Novel attachment antiviral inhibitors

Abstract

The invention relates to a compound comprising a core and at least one moiety L which is attached to the core, wherein the moiety L is a moiety of formula (I): or a pharmaceutically acceptable salt thereof.

Description

[0001] Novel attachment antiviral inhibitors

[0002] Viruses are of intense interest as they cause serious illnesses in humans, domestic animals, and crop plants. During the last century, progress in the control of infectious diseases through improved sanitation, safer water supplies, the development of antibiotics, antivirals and vaccines, and better medical care have dramatically reduced the threat to human health from viral agents, especially in developed countries, for example, the death rate from infectious disease in the United States during the last century has dropped from around 800 deaths per 100,000 population per year to about 50. In particular, the development of vaccines has led to effective control of the most dangerous viruses, including, smallpox virus which has been eradicated worldwide by means of an ambitious and concerted effort sponsored by the World Health Organization (WHO) to vaccinate all people at risk of developing disease. Polio and measles virus have also been eliminated from the Americas by intensive vaccination programs and may also be eradicated worldwide in the near future. The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), has had a catastrophic effect globally with more than 7 million deaths to date worldwide (WHO Covid-19 dashboard) and brought to the fore the importance of developing effective vaccination and antiviral agents to tackle viral infection and spread. It is now apparent that in a globalized world with unprecedented climate change, microbial threats are emerging at an accelerating pace.

[0003] In spite of the availability of vaccines and the stringent measures often taken to tackle viral infection and spread, The COVID-19 pandemic has shown that effective treatment methods are also urgently needed to prevent infection related illness, death, outbreaks as well as allow time for the development of effective vaccines. Moreover, vaccines are not always available for newly discovered and under researched viral strains and often unavailable in developing countries. Currently, there are very few antiviral agents on the market, due in large part to the challenges of developing such drugs, their associated side effects, and the emergence of antiviral resistance. Antiviral drugs, unlike most antibiotics, typically do not destroy their target pathogens but rather inhibit their development, this is due to the fact that viruses use the host’s cells to replicate which makes it difficult to design a safe and effective antiviral drug. A major challenge in the development of antiviral drugs is the difficulty in finding drug targets that interfere with the virus without damaging the host’s cells. A further issue that complicates developing broad-spectrum anti-viral drugs is viral variation, however very few specific antivirals are currently available as they may cause more severe side effects if targeting the biosynthetic machinery of the infected cells.

[0004] To tackle the challenges of being able to target new viruses and viral variations, the ideal antiviral would have broad-spectrum activity, similar to that of penicillin, where one drug would be suited as an antiviral against viruses from different families as well as viruses that have mutated within a family. To be broad spectrum an antiviral drug would need to be effective against nonenveloped and enveloped viruses, with dense or sparse glycoprotein corona, with RNA and / or DNA based genome, and diverse, dissimilar viral proteins.

[0005] The most common inhibitory actions of antiviral drugs target either viral function or the cellular functions that viruses need. For example, for the treatment of COVID-19, Remdesivir and Paxlovid are antivirals that inhibit viral polymerase and viral protease, respectively. Drugs are also available which inhibit viral cell entry by changing endosomal pH (e.g., hydroxychloroquine) and which act as immunomodulators (e.g., Nitazoxanide, Ivermectin). Other than the target mechanism, a further consideration in designing antivirals is whether a drug is virustatic or virucidal in action. The majority of antiviral drugs are virustatic, meaning they inhibit viral function via a reversible mechanism, e.g., Heparin, a polymer, is capable of binding to viral attachment receptors and by doing so inhibiting virus-cell interaction. Although this mechanism is broad-spectrum and non-toxic, it has the disadvantage of being ineffective due to dilution in bodily fluids, which causes the drug to be released from the virus and leaving the virus intact to continue infecting cells. Moreover, such a mechanism may also lead to resistance, as viruses develop mechanisms to overcome the virustatic drug. The best approach to viral inhibition would thus be virucidal, i.e., an irreversible inhibition of the virus, rendering it permanently incapable of infecting cells and significantly reducing the possibility of developing resistance. Common virucidal agents include surfactants, strong acids and bases, certain polymers and nanoparticles, however, many of these agents are too toxic to be useful as a drug. Indeed, to date there are no approved virucidal drugs due to their intrinsic toxicity.

[0006] The development of virucidal agents has been of intense interest with current research heavily focused on the use of polymers bearing hydrophobic groups which show virucidal activity or enhanced antiviral activity (J. Haidar et al., Proc. Natl. Acad. Sci. 2006, 103, 17667; M. Tengdelius, et al., Eur. Polym. J. 2018, 98, 285), as well as nanoparticles (V. Cagno et al., Nat. Mater. 2018, 17, 195) and macrocyclic compounds, in particular p-cyclodextrins modified with e.g., 11 -undecane sulfonic acid (S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318). The most promising therapeutic of the aforementioned are modified 0- cyclodextrins, which show virucidal activity against a wide range of heparan sulfate proteoglycan (HSPG) binding viruses without cellular toxicity. The cyclodextrin- based compounds work by mimicking cell receptors such that they are able to attach to their corresponding viral ligand and cause a local viral deformation that ultimately leads to irreversible viral mutations, and possibly also viral disassembly. This approach allows for broad-spectrum efficacy as it focuses on a virus-cell interaction that is common to many viruses, in particular, the very first step of viral infection when the virus attaches to the cell surface attachment receptors, thereby stopping the life cycle of the virus entirely. Many viruses exploit heparan sulfate proteoglycans (HSPGs) as attachment receptors since HSPGs are expressed on the surface of almost all eukaryotic cell types, including, but not limited to human immunodeficiency virus 1 (HIV-1), herpes simplex virus (HSV), Human Cytomegalovirus (HCMV), human papillomavirus (HPV), Respiratory syncytial virus (RSV) and filoviruses. The binding between the virus and HSPG is achieved via the interaction of stretches of basic amino acids on viral proteins (basic domains) and the negatively charged sulfate groups of heparan sulfate (HS) chains that are covalently attached to the HSPG in the glycocalyx of the cell surface. Therefore, by designing a compound with a high density of long sulfonic acid terminated molecules, a strong multivalent binding to the virus is achieved by imitating the cell attachment receptor HS(s). The inventors of the present invention previously found that macrocyclic compounds comprising HS-like chains were able to interact with a virus and cause an irreversible change leading to the virus destruction and the permanent loss of viral infectivity. For example, it was found that by a chemical modification of a cyclic sugar unit, such as cyclodextrin, it is possible to provide a biocompatible virucidal molecule that shows virucidal properties at low concentrations against a wide range of viruses including herpes simplex virus (HSV), human papillomavirus virus (HPV), respiratory syncytial virus (RSV), dengue virus and lentivirus (a human immunodeficiency virus (HIV) derived virus).

[0007] Document WO 2018 / 015465A1 describes virucidal compounds comprising a carbohydrate based polymeric macrocycle, namely p-cyclodextri n, comprising a plurality of alkyl sulfate groups to which HSPG binding viruses attach. The virucidal compounds can be used for the treatment and / or prevention of viral infections and / or diseases associated with viruses. The inventors also found that these virucidal compounds can be used at low concentrations (pM or nM range) and can be used for the treatment or prevention of HSV, HPV, RSV, dengue virus and lentivirus (a HIV derived virus). Moreover, the virucidal compounds may be used for sterilization and / or disinfection.

[0008] Document WO 2020 / 048976A1 describes a virucidal nanoparticle comprising a cyclodextrin core and a plurality of optionally substituted alkyl-based ligands covalently attached thereto. At least one portion of some of the ligands further comprise a trisaccharide moiety selected from 3-sialyl-N-acetyllactoseamine (3’SLN) and 6-sialyl-N-acetyllactoseamine (6’SLN). The virucidal nanoparticles are useful for treating and / or preventing influenza virus and were found to show strong in vitro inhibitory activity against infection of cells by influenza (H1 N1) A / Netherlands / 2009 (A / NL / 09) strain, displaying ECso values in the nanomolar range. Moreover, it was also found to be effective ex-vivo (in a 3D model of human airway reconstituted epithelia) and in-vivo (in mice) in the pM range.

[0009] Although much effort is being invested into developing antivirals for more prevalent viral infection, one viral infection that has received less attention is human parainfluenza virus ((H)PIV), which belongs to the Paramyxoviridaie virus family. PIV is genetically and antigenically divided into four main serotypes, numbered as PIV-1 to PIV-4, with further subtypes of PIV-4a and PIV-4b. The human parainfluenza viruses 1 and 3 belong to the genus of Respirovirus, and the genus Rubulavirus includes PIV-2 and 4. PIV-1 to PIV-3 are the leading causes of lower respiratory infections in infants, young children, adults, the immunocompromised, and the elderly. Moreover, PIVs are one of the main causes of hospitalization in children under 5 years of age due to acute respiratory tract infection, with a rate accounting for up to 17% of hospitalizations. Serological surveys have demonstrated that 60% of children infected with PIV-3 are around 2 years of age, whereas for children around 4 years of age, the rate of PIV-3 infection increases to up to 80%. Co-infections of PIV and other respiratory viruses are frequent and may cause more serious, severe, and prolonged symptoms. Parainfluenza virus spreads through direct person-to-person contact or from large droplets; outbreaks can occur, for example, in hospitals, nursing homes and daycare facilities. Symptoms of PIV include croup (i.e., swelling of the airways), which causes a hoarse barking cough, as well as laryngeal obstruction, wheezing and air trapping. Furthermore bronchitis, pneumonia and tracheobronchitis are also common illnesses reported for those infected by PIV. Currently, there are no antivirals or vaccines available for the treatment and / or prevention of PIV infection and / or diseases associated with PIV infection; treatments at present remain largely focused on being supportive. There is therefore an urgent and unmet need to develop antivirals against parainfluenza, in particular due to the fact that PIV infection may lead to severe and serious problems that may lead to the death in immunocompromised patients.

[0010] Considering that there are no virucidal antivirals approved for treating or preventing viral infectious disease, there is an urgent and unmet need to provide such virucidal antiviral agents for the treatment and / or prevention of viral infectious disease.

[0011] The present invention addresses this need and solves the problem of providing novel virucidal and / or antiviral agents for the treatment and / or prevention of viral infectious disease, with a particularly advantageous safety and efficacy profile.

[0012] Accordingly, the present invention provides

[0013] 1. A compound comprising a core and at least one moiety L which is attached to the core, wherein the moiety L is a moiety of formula (I): wherein the compound includes up to 5 moieties -L of formula (I), preferably wherein the compound includes from 1 to 5 moieties -L, more preferably from 1 to 3 moieties -L; or a pharmaceutically acceptable salt thereof.

