WO2021224234A1

WO2021224234A1 - Antiviral use of cilengitide

Info

Publication number: WO2021224234A1
Application number: PCT/EP2021/061687
Authority: WO
Inventors: Luka CICIN-SAIN; Kathrin ESCHKE; Yeonsu KIM
Original assignee: Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Current assignee: Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Priority date: 2020-05-04
Filing date: 2021-05-04
Publication date: 2021-11-11
Anticipated expiration: 2022-11-04

Abstract

The present invention relates to cilengitide or derivatives thereof, wherein said cilengitide competitively inhibits the binding of a viral envelope protein to integrins, for use in the treatment and prevention of viral infection in viruses comprising such RGD motifs, including, but not limited, to viral infection caused by SARS-CoV-2 and in particular COVID-19.

Description

Antiviral use of cilengitide

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.

Background of the invention

Betacoronaviruses (b-CoVs or Beta-CoVs) 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.

Recently, a novel coronavirus emerged in the Chinese city of Wuhan in December 2019. After 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 (. Alphacoronavirus 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. Evidence was rapidly reported that patients were suffering from an infection with a novel Betacoronavirus tentatively named 2019 novel coronavirus (2019-nCoV). Despite drastic containment measures, the spread of 2019-nCoV, now officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is ongoing. Phylogenetic analysis of this virus indicated that it is different (-80% nucleotide identity) but related to SARS-CoV-1.

Although since 2021 numerous vaccines are available and, although numerous pharmacological interventions are under clinical investigation, clear efficacy has not yet been determined for any drug.

Several drugs 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). Recently, 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). Although some promising results were obtained with chloroquine (Millan-Onate et al, 2020), a phase lib-study identified heart arrhythmia as side-effects at higher concentrations (Borba et al., 2020). Similarly, the drug lopinavir was found to have no effect in clinical tests (Cao et al., 2020).

It is therefore an object of the present invention to provide effective agents that can be used for the prevention and treatment of viral infection, in particular SARS-CoV-2 infection. Other objects and advantages will become apparent to the person of skill when studying the present description of the present invention.

In a first aspect of the present invention, 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. It was surprisingly found in the context of the present invention, that 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. 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). According to the present invention, it was reasonable to assume that cilengitide competitively inhibits such viral binding in order to block the replication and spread of viruses having an RGD-motif in their surface proteins, such as the spike protein of SARS-CoV-2.

The SARS-CoV-2 spike protein (S) 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. Surprisingly, our data indicate that SARS-CoV-2 seems to use integrins as cell receptors, likely by binding to them through the RGD (403-405: Arg-Gly-Asp) motif that is present in the receptor-binding domain of the spike proteins of all SARS-CoV-2 sequences analyzed so far (Sigrist et al., 2020), but not in other corona viruses.

Such 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.

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.

In the context of the present invention, the term “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. As shown above, 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.

Preferred is the compound for use according to the present invention, wherein said viral protein comprising an RGD amino acid motif is a viral spike protein (usually abbreviated as “S”). As described above, 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. Further preferred is the compound for use according to the present invention, wherein 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.

According to the present invention, 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.

According to the present invention, 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.

By “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. By “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.

In another important aspect according to the present invention regarding the compound for use, 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 + lamivudine (TRIUMEQ®), elvitegravir + cobicistat +emtricitabine + tenofovir alafenamide (GENVOYA®), and elvitegravir + cobicistat + emtricitabine + tenofovir disoproxil fumarate + emtricitabine (STRIBILD®). Preferred is a combination with remdesivir, chloroquine and/or hydroxychloroquine.

It is to be understood that 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. It is thus envisaged that 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. Nevertheless, 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.

Thus, 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.

