941 (Pictlisib, Genentech), IPI145 (Duvelisib, Infinity), SAR405 (Sanofi), PX-866 (Oncothyreon), MEN1611, ZSTK474, WX-037; GS-1101 or is GSK 2126458 (omipalisib, GSK).

8. The GFR antagonist for use of any one of claims 1 to 3, wherein the GFR antagonist is an inhibitor of Epidermal Growth Factor Receptor (EGFR) antagonist.

9. The GFR antagonist for use of claim 8, wherein the EGFR antagonist is a compound selected from Gefitinib, Erlotionib, Dacomitinib, Lapatinib (GW-572016), Neratinib, Canertinib, Sapitinib, Pelitinib, AC480, AEE788, and Varlitinib.

10. The GFR antagonist for use of any one of claims 1 to 3, wherein the GFR antagonist is selected from the group consisting of pictilisib, omipalisib, RO5126766, lonafarnib and sorafenib; or is combination of any of the aforementioned compounds.

11. The GFR antagonist for use of any one of the preceding claims, wherein the GFR antagonist is administered to the subject in the form of a pharmaceutical composition comprising the GFR antagonist and a pharmaceutically acceptable carrier and/or excipient.

12. A growth factor receptor (GFR) antagonist for use in the treatment or prevention of respiratory virus-induced exacerbation of a chronic lung disease in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of the GFR antagonist.

13. The GFR antagonist for use of claim 12, wherein the chronic lung disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial lung disease, bronchitis, sarcoidosis, idiopathic pulmonary fibrosis, bronchiectasis, or bronchiolitis.

14. The GFR antagonist for use of any one of the preceding claims, wherein the subject receives lung supporting therapy, such as active respiratory assistance, and/or wherein the subject is intubated with a tracheal canula suitable for active respiratory assistance.

15. A pharmaceutical composition for use in the treatment or prevention of a viral infection caused by a virus of the family of Coronaviridae in a subject, the pharmaceutical composition comprising (i) a GFR antagonist as recited in any one of claims 1 to 11, and (ii) a pharmaceutically acceptable carrier and/or excipient.