[0014] 2. The compound of item 1 , wherein the core is a macrocyclic core. 3. The compound of item 2, wherein the macrocyclic core is selected from a cyclodextrin (alpha, beta and gamma), a modified cyclodextrin, a cyclic biotin, a crown ether, a pillararene, a calixarene, a corrole, a phthalocyanine, a cucurbituril, a porphyrin, a macrocyclic peptide, a macrocyclic glycopeptide, a carbohydrate containing macrocycle, including Ipomomeassin F, glucolipsin A, forsytheenthoside A, clemahexapetoside A, clemahexapetoside B, clemoarmanoside A and tricolorin A, a macrocyclic lactone, including macrolides, a macrocyclic drug, including bacitracin, dactinomycin, geldanamycin, azithromycin, vancomycin, clarithromycin, roxithromycin, telithromycin, dirithromycin, carbomycin, josamycin, kitasamycin, midecamycin, oleandomycin, solithromycin, spiramycin, leucomycin, amphotericin B, simeprevir, lorlatinib, epothilone B, alisporivir, pacritinib, grazoprevir, paritaprevir, glecaprevir, sanglifehrin A, and cyclosporine, and macrocycle-based PROTAC.

[0015] 4. The compound of item 2 or 3, wherein the macrocyclic core is selected from a-cyclodextrin, 0- cyclodextrin and y-cyclodextrin, preferably.

[0016] 5. The compound of any one of items 1 to 4, wherein the compound includes from 1 to 5 moieties - L, more preferably from 1 to 3 moieties -L.

[0017] 6. The compound of any one of items 1 to 5, represented by formula (II): wherein x is 6, 7 or 8; each occurrence of each R’ and R” is independently selected from H, -(CH2)yi-COOH, and - (CH2)yi-SO3H, wherein each occurrence of y1 is independently an integer from 4 to 20; each occurrence of R is independently selected from -(CH2)y2-SO3-, -(CH2)y2-NH-(CH2)y3-L, - (CH2)y2-COOH, -(CH2)y2-CONH-(CH2)y3-L, and -(CH2)y2-CONHCH2CH2SO3H; each occurrence of Z is independently selected from -S-, -NH-, -N(Ci-s alkyl)-, -NH-C(=O)-, -N(Ci- 8 alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(Ci-e alkyl)-, -O-C(=O)-, -C(=O)-O-, -C(=O)-, and -O-; each occurrence of Y2 is independently an integer from 8 to 14; each occurrence of y3 is independent an integer from 2 to 5; provided that at least one R is either -(CH2)y2-NH-(CH2)y3-L or -(CH2)y2-CONH-(CH2)y3-L, preferably wherein at least one R is -(CH2)y2-NH-(CH2)y3-L; or a pharmaceutically acceptable salt thereof.

[0018] 7. The compound of item 6, wherein x is 7.

[0019] 8. The compound of item 6 or 7, wherein each R’ is H.

[0020] 9. The compound of any one of items 6 to 8, wherein each R” is H.

[0021] 10. The compound of any one of items 6 to 9, wherein at least one instance of R is selected from -

[0022] (CH2)y2-SO3-, -(CH2)y2-COOH, and -(CH2)y2-CONHCH2CH2SO3H, preferably wherein one or more R is -(CH2)y2-NH-(CH2)y3-L and each of the remaining instances of R is -(CH2)y2-SO3’.

[0023] 11 . The compound of any one of items 6 to 10, wherein each occurrence of y2 is an integer from 6 to 10.

[0024] 12. The compound of item of any one of items 6 to 11 , wherein each occurrence of y2 is 8.

[0025] 13. The compound of item of any one of items 6 to 12, wherein each occurrence of y3 is independently an integer from 2 to 4.

[0026] 14. The compound of any one of items 6 to 13, wherein each occurrence of y3 is 4.

[0027] 15. The compound of any one of items 6 to 14, wherein each occurrence of Z is independently selected from -S-, -NH-, N(CI-3 alkyl)-, and -O-.

[0028] 16. The compound of any one of items 6 to 15, wherein each occurrence of Z is S.

[0029] 17. The compound of any one of items 6 to 16, wherein at least one R is -(CH2)s-NH-(CH2)4-L.

[0030] 18. The compound of any one of items 6 to 17, wherein exactly one R is -(CH2)s-NH-(CH2)4-L and each of the remaining instances of R is -(CH2)s-SO3’.

[0031] 19. The compound of any one of items 6 to 18, wherein the compound of formula (II) is a compound of formula (Ila): or a pharmaceutically acceptable salt thereof, wherein x, Z, R, R’ and R” are as defined in any one of items 6 to 18.

[0032] 20. A pharmaceutical composition comprising the compound of any one of items 1 to 19 and a pharmaceutically acceptable carrier.

[0033] 21 . The compound of any one of items 1 to 19 or the pharmaceutical composition of item 20 for use as a medicament.

[0034] 22. The compound of any one of items 1 to 19 or the pharmaceutical composition of item 20 for use in treating and / or preventing a viral infectious disease.

[0035] 23. The compound for use of item 22 or the pharmaceutical composition for use of item 22, wherein the viral infectious disease is caused by a virus that binds sialic acid and / or a sulfonated / sulfated group(s).

[0036] 24. The compound for use of item 22 or 23 or the pharmaceutical composition for use of item 22 or 23, wherein said virus is a respiratory virus, sexually transmitted virus and / or vector transmitted virus.

[0037] 25. The compound for use of any one of items 22-24, or the pharmaceutical composition for use of any one of items 22-24, wherein the viral infectious disease is caused by a virus that binds to sialic acid and / or a sulfonated / sulfated group(s), selected from Paramyxoviridae family (such as PIV1 , PIV2, PIV3, PIV4, Nipah, Hendra virus or mumps), Orthomyxoviridae (such as influenza A virus H5N1 , H1 N1 or H3N2 or influenza B virus), Pneumoviridae (such as Respiratory Syncytial Virus and Human Metapneumovirus), Coronaviridae (such as SARS-CoV-2, MERS-CoV, Human Coronavirus OC43), Herpesviridae (such as Herpes Simplex Virus (HSV) 1 , HSV2, cytomegalovirus), Caliciviridae (such as norovirus), Reoviridae (such as rotavirus), Papillomaviridae, Polyomaviridae, Adenoviridae and Flaviviridae (such as Zika virus, Dengue virus, West Nile Virus and Tick Borne Encephalitis Virus) and Poxviridae (such as Monkeypox). 26. The compound of any one of items 1 to 19 for use in disinfection and / or sterilization.

[0038] 27. A method of treating or preventing a disease / disorder in a subject, wherein the disease / disorder is a disease or disorder caused by a virus, the method comprising administering the compound according to any one of items 1 to 19, or the pharmaceutical composition of item 20 to a subject in need thereof.

[0039] 28. The method of item 27, wherein the disease or disorder caused by a virus is caused by a virus that binds sialic acid and / or a sulfonated / sulfated group(s).

[0040] 29. The method of item 27 or 28, wherein said virus is a respiratory virus, sexually transmitted virus and / or vector transmitted virus.

[0041] 30. The method of any one of items 27-29, wherein the disease or disorder caused by a virus is caused by a virus that binds to sialic acid and / or a sulfonated / sulfated group(s), selected from Paramyxoviridae family (such as PIV1 , PIV2, PIV3, PIV4 Nipah, Hendra virus or mumps), Orthomyxoviridae (such as influenza A virus H5N1 , H1 N1 or H3N2 or influenza B virus), Pneumoviridae (such as Respiratory Syncytial Virus and Human Metapneumovirus), Coronaviridae (such as SARS-CoV-2, MERS-CoV, Human Coronavirus OC43), Herpesviridae (such as Herpes Simplex Virus (HSV) 1 , HSV2, cytomegalovirus), Caliciviridae (such as norovirus), Reoviridae (such as rotavirus), Papillomaviridae, Polyomaviridae, Adenoviridae and Flaviviridae (such as Zika virus, Dengue virus, West Nile Virus and Tick Borne Encephalitis Virus) and Poxviridae (such as Monkeypox).

[0042] Accordingly, the present invention provides a compound comprising a core and at least one moiety L which is attached to the core, wherein the moiety L is a moiety of formula (I): wherein the compound includes up to 5 moieties -L of formula (I), preferably wherein the compound includes from 1 to 5 moieties -L, more preferably from 1 to 3 moieties -L; or a pharmaceutically acceptable salt thereof. According to the present invention, the compound may be a heterogenous mixture of different substitution levels, rather than a single, well-defined chemical entity. Thus, the compound may comprise a mixture of species with substituents present in different ratios for each of said species. Accordingly, the ratio of moiety L to any other specific substituent on the core may vary, for example, from 1 -7:7-1 such as about 1 :5, 1 :6, 1 :7, 2:4, 2:5, 2:6, 3:3, 3:4, 3:5, 4:2, 4:3, 4:4, 5:1 , 5:2, 5:3 or a mixture of any of the aforementioned ratios, preferably wherein said specific substituent is the moiety comprising groups R and Z. The most abundant species present in the mixture may, for example, contain the moiety L in a ratio ranging from 1- 7:7-1 such as about 1 :5, 1 :6, 1 :7, 2:4, 2:5, 2:6, 3:3, 3:4, 3:5, 4:2, 4:3, 4:4, 5:1 , 5:2, 5:3 to any other specific substituent on the core, preferably wherein said specific substituent is the moiety comprising groups R and Z.

[0043] In a preferred embodiment, the ratio of the moiety L to the moiety comprising R and Z is about 1 :5, 1 :6, 1 :7, 2:4, 2:5, 2:6, 3:3, 3:4, 3:5, 4:2, 4:3, 4:4, 5:1 , 5:2, 5:3 or a mixture of any of the aforementioned ratios.

[0044] In another preferred embodiment, the most abundant species present in the mixture contains the moiety L in a ratio of about 1 :5, 1 :6, 1 :7, 2:4, 2:5, 2:6, 3:3, 3:4, 3:5, 4:2, 4:3, 4:4, 5:1 , 5:2, 5:3 to the moiety comprising R and Z.

[0045] In a more preferred embodiment, the ratio of the moiety L to the moiety comprising R and Z is about 1 :5, 1 :6 or 1 :7 or a mixture of any of the aforementioned ratios.

[0046] In another more preferred embodiment, the most abundant species present in the mixture contains the moiety L in a ratio of about 1 :5, 1 :6 or 1 :7 to the moiety comprising R and Z.

[0047] In an even more preferred embodiment, the ratio of the moiety L to the moiety comprising R and Z is about 1 :6.

[0048] In another even more preferred embodiment, the most abundant species present in the mixture contains the moiety L in a ratio of about 1 :6 to the moiety comprising R and Z.

[0049] In a yet more preferred embodiment, the most abundant species of the compound of the present invention present in the mixture comprises about 1 moiety L of formula (I) and up to about 6 moieties comprising R and Z, wherein R is -(CH2)s-SO3’ and Z is S.