In another aspect of the present invention, 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. 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. In this case, 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. Na benzoate, parabens (Me, Pr and Bu), BKC), anti -oxidants (e.g. BHT, BHA, Ascorbic acid), wetting agents (e.g. polysorbates, sorbitan esters), thickening agents (e.g. methylcellulose or hydroxyethylcellulose), sweetening agents (e.g. sorbitol, saccharin, aspartame, acesulfame), flavoring agents (e.g. peppermint, lemon oils, butterscotch, etc.), humectants (e.g. propylene, glycol, glycerol, sorbitol). Other suitable pharmaceutically acceptable excipients are inter alia described in Remington's Pharmaceutical Sciences, 15^th Ed., Mack Publishing Co., New Jersey (1991) and Bauer et ak, Pharmazeutische Technologic, 5^th Ed., Govi-Verlag Frankfurt (1997). The person skilled in the art knows suitable formulations for cilengitide and/or respective derivatives and will readily be able to choose suitable pharmaceutically acceptable carriers or excipients, depending, e.g., on the formulation and administration route of the pharmaceutical composition.

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.

In addition to the aforementioned compounds for use of the invention, the pharmaceutical composition can contain further customary, usually inert carrier materials or excipients. Thus, 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. Preferred is 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). Nevertheless, this exemplary dose can vary within wide limits and is to be suited to the individual conditions in each individual case. For the above uses 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, for example humans, 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. In general, 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.

In the context of the present invention, the term “about” shall mean a deviation of +/- 10% of the value as indicated, unless indicated otherwise.

In the preventive approach, 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.

In the treatment approach, 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.

In another aspect thereof, 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.

It was surprisingly found in the context of the present invention, that 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.

Preferred is the method according to the present invention, wherein 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.

In anotherembodiment of the method according to the present invention, 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 + lamivudine (TRIUMEQ®), elvitegravir + cobicistat +emtricitabine + tenofovir alafenamide (GENVOYA®), and elvitegravir + cobicistat + emtricitabine + tenofovir disoproxil fumarate + emtricitabine (STRIBILD®).

In the method, 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.

In the context of the method of the present invention, it was surprisingly found that 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.

In the preventive approach of the method according to the present invention, the compound 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.

In the treatment approach of the method according to the present invention, the compound 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.

The present invention will now be described further in the following examples with reference to the accompanying Figures, nevertheless, without being limited thereto. For the purposes of the present invention, all references as cited herein are incorporated by reference in their entireties.

Figure 1 shows the results of a WST-1 toxicity assay over a potential therapeutic range of cilengitide.

Examples

In order to test any toxicity of cilengitide, a WST-1 toxicity assay over a potential therapeutic range of cilengitide was performed on Vero E6 cells. The results are shown in Figure 1, no substantial cytotoxicity was found. The method is based on the conversion of water soluble MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) compound to an insoluble formazan product. Viable cells with active metabolism convert MTT into formazan, however, dead cells lose this ability. Thus color formation serves as a useful and convenient marker of only the viable cells. The measured absorbance (590 nm) is proportional to the number of viable cells.

For testing the efficiency of the drug, 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.

All wells were infected with the same PFU (80 PFU). It was found that viral plaques decreased in the presence of cilengitide, and the decrease was quantified. The assay was repeated, and the results are presented in the table below. It was found that a clear anti-viral effect of cilengitide already and reproducibly starts at a concentration of about 1 mM. In the untreated control, the cell layer is almost completely destroyed by the virus. At ImM, the cell layer is mostly destroyed by the virus, and at IOmM, some plaques are still visible in the well were the cells are treated with the highest concentration of cilengitide, but the virus counts are substantially reduced.

Table 1 - Effect of cilengitide on SARS-CoV-2 virus

References as cited

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.V.F., etal. (2020). 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. JAMANetw Open 3, e208857.

Cao, B., Wang, Y., Wen, D., Liu, W., Wang, T, Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M., et al. (2020). A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. The New England journal of medicine.

Lan, T, Ge, T, Yu, T, Shan, S., Zhou, H., Fan, S., Zhang, Q., Shi, X., Wang, Q., Zhang, L., et al. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature.

Matrosovich, M., Matrosovich, T., Garten, W., and Klenk, H.-D. (2006). New low-viscosity overlay medium for viral plaque assays. Virology Journal 3, 63.

Millan-Onate, J., Millan, W., Mendoza, L.A., Sanchez, C.G., Fernandez- Suarez, H., Bonilla- Aldana, D.K., and 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 19, 16. Sigrist, C.J., Bridge, A., and Le Mercier, P. (2020). A potential role for integrins in host cell entry by SARS-CoV-2. Antiviral research 177, 104759-104759.