[0050] The term “core” as used herein, refers to a central moiety to which at least one moiety L of formula (I) is attached. The core moiety may be any atom or molecule / group to which at least one moiety L of formula (I) may be linked or attached. Accordingly, the core moiety may be comprised of one or more atoms, preferably wherein the one or more atoms are selected from from H, B, C, N, 0, F, Si, P, S, Cl, Br and I, preferably C, 0, N and H. In some embodiments, the core moiety is a molecule / group, preferably selected from an optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-6 haloalkyl, optionally substituted C1-10 cycloalkyl and an optionally substituted C1-10 heterocycloalkyl; wherein preferably the optionally substituted aryl is an optionally substituted monocyclic aryl, bicyclic aryl, tricyclic aryl and the optionally substituted heteroaryl is an optionally substituted monocyclic heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl. In preferred embodiments, the core is selected from: wherein, A is independently selected from -C-, -0-, -N-; Rato R1is independently selected from moiety L of formula (I), H, an optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl, -C00H, -SO3-, -O-SO3-, -OH, -0(Ci-6 alkyl), -C(0)Ci-6 alkyl, -CN, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)(Ci-6 alkyl), halogen, optionally substituted aryl and optionally substituted heteroaryl.

[0051] The linkage of the moiety L to the core molecule may be covalent, ionic or electrostatic, preferably the linkage is covalent. The term “attached to the core”, or grammatical variations thereof, as used herein, refers to the direct or indirect linkage of the at least one moiety L of formula (I) to the core. The linkage is not particularly limited and may be via covalent, ionic or electrostatic linkage. Indirect linkage of the at least one moiety L of formula (I) refers to the linkage of the moiety L to the core via a linker moiety (commonly also referred to as a spacer group). In the present invention, the linker moiety forms a covalent, ionic or electrostatic bond with one or both the moiety L of formula (I) and the core moiety. The linker group may, in principle, be any chemical group which is capable of forming bonds with both the moiety L of formula (I) and the core. Preferably, the linker group contains only atoms selected from H, B, C, N, 0, F, Si, P, S, Cl, Br and I. Exemplary linker moieties include, but are not limited to, an optionally substituted -Ci-30-alkylene-, -C(0)-, -N(R1)-, -C(0)-, -0-, -heteroarylene-, -phenylene-, -S-, -S(0)- and -S(0)2- Preferably the linker moiety is a linear optionally substituted -(C1-30 alkylene)- group, wherein one or more -CH2- units in said alkylene are optionally replaced by a group independently selected from -C0NH-, - NHCO-, -0-, -NH-, -N(CI-6alkyl) -, -CHR1-, -C(R1)2-, -CO-, -S-, -SO-, -SO2- or -(C3-6 cycloalkylene)-; wherein each R1is independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -OH, -0(Ci-6 alkyl), -C(0)Ci-6 alkyl, -CN, -NH2, -NH(CI-6alkyl) and -N(CI-6 alkyl)(Ci-6 alkyl).

[0052] The present invention further provides a compound comprising a macrocyclic core and at least one moiety L which is attached to the macrocyclic core, wherein the moiety L is a moiety of formula (I): or a pharmaceutically acceptable salt thereof.

[0053] The term “macrocyclic core” or grammatical variations thereof, as used herein refers to a molecule containing 9 or more atoms in a ring, wherein the atoms in the ring are covalently bonded and the ring is optionally substituted. The macrocyclic core, according to the present invention may be selected a cyclodextrin (alpha, beta and gamma), a modified cyclodextrin, a cyclic biotin, a crown ether, a pillararene, a calixarene, a corrole, a phthalocyanine, a cucurbituril, a porphyrin, a macrocyclic peptide, a macrocyclic glycopeptide, a carbohydrate containing macrocycle, including Ipomomeassin F, glucolipsin A, forsytheenthoside A, clemahexapetoside A, clemahexapetoside B, clemoarmanoside A and tricolorin A, a macrocyclic lactone, including macrolides, a macrocyclic drug, including bacitracin, dactinomycin, geldanamycin, azithromycin, vancomycin, clarithromycin, roxithromycin, telithromycin, dirithromycin, carbomycin, josamycin, kitasamycin, midecamycin, oleandomycin, solithromycin, spiramycin, leucomycin, amphotericin B, simeprevir, lorlatinib, epothilone B, alisporivir, pacritinib, grazoprevir, paritaprevir, glecaprevir, sanglifehrin A, and cyclosporine, macrocycle-based PROTAC, and mixtures thereof. Preferably the macrocyclic core is selected from a-cyclodextrin, p-cyclodextrin and y-cyclodextrin and mixtures thereof. More preferably, the macrocyclic core is p-cyclodextrin.

[0054] The term "cyclodextrin" (CD), as used herein, refers to cyclic oligosaccharides comprising a-(1 — >4)-linked a-d-glucosyl units. CD’s are cheap, widely available, biocompatible and biodegradable, making them ideal compounds for therapeutic applications. Their cyclic structure creates a hollow truncated cone shape with the primary hydroxy groups of the glucose unit on the narrow face and the secondary hydroxy groups on the wider face of the cone. Each face of the CD can be readily and independently functionalised; the secondary hydroxy groups have a strong hydrophilic and acidic in character and can form hydrogen bonds to rigidity the wider face; the primary hydroxy groups are nucleophilic and basic. The most used natural CDs have 6-, 7-, and 8-glucopyranoside units (linked via a-1 ,4-glycosidic bonds), referred to as a-, 0- and y-CD, respectively. The structure of a-, 0- and y-CD is shown hereinbelow:

[0055] Because of the cyclic structure of CDs, they have a hydrophobic cavity capable of forming supramolecular inclusion complexes with guest molecules. As CDs are naturally occurring, readily functionalised, have a cavity for guest inclusion and are biocompatible, they have found use in many commercial applications including drug delivery, air fresheners, etc. The difference in reactivity of each face of CDs has been used for the synthesis of a wide range of modified cyclodextrins. The primary (i.e., narrow) face of CD is more readily modified, with control over the degree and location of substitution being possible. CD derivatives that bear a good leaving group, such as halogenated CDs, are important intermediates in CD functionalisation. By replacing all of the primary hydroxy units in the CD with iodo-units, the primary face of the CD can be completely functionalised, leaving the secondary hydroxy groups unchanged and the rigid truncated cone shape intact, p-cyclodextrin is the most preferred cyclodextrin due to its availability and rigidity, which can form a complete set of six intramolecular hydrogen bonds, making it less hydrophilic and more able to encapsulate hydrophobic molecules. To improve hydrophilicity, some or all of the hydroxy groups can be converted into other water-soluble groups.

[0056] The term “modified cyclodextrin”, as used herein, refers to a cyclodextrin containing compound in which one or more hydroxyl groups or hydroxyl hydrogens have been replaced with a group RM, wherein each RMis independently selected from H, Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halogen, -O-(Ci- 8 alkyl), -NH2, -NH(CI-8 alkyl), -N(Ci-s alkyl)2, -SH, -S-(Ci-s alkyl), (Co-3)-carbocyclyl, and (C0-3)- heterocyclyl. The term “modified cyclodextrin”, as used herein, further encompasses two or more cyclodextrins are linked together.

[0057] The term “cyclic biotin”, as used herein, refers to a macrocyclic compound comprising biotin, in particular D-biotin, for example biotin[6]uril, which comprises six D-biotin units. Biotin[6]uril may be formed, for example, by the acid-mediated reaction between D-biotin and formaldehyde in hydrochloric acid, providing biotin[6]uril, wherein the biotin units are connected via methylene bridges (M. Lisbjerg et al., Chem. Sci., 2014, 5, 2647-2650). Macrocycles comprising biotin, in particular D-biotin, are advantageous due to their hydrophilic properties, thus forming strong hydrogen bonds with water molecules. Biotin is also bioavailable, making it well-suited to therapeutic applications and can form complexes with cationic species.

[0058] As used herein, a “crown ether”, refers to a cyclic ether containing at least carbon and oxygen atoms, with two or more carbon atoms between oxygen atoms. Crown ethers are macrocyclic polyether compounds that are capable of selectively forming complexes with a variety of different cationic species. Crown ethers are referred to as “crowns” due to their cyclic structure and their ability to form complexes with cationic species. The crown ether of the present invention is preferably selected from 18-crown-6, dibenzo-18- crown-6, 15-crown-5, 12-crown-4, 4,13-diaza-18-crown-6, 1 ,7-diaza-12-crown-4, dicyclohexano-18- crown-6, 1 -aza-18-crown-6, 4', 4" (5")-di-tertbutyl dicyclo hexano- 18-crown-6, 2-hyd roxy methyl- 18-crown-6, 2-hydroxymethyl-12-crown-4, 2,3-naphtho-15-crown-5, 2-hydroxymethyl-15-crown-5, 4'-amino-5'- nitrobenzo-15-crown-5, 4-tert-butylcyclohexano-15-crown-5, 1 -aza-15-crown-5, 4'-aminobenzo-15- crown-5, 2-aminomethyl-18-crown-6, 1 -aza-12-crown-4, 4'-aminobenzo-18-crown-6, dibenzo-24-crown- 8, 2-aminomethyl-15-crown-5, 4'-aminodibenzo-18-crown-6, benzo-15-crown-5, benzo-18-crown-6, 4'- carboxybenzo-15-crown-5, dibenzo-30-crown-10, dibenzo-21 -crown-7, dibenzo-15-crown-5, 4'- formylbenzo-15-crown-5, 4'-nitrobenzo-15-crown-5, 1 ,10-diaza-18-crown-6, 1 , 10-Dibenzyl-1 , 10-diaza- 18-crown-6, and dinitrodibenzo-18-crown-6. Preferably, the crown ether is 18-crown-6.

[0059] The term “calixarene”, as used herein, refers to macrocyclic oligomers comprising methylene-bridge linked phenols, wherein the methylene bridge is typically in a position ortho to the hydroxy group. The number of aryl groups within a calixarene ring can be between 4 and 20, preferably 4, 5, 6, 7, and 8 aryl groups. The cyclic structure of calix[n]arenes is similar to other polyhydroxylated macrocycles. These compounds have a three-dimensional cavity that can accommodate host molecules during host-guest complexation and is likened to a synthetic receptor; the macrocycle cavity size will depend on the number of aromatic units in the system and also determines the size of guest molecule that can be accommodated. Calixarenes have different conformational isomeric forms, which allow different uses and applications. For instance, the calix[4]arenes can adopt several different conformers, including the cone, partial cone, 1 ,2-alternate, and 1 ,3-alternate structures. In the rigid cone conformation, all the phenolic -OH groups form strong hydrogen bonds that stabilize the structure. Calixarenes may be functionalized with one or more substituents, for example, by reaction of the hydroxy group or para to the hydroxy group. The calixarenes of the present invention further include oxacalixarenes, azacalixarenes, silicacalixarenes and thiacalixarenes, which contain one or more oxygen, nitrogen, silicon or sulfur bridges, respectively, between phenolic groups, as well as calixarene compounds having one or more platinum bridges. Preferred calixarenes of the present invention may be selected from calix[4]arenes, calix[6]arenes, and calix[8]arenes. The term “porphyrin”, as used herein, refers to heterocyclic macrocycles composed of four pyrrole units, typically, but not necessarily, interconnected via methine bridges (=CH— ) at their a-position (or meso position). The most common porphyrin compounds include heme, a naturally occurring compound comprising protoporphyrin IX complexed with iron, as well as chlorophylls, and bacteriochlorophylls. Unsubstituted porphyrins are typically hydrophobic molecules and may be substituted to improve hydrophobicity.

[0060] The term “pillararene”, as used herein, refers to refers to macrocyclic oligomers comprising methylene- bridge linked hydroquinone and / or dialkoxybenzene units, wherein typically one of the hydroxy or alkoxy groups is ortho and the other hydroxy or alkoxy group is meta to the methylene bridge. The number of aryl groups within a pillararene ring can be between 4 and 20, preferably 4, 5, 6, 7, and 8 aryl groups. The cyclic structure of pillar[n]arenes is similar to other polyhydroxylated macrocycles. These compounds have a three-dimensional cavity that can accommodate host molecules during host-guest complexation and is likened to a synthetic receptor; the macrocycle cavity size will depend on the number of aromatic units in the system and also determines the size of guest molecule that can be accommodated. Pillararenes have different conformational isomeric forms, which allow different uses and applications. Pillararenes may be functionalized with one or more substituents, for example, by reaction of one or both of the hydroxy and / or alkoxy groups. Preferred pillararene of the present invention may be selected from pillar[5]arenes, pillar[6]arenes, and pillar[7]arenes.

[0061] The term “corrole” as used herein, refers to heterocyclic macrocycles composed of four pyrrole units, typically, but not necessarily, interconnected via methine bridges (=CH— ) at their a-position (or meso position). The ring typically consists of nineteen carbon atoms, with four nitrogen atoms in the core of the molecule. In this sense, corrole is very similar to porphyrin, however, corroles are triprotic, whereas porphyrins are diprotic. Corroles of the present invention may be substituted with one or more substituents, or unsubstituted.

[0062] The term “phthalocyanine” as used herein, refers to heterocyclic macrocycles composed of four isoindole units typically, but not necessarily, interconnected via nitrogen atoms. “Phthalocyanine” of the present invention may be substituted with one or more substituents, such as halogens, hydroxyl, amine, alkyl, aryl, thiol, alkoxy and nitrosyl groups, or unsubstituted. The term “phthalocyanine” as used herein, also refers to substituted or unsubstituted derivatives where one or more ring atom has been replaced with another atom, such as tetrapyrazinoporphyrazine.

[0063] The term “cucurbituril” as used herein, refers to macrocyclic molecules made of glycoluril (=C4H2N4O2=) monomers linked by methylene bridges, wherein each monomer is linked by two methylene bridges which are attached via the two glycoluril nitrogen atoms. The oxygen atoms are located along the edges of the band and are tilted inwards, forming a partly enclosed cavity, which can effectively accommodate various guest unit molecules. The interaction between cucurbituril and guest unit molecules is very strong, and stable complexes can be formed with guest molecules through hydrogen bonds and hydrophobic effects. Cucurbituril is named Cucurbit[n]uril according to the number of glycoluril units it contains, abbreviated as CB[n], The main products include CB[5], CB[6], CB[7], CB[8], and CB

[0010] .

[0064] The term “macrocyclic peptide” as used herein, refers to refers to a peptide molecule that contains at least one ring formed by interconnected amino acids comprised in the molecule. The macrocyclic peptide may refer to a peptide comprising a macrocyclic structure of three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more amino acids. The ring structure can be formed by binding two amino acids directly or via a linker. The macrocyclic peptide or macrocycle can comprise one, two, three, four, five, or more rings.The macrocyclic peptides of the disclosure may be glycosylated. The macrocyclic peptides may one or more contain non-canonical amino acids. Macrocyclic peptides of the present invention may be substituted with one or more substituents, or unsubstituted.

[0065] The term “macrocyclic glycopeptide” as used herein, refers to macrocyclic peptide as defined hereinabove albeit wherein one or more amino acid and / or linker unit is glycosylated. Non-limiting examples of macrocyclic glycopeptides are vancomycin, teicoplanin, telavancin, ramoplanin, avoparcin, and corbomycin. Macrocyclic glycopeptides of the present invention may be substituted with one or more substituents, or unsubstituted.

[0066] The term “carbohydrate containing macrocycle” as used herein, refers to any macrocycle comprising one or more carbohydrate units, wherein the carbohydrate units (if there are several) can be attached directly to each other or connected via a linker. Non-limiting examples of carbohydrate containing macrocycles are Ipomomeassin F, glucolipsin A, forsytheenthoside A, clemahexapetoside A, clemahexapetoside B, clemoarmanoside A and tricolorin A. The carbohydrate may be a saccharide.

[0067] The term “macrocyclic lactone” as used herein, refers to a macrocyclic ring comprising at least one ester functionality as part of said ring. Macrocyclic lactones of the present invention may be macrolides, which are macrocyclic lactone rings to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Further macrocyclic lactones such as avermectins according to the present invention include, but are not limited to, ivermectin, doramectin, abamectin, milbemycin, and moxidectin.

[0068] The term “macrocyclic drug” as used herein, refers to a drug or medicament that comprises one or more macrocyclic moieties such as for example, but not limited to, a cyclodextrin, a macrocyclic peptide or a macrocyclic lactone. Non-limiting examples of such macrocyclic drugs are bacitracin, dactinomycin, geldanamycin, azithromycin, vancomycin, clarithromycin, roxithromycin, telithromycin, dirithromycin, carbomycin, josamycin, kitasamycin, midecamycin, oleandomycin, solithromycin, spiramycin, leucomycin, amphotericin B, simeprevir, lorlatinib, epothilone B, alisporivir, pacritinib, grazoprevir, paritaprevir, glecaprevir, sanglifehrin A, and cyclosporine. The term “macrocycle-based PROTAC” as used herein, refers to a PROTAC comprising at least one acrocyclic moieties such as for example, but not limited to, a cyclodextrin, a macrocyclic peptide or a macrocyclic lactone. The term “PROTAC” stands for proteolysis targeting chimera and refers to a bifunctional small molecule composed of two active domains and a linker. A term “PROTAC” can typically rely on the ubiquitin-proteasome system to degrade the target protein, which induces ubiquitination by utilizing a ligase (such as an E3 ligase) and degrades the protein of interest. PROTAC compounds are generally designed to have three parts: 1) a ligand / molecule that binds to and / or regulates a ubiquitin ligase; 2) a small molecule that binds to the target protein of interest for proteolysis; and 3) a linker that connects the two molecules together. Therefore, a PROTAC works by allowing the ligand / molecule to bind to the ubiquitin ligase, thereby recruiting the target of the protein of interest to the ligase for ubiquitination and ultimately proteolysis and degradation.

[0069] In the context of the present invention, each negatively charged substituent (such as -(CH2)y2-SO3 may be present in combination with a positive counter ion of equal charge. The presence of multiple singly charged ions or substituents in combination with one more oppositely charged ions or substituents of higher charge (such as, for instance, 2 -(CH2)y2-SO3- substituents being combined with a single Ca2+counter ion) is equally part of the present invention. Such counter ions can be organic or inorganic. Such counter ions are, for example, selected from a proton, an alkali metal (such as Li+, Na+, K+, Rb+and Cs+), a transition metal (such as Ag+, Cu+, Cu2+, Zn2+, Mn2+, Ni2+, Co2+, Fe2+, Fe3+, or Al3+), an alkaline earth metal (e.g. Be2+, Ca2+or Mg2+), ammonium (including NH and tetraalkylammonium), an amine derived cation and a positively charged heterocycle (such as pyridinium or imidazolium). The presence of two or more different counter ions within a single compound are also included in the scope of the invention.

[0070] In a preferred embodiment, each of the counter ions present in the compound of the invention is either Na+or K+. For example, each instance of the substituent -(CH2)y2-SO3- may be present in combination with one Na+ion (i.e. as -(CH2)y2-SO3 Na+or -(CH2)y2-SO3Na) or each instance of the substituent -(CH2)y2- SO3- may be present in combination with one K+ion (i.e. as -(CH2)y2-SO3’K+or -(CH2 2-SO3K). Mixtures of Na+and K+counter ions, wherein some substituents of a given compound are paired with a Na+ion, while other substituents of the same compound are paired with a K+ion, are also possible.

[0071] In a more preferred embodiment, each of the counter ions present in the compound of the invention is Na+. For example, each instance of the substituent -(CH2)y2-SO3- may be present in combination with one Na+ion (i.e. as -(CH2)y2-SO3 Na+or -(CH2)y2-SO3Na).

[0072] Preferably, the compound according to the invention comprising the macrocyclic core has at least one moiety L, which is attached to the macrocyclic core, wherein the moity L is a moiety of the formula (I):

[0073] The inventors of the present invention have surprisingly found that macrocyclic compounds comprising at least one moiety L of formula (I) attached thereto are able to mimic sialic acid groups, thus acting as an attachment inhibitor for viruses which bind to said groups. As can be seen from the appended examples, compounds comprising a macrocyclic core and at least one moiety L attached thereto show antiviral and / or virucidal activity and have been demonstrated against clinical isolates, in particular of parainfluenza virus (PIV) without resulting in resistance. The inventors further surprisingly found that the compounds have broad spectrum activity, for example, high efficacy was found for Avian flu A (H5N1 IAV) as well as PIV3. Furthermore, the compounds of the invention are effective in limiting infection in a human upper respiratory model, thereby demonstrating their high clinical relevance, displaying high potency and limited cytotoxicity. These properties render the compounds provided herein outstandingly well-suited for use as an antiviral and / or virucidal agent, thus allowing for the treatment and / or prevention of a viral infectious disease.

[0074] The inventors of the present invention have further surprisingly found that macrocyclic compounds comprising at least one moiety L of formula (I) and at least one moeity comprising SO3- attached thereto are able to mimic sulfonated / sulfated groups, such as heparan sulfate, and / or sialic acid groups, thus acting as an attachment inhibitor for viruses which bind to said groups. Such macrocyclic compounds were further found to have broad spectrum activity, with high efficacy for Avian flu A (H5N1 IAV), PIV3 as well as Respiratory Syncytial Virus (RSV).