Wang, M., Cao, R., Zhang, L., Yang, X., Liu, L, Xu, M., Shi, Z., Hu, Z., Zhong, W., and Xiao, G. (2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus 2019-nCoV) in vitro. Cell Research 30, 269-271.

Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K., and Hilgenfeld, R. (2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors. Science (New York, NY) 368 , 409-412.

Claims

1. A compound selected from Formula (I) (cilengitide)

involved, 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.

2. The compound for use according to claim 1, wherein said viral infection is by a virus selected from 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), Coxsackievirus A9, and SARS-CoV-2.

3. The compound for use according to claim 1 or 2, wherein said viral protein comprising an RGD amino acid motif is a viral envelope protein.

4. The compound for use according to any one of claims 1 to 3, wherein said disease is selected from bronchitis, diarrhea, gastroenteritis, conjunctivitis, herpes, viral flu, respiratory disease, acute respiratory disease, pneumonia, 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.

5. The compound for use according to any one of claims 1 to 4, wherein said prevention and/or treatment is in combination with standard antiviral therapy, for example selected from at least one of neuraminidase inhibitors, for example oseltamivir, zanamivir; favipiravir, remdesivir, ribavirin, interferon alfa-2b/ribavirin systemic, interferon alpha 2a or 2b, or pegylated derivatives thereof, chloroquine or hydroxychloroquine, optionally combination with azithromycin, dolutegravir + rilpivirine (JULUCA®), dolutegravir + lamivudine (DOVATO®), ritonavir + lopinavir (Kaletra®), bictegravir + tenofovir alafenamide + emtricitabine (BIKTARVY®), dolutegravir + abacavir + lamivudine (TRIUMEQ®), elvitegravir + cobicistat +emtricitabine + tenofovir alafenamide (GENVOYA®), and elvitegravir + cobicistat + emtricitabine + tenofovir disoproxil fumarate + emtricitabine (STRIBILD®).

6. The compound for use according to any one of claims 1 to 5, wherein said compound is provided as a suitable pharmaceutical composition, such as a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler and/or chewable, and preferably is provided for inhalation.

7. The compound for use according to any one claims 1 to 6, wherein said compound is administered to said subject 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.

8. The compound for use according to any one claims 1 to 6, wherein for prevention said compound is administered to said 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.

9. The compound for use according to any one claims 1 to 8, wherein said compound is administered to said subject at a dosage to reach a concentration of about 1 mM at the site of treatment, such as the respiratory tract.

10. A method for preventing and/or treating 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, comprising administering to said mammal an effective amount of a compound compound selected from Formula (I) (cilengitide)

involved, both the D and the L forms are also included, and physiologically acceptable salts thereof.

11. The method according to claim 10, wherein said viral infection is by a virus selected from 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), Coxsackievirus A9, and SARS-CoV-2.

12. The method according to claim 10 or 11, wherein said viral protein comprising an RGD amino acid motif is a viral envelope protein.

13. The method according to any one of claims 10 to 12, wherein said preventing and/or treating is in combination with standard antiviral therapy, for example selected from at least one of neuraminidase inhibitors, for example oseltamivir, zanamivir; favipiravir, remdesivir, ribavirin, interferon alfa-2b/ribavirin systemic, interferon alpha 2a or 2b, or pegylated derivatives thereof, chloroquine or hydroxychloroquine, optionally combination with azithromycin, dolutegravir + rilpivirine (JULUCA®), dolutegravir + lamivudine (DOVATO®), ritonavir + lopinavir (Kaletra®), bictegravir + tenofovir alafenamide + emtricitabine (BIKTARVY®), dolutegravir + abacavir + lamivudine (TRIUMEQ®), elvitegravir + cobicistat +emtricitabine + tenofovir alafenamide (GENVOYA®), and elvitegravir + cobicistat + emtricitabine + tenofovir disoproxil fumarate + emtricitabine (STRIBILD®).

14. The method according to any one of claims 10 to 13, wherein said compound is administered to said subject at a dosage to reach a concentration of about 1 mM at the site of treatment, such as the respiratory tract.

15. The method according to any one of claims 10 to 14, wherein for prevention said compound is administered to said 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 and/or wherein for treatment said compound is administered to said subject 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.