[0075] The term “attached to the macrocyclic core”, or grammatical variations thereof, as used herein, refers to the direct or indirect linkage of the at least one moiety L of formula (I) to the macrocyclic core. The linkage is not particularly limited and may be via covalent, ionic or electrostatic linkage. Indirect linkage of the at least one moiety L of formula (I) refers to the linkage of the moiety L to the macrocyclic core via a linker moiety (commonly referred to as a spacer group). In the present invention, the linker moiety forms a covalent, ionic or electrostatic bond with both the moiety L and the macrocyclic core. The linker group may, in principle, be any chemical group which is capable of forming bonds with both the moiety L of formula (I) and the macrocyclic core. Preferably, the linker group contains only atoms selected from H, B, C, N, 0, F, Si, P, S, Cl, Br and I. Exemplary linker moieties include, but are not limited to, an optionally substituted -Ci-30-alkylene-, -C(0)-, -N(R1)-, -C(0)-, -0-, -heteroarylene-, -phenylene-, -S-, -S(0)- and -S(0)2-. Preferably the linker moiety is a linear optionally substituted -(C1-30 alkylene)- group, wherein one or more -CH2- units in said alkylene are optionally replaced by a group independently selected from - CONH-, -NHCO-, -0-, -NH-, -N(Ci-6 alkyl) -CHR1-, -C(R1)2-, -CO- -S-, -SO- -SO2- or -(C3-6 cycloalkylene)-; wherein each R1is independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alky nyl, C1-6 haloalkyl, -OH, -O(Ci-6 alkyl), -C(O)Ci-6 alkyl, -ON, -NH2, -NH(CI-6alkyl) and -N(CI-6alkyl)(Ci- 6 alkyl).

[0076] In some embodiments, the invention relates to the compound comprising a macrocyclic core and at least one moiety L of formula (I), further comprising a linker moiety between the macrocyclic core and the at least one moiety L of formula (I). In further embodiments, the linker moiety is preferably:

[0077] (i) -(Cs-14 alkylene)-CONH-(C2-5 alkylene)-L;

[0078] (ii) -(Cs-14 alkylene)-NHCO-(Ci-io alkylene)-L; or

[0079] (iii) -(Cs-14 alkylene)-NH-(C2-5 alkylene)-L.

[0080] More preferably, the linker moiety is:

[0081] (i) -(C10-12 alkylene)-CONH-(C2-5 alkylene)-L;

[0082] (ii) -(C10-12 alkylene)-NHCO-(C2-5 alkylene)-L; or

[0083] (iii) -(C6-10 alkylene)-NH-(C2-5 alkylene)-L.

[0084] Even more preferably, the linker moiety is -(C11 alkylene)-CONH-(Cs alkylene)-L, having the formula:

[0085] In some embodiments, the at least one moiety L of formula (I) is attached to the macrocyclic core via a direct covalent or electrostatic linkage, more preferably via direct covalent linkage. Direct linkage of the at least one moiety L of formula (I) to the macrocyclic core means the moiety is directly linked, i.e., without a linker moiety.

[0086] The term “attachment inhibitor”, or grammatical variations thereof, as used herein, refers to a compound that interferes with the interaction and attachment of a virus with an attachment receptor on the host cell. Preferably, the attachment inhibitor of the present invention prevents the virus from entering the host cell. Within the meaning of the present invention, the attachment inhibitor preferably mimics sulfonated / sulfated (7” refers to “or”) groups and / or sialic acid groups, thereby interfering with the of viruses which bind to said groups.

[0087] Sulfonated / sulfated groups are ubiquitous in cells and are biosynthesized within organisms, for example, by a 3'-phospoadenosine 5'-phosphosulfate synthase 1 (PAPSS1) mediated reactions which transfer sulfonate groups (SO3 ) from 3'-phospoadenosine 5'-phosphosulfate (PAPS) to hydroxyl or amino groups. The reaction catalysed by PAPPS1 occurs in the nucleus, whereas the same reaction in the cytoplasm is catalysed by PAPPS2. Cytosolic PAPS can be transported to the Golgi apparatus via the PAPS translocase, where tyrosine sulfation of proteins and sulfo-conjugation of polysaccharides occur. Sulfonated / sulfated molecules, such as heparan sulfates (HSs), may be secreted to the extracellular matrix or attached to cell surface proteins. Sulfonated / sulfated groups play an important role in viral infections, in particular the polysaccharide heparan sulfate, that is produced by virtually all cells. Heparan sulfate is part of the glycosaminoglycan family, which also includes heparin, HS and heparin are highly anionic molecules which differ in their levels and positions of sulfation, but also in their glucuronic acid (GlcA) and iduronic acid (IdoA) content and location. Both contain variable levels of sulfation on the glucosamine residues at carbons 2 and 6 (and rarely 3), while the N-positions of glucosamines can be modified with either a sulfate or an acetate (and sometimes a free amino group). Heparin tends to be a more heavily sulfated molecule (average of ~2.6 sulfates per disaccharide) with L-ldoA predominating over D-GIcA (~9 : 1), whereas HS is more heterogeneous with fewer negative charges per disaccharide (typically ~1-2 sulfates per disaccharide unit) and with d-GIcA predominating. These differences have been related to the protein interactions and the regulatory functions of heparin and HS. HSs are often attached to proteins forming heparin sulfate proteoglycans (HSPGs) at the cell surface or in the extracellular matrix (ECM). The basic structure comprises alternating hexuronic acid (D-glucuronic acid (GlcA) or L-iduronic acid (IdoA)) and D-glucosamine (GlcN) units. The carbohydrate backbone is constructed as a polymer and then modified by a series of enzymes including glycosyltransferases, 0- sulfotransferases, and an epimerase in the Golgi apparatus to form the final structure. HSPGs are structurally diverse, with great variability in their chain lengths and sulfation patterns. This gives rise to an immense number of HS species that can bind different proteins such as chemokines, growth factors, and enzymes and serve a variety of functions including immobilization, protection from proteolytic cleavage, as well as roles in embryonic development, angiogenesis, cell adhesion, blood coagulation, and lipid metabolism. HS typically comprises one or more negative charges which interact with positively charged viral proteins, thus promoting the initial interaction between the virus and host cell. To date, HSs are known to be involved in, at least 16, different types of viral infections (Liu, J. and Thorp, S.C., Med. Res. Rev., 2002, 22, 1-25). Accordingly, in some embodiments, the compound of the invention comprising a macrocyclic core and at least one moiety L of formula (I) which is attached to the macrocyclic core, preferably mimics (a) sulfonated / sulfated group(s) that are involved viral infection. The sulfonated / sulfated group may be any group which comprises a sulfonate group (-SO3 ), preferably the sulfonated group is selected from heparan sulfate, chondroitin sulfate, dermatan sulfate and keratan sulfate, preferably the sulfonated / sulfated group is heparan sulfate and / or heparan octasaccharide. Heparan octasaccharide is similar to heparan sulfate and has been found by the inventors of the present invention to be a glycan that is bound by PIV3. The term “sulfated group” as used herein, also refers to a group comprising the -SO3- and is thus used interchangeably with the term “sulfonated group”, as previously described. The term “sulfonated” and “sulfated” used herein are also used interchangeably with the term “sulfonate” and “sulfate”, respectively.

[0088] The term "heparan sulfate" or the abbreviation "HS", as used herein, refers to a polysaccharide made up of repeated disaccharide units D-glucuronic acid (GlcA) or L-iduronic acid (IdoA) linked to N-acetyl or N- sulfated D-glucosamine. The polysaccharide is modified to a variable extent by sulfation of the 2-0- position of GlcA and IdoA residues, and the 6-0-and 3-0-positions of GlcN residues and acetylation or de-acetylation of the nitrogen of GlcN residues. Therefore, this definition encompasses all of the glycosaminoglycan compounds variously referred to as heparan(s), heparan sulfate(s), heparin(s), heparin sulfate(s), heparitin(s), heparitin sulfate(s), heparanoid(s), heparosan(s). The sulfonated / sulfated groups may be pure glycosaminoglycans or can be linked to other molecules, including other polymers such as proteins, and lipids, or small molecules such as biotin. An exemplary structure of heparan sulfate is shown hereinbelow, however the person skilled in the art is aware of the various heparan sulfate structures that the compounds of the invention can mimic in order to bind to a virus that causes a viral infectious disease.

[0089] Sialic acid groups are also important for the binding of certain viruses as they are comprised on host cell receptors, for example, viruses of the family Paramyxoviridae including parainfluenza virus (PIV such as PIV1 , PIV2, PIV3, PIV4), influenza virus, and viruses of the Coronaviridae family interact with sialic acid during their life cycle. For Paramyxoviridae viruses, two cell surface glycoproteins, hemagglutininneuraminidase protein and fusion protein are typically involved in the initial steps of viral-cell interactions. Hemagglutinin-neuraminidase protein comprises a sialic acid binding site, which promotes membrane fusion of the virus. For example, PIV3, the clinically most prevalent PIV subtype, recognizes a2,3-linked sialic acids in branched and unbranched polysaccharides present on either glycoproteins or glycolipids (including gangliosides), which initiates infection. Sialic acid present on either glycoproteins or glycolipids are typically, but not necessarily, linked via a a2, 3-linkage or a2,6-linkage at the terminal position. An a2, 3 glycosidic linkage refers to a glycosidic linkage where the carbon atom at the C2-position of the sialic acid hexose is linked, via an oxygen atom, to the C3-position of the hexose of, for example, galactose as part of a glycan. The specificity of the linkage is naturally achieved, by, e.g., by sialyltransferase enzymes and may be cleaved by neuraminidase. In natural glycoconjugates, sialic acids are typically, but not necessarily, a2-3- or a2-6-linked to D-galactose (Gal) and N-Acetyl-D-galactosamine (GalNAc), a2-6- linked to N-Acetyl-D-glucosamine (GIcNAc), or a2-8-linked to the second Sialic acid moiety. Recognition of various sialic acid residues may differ between virus families and within the same family, for example, human influenza viruses preferentially bind to a2-6-li nked sialic acids (e.g., N-acetyl-D-neuraminic acid 2-6-D-galactose (Neu5Aca2-6Gal)), whereas avian influenza viruses preferentially recognize a2-3-linked sialic acids (e.g., N-acetyl-D-neuraminic acid 2-3-D-galactose (Neu5Aca2-3Gal)). Accordingly, in some embodiments, the compound of the invention comprising a macrocyclic core and at least one moiety L of formula (I) which is attached to the macrocyclic core, preferably mimics (a) sialic acid group(s) involved viral infection. The sialic acid group (also referred to as neuraminic acid (5-amino-3,5-dideoxy-D-g / ycero- D-ga / acfo-non-2-ulosonic acid), such as N-acetylneuraminic acid (Neu5Ac or NANA)) may be any amino sugar having a N-acetylated, N-glycosyl ated, or O-acetylated chemical structure of neuraminic acid, which is an aldol condensation product of pyruvic acid with mannosamine (2-amino-2-deoxy-mannose). The sialic acid groups may be a part of other molecules, including other polymers such as proteins, and lipids, or small molecules such as biotin. Preferably, the compounds of the invention mimic a sialic acid group that is a part of a polymer, more preferably a protein or lipid. Moreover, the sialic acid group may be LS- tetrasaccharide D (LSTd), an n-acylneuraminic acid, 3'sialyl-N-acetyllactosamine (3’SLN). The structure of LSTd is provided hereinbelow.

[0090] Provided hereinbelow is the structure of neuraminic acid (Neu), wherein the 0- or N- acetylated or substituted derivatives (substituted with e.g., phosphate, sulfate, alkyl, such as methyl, lactyl groups) are the most common forms of sialic acids. More than 50 derivatives of sialic acids have been reported, with the two most commonly expressed being Neu5Ac and Neu5Gc followed by KDN (2-keto-3-deoxy-nononic acid) and Neu (S. Ghosh, “Sialic Acids and Sialoglycoconjugates in the Biology of Life, Health and Disease”, 2020, Pages 1-61 ). Alpha 2,3 and a2,6 linked sialic acid groups are typically found to be comprised on glycans that are found on ciliated epithelial cells, for example, on human respiratory epithelium including on some epithelial cells of the lower respiratory tract.

[0091] In some embodiments, the compound of the invention comprising a macrocyclic core and at least one moiety L of formula (I) which is attached to the macrocyclic core, preferably mimics (a) sialic acid group(s) involved viral infection, preferably wherein the sialic acid group is a part of a glycan, particularly a glycoprotein, glycolipid, or proteoglycan. In specific embodiments, the compound of the invention comprising a macrocyclic core and at least one moiety L of formula (I) which is attached to the macrocyclic core, preferably mimics (a) sialic acid group(s) involved viral infection, wherein the sialic acid group comprises a sialic acid group bound via a 2,3- or 2,6- or 2, 8-glycosidic linkage, preferably a 2,3-linkage, particularly an a2,3- ,a2,6- or a2, 8-glycosidic linkage, preferably an a2,3-glycosidic linkage.

[0092] In some embodiments, the compound of the present invention comprising a macrocyclic core and at least one moiety L of formula (I) which is attached to the macrocyclic core, preferably mimics (a) sulfonated / sulfated group(s) and or sialic acid group(s) that are involved viral infection. Mimicking of sulfonated / sulfated group(s) may, for instance, be achieved by the presence of one or more moieties comprising SOr, e.g. if at least one R is -(CH2)y2-SO3’. The viral infection may be any virus which interacts with a sulfonated / sulfated group and / or sialic acid group during its lifecycle, these include, but are not limited to, Paramyxoviridae family (such as PIV1 , PIV2, PIV3, PIV4, Nipah, Hendra virus or mumps), Orthomyxoviridae (such as influenza A virus H5N 1 , H1 N1 or H3N2 or influenza B virus), Pneumoviridae (such as Respiratory Syncytial Virus (RSV) and Human Metapneumovirus), Coronaviridae (such as SARS-CoV-2, MERS-CoV, Human Coronavirus OC43), Herpesviridae (such as Herpes Simplex Virus (HSV) 1 , HSV2, cytomegalovirus), Caliciviridae (such as norovirus), Reoviridae (such as rotavirus), Papillomaviridae, Polyomaviridae, Adenoviridae and Flaviviridae (such as Zika virus, Dengue virus, West Nile Virus and Tick Borne Encephalitis Virus), Poxviridae (such as Monkeypox).

[0093] The term “mimics”, as used herein, refers to a compound which has substantially the same structural and / or functional characteristics as the reference molecule (e.g., sulfonated / sulfated group such as heparan sulfate and / or a sialic acid group such as an N-acetylated, N-glycosylated, or O-acetylated amino sugar, such as neuraminic acid). For example, a “heparan sulfate mimic” exhibits similar structural and / or functional (e.g., acts as a viral receptor) features as heparan sulfate.

[0094] In some embodiments, the compound of the invention is a compound wherein the macrocyclic core is selected from a-cyclodextrin, p-cyclodextrin and y-cyclodextrin, preferably wherein the macrocyclic core is p-cyclodextrin.

[0095] CD’s are naturally occurring compounds that are often used as solubilising, taste-masking and / or stabilising agents in various drug formulations (e.g., solid oral dosage forms and injectables); they are safe for ingestion because they are practically not absorbed from the gastrointestinal (Gl) tract. Two of the native cyclodextrins, a-CD and 0-CD, can display renal toxicity and should thus not be administered directly into the bloodstream. The physicochemical properties of CD’s make it an ideal candidate for pharmaceutical applications, where it may be modified to bear further useful functional groups. CD’s have already been used in combination with antiviral drugs, such as Acyclovir (i.e., 9-((2-hydroxyethoxy)- methyl)-guanine), Ganciclovir (9-[1 ,3(dihydroxy)-2-(propoxy)-methyl]guanine), Efavirenz ((S)-6-chloro-4- (cyclopropylethynyl)-1,4-dihydro-4-(trifluoro-methyl)-2H-3,1-benzoxazin-2-one), Rilpivirine, Saquinavir, Lopinavir, Oseltamivir (Tamiflu™) and Remdesivir, to improve the solubility and bioavailability of the drug, typically via inclusion of the drug or part thereof within its hollow interior. 0-CD is the most preferred cyclodextrin due to its widespread availability and rigidity, which can form a complete set of six intramolecular hydrogen bonds.

[0096] It was surprisingly found by the inventors of the invention that a compound comprising an a-cyclodextrin, P-cyclodextrin or y-cyclodextrin macrocyclic core, preferably a p-cyclodextrin macrocyclic core, and at least one moiety L of formula (I) attached to said macrocyclic core is an effective antiviral and / or virucidal agent. The moiety L of formula (I) is a bio-mimetic of cell receptor sialic acid group(s). Cell sialic acid receptors play an important in the very first step of viral infection and enable the fusion of the virus with the cell membrane. Accordingly, by designing a sialic acid receptor mimetic, the inventors of the present invention have found that the compounds of the invention are able to act as an attachment inhibitor for sialic acid binding viruses, displaying virucidal and / or antiviral properties. The virucidal activity of the compounds of the invention is irreversible and is likely due to the strong interaction of the compound and virus which generates local viral deformation leading to irreversible viral mutations and possibly even viral disassembly. The strong interaction of the compounds of the invention is likely due to the fact that the moiety L of formula (I) is a long sialic acid terminated molecule which is sterically unhindered and thus may bind to the virus. The preferred structures of the macrocyclic core, preferably selected from a- cyclodextrin, p-cyclodextrin and y-cyclodextrin, more preferably wherein the macrocyclic core is 0- cyclodextrin, comprising at least one moiety L of formula (I) is:

[0097] As used herein, the term "virucidal" refers to the neutralization and / or deactivation and / or destruction of a virus such that it is unable to infect a host cell. Interaction with virucidal compounds alters the virus, rendering it inert, and thereby prevents further infections. The term “antiviral”, as used herein, refers to a compound that is effective in directly or indirectly interfering with at least one viral action selected from the group consisting of virus penetration of eukaryotic cells, virus replication in eukaryotic cells, virus assembly, virus release from infected eukaryotic cells, or that is effective in non-specifically inhibiting a virus titer increase or in non-specifically reducing a virus titer level in a eukaryotic or mammalian host system. It also refers to a compound that prevents or reduces the likelihood or risk of getting a viral infection.

[0098] An advantage of the present invention is the provision of multivalent attachment inhibitors that are capable of strongly binding to a virus thereby preventing viral cell infection. Non-multivalent attachment inhibitors, i.e., monovalent attachment inhibitors, have the risk that they may not bind as strongly and thus the interaction with the virus may be reversible, in particular when diluted by bodily fluids, and result in weak inhibition and only antiviral activity. However, it is also important to maintain an optimal number of moieties, e.g., moiety L of formula (I), that are capable of binding the virus, as having too many may result in steric hindrance of the viral-attachment inhibitor interaction. The inventors of the present invention have that compounds of the invention optimally have up to 2, up to 3, up to 4, or up to 5 moieties L of formula (I), for example, in some embodiments the compound of the invention may have the following structure: wherein, m is 1 , 2, 3, 4, 5, 6 or 7, q is 1 , 2, 3, 4, or 5 and n is 1 , 2, 3, 4 or 5; R is independently selected from -(CH2)y2-SO3-, -(CH2)y2-COOH and -(CH2)y2-CONHCH2CH2SO3H; and R’ and R” are as defined hereinabove. In preferred embodiments, q and m together comprise up to 6, 7 or 8 glucose units, preferably up to 7 glucose units. In further preferred embodiments, q is 1 , 2, or 3 glucose units and n is 1 , 2, 3.

[0099] The interaction of the compounds of the invention and virus may be any interaction, including but not limited to ionic interaction, electrostatic interaction, hydrophobic interaction, hydrophilic interaction, covalent interaction. Preferably, the interaction of the compounds of the invention and a virus is an ionic interaction.

[0100] In some embodiments, the compound of invention is represented by formula (II): wherein x is 6, 7 or 8; each occurrence of each R’ and R” is independently selected from H, -(CH2)yi-C00H, and -(CH2)yi-SO3H, wherein each occurrence of y1 is independently an integer from 4 to 20; each occurrence of R is independently selected from -(CH2)y2-SO3-, -(CH2)y2-NH-(CH2)y3-L, -(CH2)y2- COOH, -(CH2)y2-CONH-(CH2)y3-L, and -(CH2)y2-CONHCH2CH2SO3H; each occurrence of Z is independently selected from -S-, -NH-, -N(Ci-s alkyl)-, -NH-C(=O)-, -N(Ci-s alkyl)- C(=0)-, -C(=O)-NH-, -C(=O)-N(CI-8 alkyl)-, -0-C(=0)-, -C(=0)-0-, -C(=0)-, and -0-; each occurrence of Y2 is independently an integer from 8 to 14; each occurrence of y3 is independent an integer from 2 to 5; provided that at least one R is either -(CH2)y2-NH-(CH2)y3-L or -(CH2)y2-CONH-(CH2)y3-L, preferably wherein at least one R is -(CH2)y2-NH-(CH2)y3-L; or a pharmaceutically acceptable salt thereof.

[0101] Preferably, the compound of the invention is a compound of formula (II) wherein x is 7.

[0102] Compounds of the invention having the formula (II), wherein x is 7, is a compound comprising 0- cyclodextrin as the macrocyclic core.

[0103] In further embodiments, the invention relates to a compound of formula (II), wherein each R’ is H and / or wherein each R” is H.

[0104] Moreover, in some embodiments, the invention is a compound of formula (II), wherein each occurrence of y2 is an integer from 6 to 10. Preferably, wherein each occurrence of y2 is 8.

[0105] In some embodiments, the invention is a compound of formula (II), wherein each occurrence of y3 is independent an integer from 2 to 4, preferably wherein each occurrence of y3 is 4.

[0106] In some embodiments, the invention is a compound of formula (II), wherein each occurrence of Z is independently selected from -S-, -NH-, N(CI-3 alkyl)-, and -O-, preferably wherein each occurrence of Z is S.

[0107] In preferred embodiments, the invention relates to a compound of formula (II), wherein the compound includes from 1 to 3 moieties L.

[0108] In some embodiments, the invention relates to a compound of formula (II), wherein at least one R is - (CH2)8-NH-(CH2)4-L, preferably wherein exactly one R is -(CH2)s-NH-(CH2)4-L and each of the remaining instances of R is -(CH2)s-SO3-.

[0109] Accordingly, the compounds of the invention preferably have the following formula: wherein, n is 1 , 2, 3, 4 or 5, preferably n is 1 , 2, or 3, more preferably n is 1 ; q is 1, 2, 3, 4 or 5, preferably q is 1 , 2, or 3, more preferably q is 1 ; m is 1 , 2, 3, 4, 5, 6 or 7, preferably m is 2, 3, 4, 5 and 6, more preferably m is 4, 5 or 6, even more preferably m is 6ln some embodiments, q and m together comprise 7 glucose units.

[0110] The inventors surprisingly found that the compound of the invention comprising p-cyclodextrin as the macrocyclic core, includes from 1 to 5 moieties L, preferably from 1 to 3 moieties L, wherein at least one R is -(CH2)y2-SO3’ is beneficial against as an antiviral and / or virucidal agent, particularly against a virus that binds to sialic acid and / or a sulfonated / sulfated group(s), selected from Paramyxoviridae family (such as PIV1 , PIV2, PIV3, PIV4, Nipah, Hendra virus or mumps), Orthomyxoviridae (such as influenza A virus H5N1 , H1 N1 or H3N2 or influenza B virus), Pneumoviridae (such as Respiratory Syncytial Virus and Human Metapneumovirus), Coronaviridae (such as SARS-CoV-2, MERS-CoV, Human Coronavirus OC43), Herpesviridae (such as Herpes Simplex Virus (HSV) 1 , HSV2, cytomegalovirus), Caliciviridae (such as norovirus), Reoviridae (such as rotavirus), Papillomaviridae, Polyomaviridae, Adenoviridae and Flaviviridae (such as Zika virus, Dengue virus, West Nile Virus and Tick Borne Encephalitis Virus) and Poxviridae (such as Monkeypox). As can be seen from the appended examples, the combination of moiety L of formula (I) and -(CH2)y2-CONHCH2CH2SO3H on the same p-cyclodextrin macrocyclic core have broad spectrum activity against various viruses due to the presence of both ligands which mimic sialic acid and sulfonated / sulfated group(s) to which numerous viruses bind to sialic acid and / or sulfonated / sulfated group, in particular a sialic acid(s) and / or sulfonated / sulfated group(s) for cell entry. In particular, the compounds showed potent antiviral and / or virucidal activity against Paramyxoviridae family (such as PIV1 , PIV2, PIV3, PIV4, Nipah, Hendra virus or mumps) of viruses, more particularly PIV3, Influenza A H1 N1 , RSV and SARS-CoV-2. The appended examples show that a higher potency can be observed for the p-cyclodextrin comprising the combination of moiety L of formula (I) and -(CH2)y2-CONHCH2CH2SO3H compared to p-cyclodextrin comprising at least one moiety L of formula (I) against 2017 PIV3 (ECso 14.4 pg / mL compared to 65.9 pg / mL) and a similar potency against 2021 PIV3 (ECso 27.6 pg / mL compared to 38.3 pg / mL). They further demonstrate that an even higher potency was observed for the p-cyclodextrin comprising the combination of moiety L of formula (I) and -(CH2)y2-SO3- compared to p-cyclodextrin comprising at least one moiety L of formula (I) against 2017 PIV3 (ECso 0.19 pg / mL compared to 65.9 pg / mL) and a similar potency against 2021 PIV3 (ECso 0.6 pg / mL compared to 38.3 pg / mL). Preferably, the invention relates to the compound of formula (II), wherein the compound of formula (Ila): or a pharmaceutically acceptable salt thereof, wherein x, Z, R, R’ and R” are as defined herein above. In some embodiments, the compounds of formula (Ila) are compounds having the following formula: wherein, n is 1 , 2, 3, 4 or 5, preferably n is 1 , 2, or 3, more preferably n is 1 ; q is 1, 2, 3, 4 or 5, preferably q is 1 , 2, or 3, more preferably q is 1 ; m is 1 , 2, 3, 4, 5, 6 or 7, preferably m is 2, 3, 4, 5 and 6, more preferably m is 4, 5 or 6, even more preferably m is 6ln some embodiments, q and m together comprise 7 glucose units.

[0111] The present invention further relates to a composition, particularly a pharmaceutical composition comprising the compound as described hereinabove and a pharmaceutically acceptable carrier. Moreover, the invention relates to a compound as described hereinabove or the composition or pharmaceutical composition thereof for use as a medicament.

[0112] Moreover, the present invention relates to the compound, composition or pharmaceutical composition of the invention for use in treating or preventing a viral infectious disease.

[0113] The terms “viral infectious disease” and “disease or disorder caused by a virus”, or grammatical variations thereof, as used herein, refers to diseases which are associated with viral infection. The viral infection may occur in animals, including mammals such as humans and / or plants. Viral infection may result in symptoms or be asymptomatic (i.e., no signs of overt symptoms) or to severe disease. Accordingly, in some embodiments, the invention relates to the compound, composition, or pharmaceutical composition of the invention for use in treating and / or preventing a viral infection. The viral infection may be symptomatic or asymptomatic. In embodiments of the invention, wherein the compound, composition or pharmaceutical composition of the invention is for use in treating a viral infectious disease, the invention preferably provides relief of symptoms associated with the viral infection or amelioration of the viral infection. The viral infection and / or viral infectious disease may be caused by DNA or RNA viruses and is not particularly limited.

[0114] In preferred embodiments, the invention relates to a compound, composition or pharmaceutical composition for use in treating and / or preventing a viral infectious disease, wherein the viral infectious disease is caused by a virus that binds to sialic acid and / or (a) sulfonated / sulfated group(s), such as neuraminic acid and / or heparan sulfate, particularly heparan octasaccheride, preferably wherein said virus is a respiratory virus, sexually transmitted virus or vector transmitted virus.

[0115] The term “respiratory virus”, as used herein, refers to a virus that is transmitted via the respiratory route, for example during sneezing, coughing, talking or barking or via direct contact and transfer of secretions. Respiratory viruses include, but are not limited to, rhinoviruses and enteroviruses (Picornaviridae), influenza viruses (Orthomyxoviridae), parainfluenza, metapneumoviruses and respiratory syncytial viruses (Pneumoviridae), parainfluenza viruses (Paramyxoviridae), coronaviruses (Coronaviridae), and several adenoviruses. Respiratory viruses, typically, but not necessarily, replicate in both upper and lower airways, and may cause numerous symptoms, including, but not limited to, common cold symptoms, acute otitis media, laryngitis, sinusitis, pneumonia, bronchiolitis, influenza, and exacerbations of asthma and chronic obstructive pulmonary disease. The respiratory virus is not particularly limited and is preferably a virus that binds to (a) sialic acid and / or sulfonated / sulfated group(s), such as heparan sulfate.

[0116] The term “sexually transmitted virus”, as used herein, refers to a virus that is transmitted via blood, semen, vaginal fluids, or other body fluids, during oral, anal, or genital sex with an infected partner. Sexually transmitted viruses include, but are not limited to, hepatitis B, herpes simplex virus (HSV), HIV and human papillomavirus (HPV). The sexually transmitted virus is not particularly limited and is preferably a virus binds to sialic acid or heparan sulfate. Sexually transmitted viruses may be asymptomatic or symptomatic; typical symptoms include, but are not limited to Sores or bumps on the genitals or in the oral or rectal area, painful or burning urination, discharge from the penis, unusual or odorous vaginal discharge, unusual vaginal bleeding, pain during sex, sore and swollen lymph nodes, particularly in the groin but sometimes more widespread, lower abdominal pain, fever, rash over the trunk, hands or feet. The sexually transmitted virus is not particularly limited and is preferably a virus binds to sialic acid and / or a sulfonate group, such as heparan sulfate.

[0117] The term “vector transmitted virus”, as used herein refers to viruses which utilize insects, nematodes, mites or fungi to transport virions. For example, insects which transport viruses include blood-feeding anthropoids, such as mosquitoes, ticks, and fleas. Moreover, the majority of plant viruses are transported via a vector. The vector transmitted viruses are not particularly limited and includes, but is not limited to, dengue virus, zika virus, yellow fever virus, West Nile virus, and Japanese encephalitis virus, Chikungunya virus, Rift Valley Fever virus. The vector transmitted virus is not particularly limited and is preferably a virus that binds to sialic acid and / or a sulfonate / sulfated group, such as heparan sulfate.

[0118] In preferred embodiments, the invention relates to the compound, composition or pharmaceutical composition of the invention for use in treating or preventing a viral infectious disease, wherein the viral infectious disease is caused by a virus which binds sialic acid and / or a sulfonated / sulfated group, such as neuraminic acid and / or heparan sulfate and derivatives thereof, respectively, wherein the virus is selected from Paramyxoviridae family (such as PIV1 , PIV2, PIV3, PIV4, Nipah, Hendra virus and mumps), Orthomyxoviridae (such as influenza A virus H5N1 , H1 N1 or H3N2 or influenza B virus), Pneumoviridae (such as Respiratory Syncytial Virus and Human Metapneumovirus), Coronaviridae (such as SARS-CoV- 2, MERS-CoV, Human Coronavirus OC43), Herpesviridae (such as Herpes Simplex Virus (HSV) 1 , HSV2, cytomegalovirus), Caliciviridae (such as norovirus), Reoviridae (such as rotavirus), Papillomaviridae, Polyomaviridae, Adenoviridae and Flaviviridae (such as Zika virus, Dengue virus, West Nile Virus and Tick Borne Encephalitis Virus), Poxviridae (such as Monkeypox). More preferably, the invention relates to the compound, composition or pharmaceutical composition of the invention for use in treating or preventing a viral infectious disease, wherein the viral infectious disease is caused by a virus which binds sialic acid and / or sulfonated / sulfated groups, such as neuraminic acid and / or heparan sulfate, respectively, wherein the virus is from the Paramyxoviridae family (such as PIV1 , PIV2, PIV3, PIV4, Nipah, Hendra virus and mumps).

[0119] As can be seen from the appended examples, the invention provides compounds which display strong antiviral and / or virucidal activity without the development of viral resistance, in particular against clinical isolates of PIV3. The compounds of the invention were effective in treating PIV3, Influenza A H1 N1 , SARS-CoV-2 and RSV infections in a human respiratory tract model. The compounds were further demonstrated to be active in vivo against Influenza A H1 N1 and RSV. The novel compounds of the invention exhibit broad-spectrum activity and may be used for the treatment or prevention of viral infectious disease caused by viruses which bind to (a) sialic acid group(s) and / or sulfonated / sulfated group(s). Preferably, the compound, compostion, pharmaceutical composition or medicament of the present invention is capable of interacting with a virus which binds sialic acid group(s) and / or sulfonated / sulfated group(s), such as neuraminic acid and / or heparan sulfate, respectively, for cell entry. Accordingly, the embodiments of the invention prevent the entry of a virus into the cell, thereby stopping the life cycle of the virus and preventing further infection of the virus.

[0120] In further embodiments, the invention relates to the use of the compound or composition of the invention in disinfection. Moreover, the invention relates to the use of the compound or composition of the invention in sterilization. The term “disinfection”, as used herein refers to the use of the compounds or compositions of the invention that removes, inactivates and / or destroy pathogens on implements and other nonliving surfaces that renders an item safe for handling, use, and disposal. The term “sterilization”, as used herein refers to the removal of all microorganisms, whereas disinfection does not necessarily remove all microorganisms. Sterilization is in particular useful in clinical settings.

[0121] The use of the invention as a disinfectant and / or in sterilization may involve the use of the compound or composition of the invention, wherein the compound or composition further comprises a liquid such as water, alcohol solution (e.g., ethanol, isopropyl alcohol, ethyl alcohol), sodium hypochlorite and the like. The skilled person is well aware of how to prepare disinfectant or sterilization compositions.

[0122] In another aspect, the invention provides a compound or composition as described hereinabove further comprising an effective amount of the compound of the invention and optionally at least one suitable carrier. The term, "an effective amount", as used herein, refers to an amount sufficient for altering viruses, and / or destroying viruses and / or neutralizing viruses; i.e., sufficient for obtaining an antiviral and / or virucidal effect. In an embodiment, the suitable carrier is selected from the group comprising stabilizers, fragrance, colorants, emulsifiers, thickeners, wetting agents and mixtures thereof. In another embodiment, the compound or composition of the invention can be in the form of a liquid, a gel, a foam, a spray or an emulsion. In a further embodiment, the compound or composition of the invention can be an air freshener, a sterilizing solution or a disinfecting solution.

[0123] In another aspect, the invention provides a device comprising the compound or composition of the invention and means for applying and / or dispensing the compound or composition. The device may be any device known to the skilled person capable of applying and / or dispensing the compound or composition of the invention, including but not limited to a spray bottle, an aerosol bottle, an automated dispenser and the like.

[0124] Another aspect of the invention provides a device (or a product) comprising the compound or composition of the invention and a means for applying and / or dispensing the compound or composition of the invention. In another embodiment, the means comprise a dispenser, a spray applicator or a solid support soaked with the compound or composition of the invention. In another embodiment, the support is a woven or non-woven fabric, a textile, a paper towel, cotton wool, an absorbent polymer sheet, or a sponge. Another aspect of the invention provides a method of disinfection and / or sterilization using the compound or composition of the invention. In a preferred embodiment, the method of disinfection and / or sterilization comprises the steps of (i) providing the compound or composition of the invention, (ii) contacting a virus contaminated surface or a surface suspected to be contaminated by viruses with the compound of the invention for a time sufficient to obtain an antiviral and / or virucidal effect. In some embodiments, the virus contaminated surface is human or animal skin. In other embodiments, the virus contaminated surface is a non-living surface, such as medical equipment, clothing, masks, furniture, rooms, etc. In an embodiment, the compound or composition is used as an antiviral and / or virucidal hand disinfectant for frequent use. In another embodiment, the compound or composition is applied by spraying. In a further embodiment, the compound or composition is applied on a protective mask.

[0125] It will be appreciated that the compounds of the invention may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto / enol tautomers or thione / thiol tautomers). Complexes of any such isomers of the compounds of the invention are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces complexes of the isolated optical isomers of the compounds of the invention as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds of the invention. It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.

[0126] The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of the formula (I), (II) and (Ila), compositions or pharmaceutical compositions thereof which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group or sulfonate group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-p henylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Further pharmaceutically acceptable salts are described in the literature, e.g., in Stahl PH & Wermuth CG (eds.), “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, 2002 and in the references cited therein.

[0127] The scope of the invention also embraces compounds of the invention, in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds, in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e. ,2H; also referred to as “D”). Accordingly, the invention also embraces compounds which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds can be increased using deuteration techniques known in the art. For example, a compound of the invention or a reactant or precursor to be used in the synthesis of the compound can be subjected to an H / D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or1H hydrogen atoms in the compounds is preferred. The present invention also embraces compounds, in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by17O atoms.

[0128] The compounds, compositions or pharmaceutical compositions provided herein may be administered as such or may be formulated as medicaments / pharmaceutical compositions. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0129] The compositions or pharmaceutical compositions of the invention may comprise one or more solubility enhancers, such as, e.g., polyfethylene glycol), including polyfethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15- hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a- cyclodextrin, p-cyclodextrin, y-cyclodextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl- - cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-p-cyclodextrin, maltosyl-y- cyclodextrin, maltotriosyl-p-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p- cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0130] The compositions or pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0131] The compositions or pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in “Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22ndedition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration.

[0132] The present invention thus relates to the compound, composition, the pharmaceutical compositions provided herein, for administration by any one of the following routes: an oral route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route;. Preferred routes of administration are oral administration or parenteral administration. A preferred route of administration is oral administration (particularly by oral ingestion). Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient / subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0133] The compound, composition, pharmaceutical composition or medicament can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be prevented or treated. However, the compound, composition, pharmaceutical composition or medicament can also be administered in combination with one or more further therapeutic agents. If the compound, composition, pharmaceutical composition or medicament is used in combination with a second therapeutically agent active against the same disease or condition, the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of the compound, composition, pharmaceutical composition or medicament with one or more further therapeutic agents may comprise the simultaneous / concomitant administration of the compound, composition, pharmaceutical composition or medicament and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential / separate administration of the compound, composition, pharmaceutical composition or medicament and the further therapeutic agent(s). If administration is sequential, either the compound, composition, pharmaceutical composition or medicament according to the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the compound, composition, pharmaceutical composition or medicament, or they may be administered in two or more different (separate) pharmaceutical formulations.

[0134] Additionally, some embodiments of the present invention are directed to the application of the compound, composition, pharmaceutical composition or medicament of the invention for the prevention of viral outbreaks by exploiting the antiviral and / or virucidal effect of the invention. The the compound, composition, pharmaceutical composition or medicament may be a simple aqueous solution, a solution with inert excipients, or in combination with a vehicle such as a gel, cream, or lotion, which may optionally contain other therapeutic ingredients. Additional embodiments that improve handling and / or prophylactic delivery, such as via viscous solutions or via solutions designed to deliver delayed or predictable delivery, are also available. Solutions and / or compositions can be administered directly to areas of the skin where outbreaks are known to occur and will be easily applied and readily blended into the desired area of application.

[0135] In some embodiments, the the compound, composition, pharmaceutical composition or medicament may be used, for example, in people who are at high risk of exposure, or who have been exposed to viral infection but are not yet showing symptoms of infection, or who are infected with such viruses, in particular for subjects who may present with life-threatening events. In some embodiments the compositions can be applied to the mouth, nose, including the nasal passages, in sprays, mists, aerosols, and mouthwashes, and / or can be formulated into a wiping solution that can be applied to the throat area.

[0136] In other embodiments, the compositions provided herein can be utilized to prevent viral outbreaks or suppress the development of viral infections, such as in the form of pills, tablets, capsules, or injections. It can be administered by enteral and parenteral methods. In further embodiments, the compositions can be administered via injection or implanted liposome delivery depots for chronic administration. In some embodiments, the composition can be in the form of a transdermal patch that administers the drug via skin contact. Additionally, various embodiments of the present invention are useful for treating and / or preventing outbreaks of viruses, suppressing the development of other chronic viruses, and for treating and preventing outbreaks of viruses. In various embodiments, the present disclosure is useful for treating, preventing, or reducing outbreaks of recurrent viruses and / or inhibiting the development or proliferation of chronic viral infections.

[0137] The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal or a bird. More preferably, the subject / patient is a human (e.g., a male human or a female human), a bird (such as e.g. a chicken or a turkey), or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig). Even more preferably, the subject / patient to be treated in accordance with the invention is a human.

[0138] The terms “treatment” and “treating” of a disorder or disease, as used herein, is well known in the art. “T reatment” of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically shows specific clinical and / or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).

[0139] The “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The “treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disorder or disease. Accordingly, the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject / patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).

[0140] As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to- carbon double bond or any carbon-to-carbon triple bond. A “C1-6 alkyl” denotes an alkyl group having 1 to 6 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term “alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl.

[0141] As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “C2-6 alkenyl” denotes an alkenyl group having 2 to 6 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-

[0142] 1-en-1-yl, prop-1 -en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3-dien-

[0143] 2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl.

[0144] As used herein, the term “alkynyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. The term “C2-6 alkynyl” denotes an alkynyl group having 2 to 6 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term “alkynyl” preferably refers to C2- 4 alkynyl.

[0145] As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “C1-5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “C0-3 alkylene” indicates that a covalent bond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (- CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2- CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). As used herein, the term "cycloalkylene” refers to a divalent cyclic saturated hydrocarbon of three to eleven carbon atoms, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). "Cycloalkylene” may, e.g., refer to cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene. Unless defined otherwise, "cycloalkylene” refers to a C3-11 cycloalkylene, and more preferably refers to a C3-7 cycloalkylene. A particularly preferred "cycloalkylene” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members. Moreover, unless defined otherwise, the term "cycloalkylene” even more preferably refers to cyclohexylene or cyclopropylene, and yet even more preferably refers to cyclohexylene.

[0146] The term "heteroarylene" refers to a divalent five or six-membered aromatic ring, wherein one or more of the carbon atoms in the ring have been replaced by 1 , 2 or 3 of the same or different heteroatoms selected from N, 0 and S. Examples of the heteroarylene group include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, triazine and the like. The term " phenylene" refers to a divalent five or sixmembered aromatic ring.

[0147] As used herein, the term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). If the aryl is a bridged and / or fused ring system which contains, besides one or more aromatic rings, at least one non-aromatic ring (e.g., a saturated ring or an unsaturated alicyclic ring), then one or more carbon ring atoms in each non-aromatic ring may optionally be oxidized (i.e., to form an oxo group). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4- tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl.

[0148] As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1- benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3- pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 1 H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 , 10]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H-1 ,2,4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4- c]pyridinyl), imidazopyridinyl (e.g., imidazo[1 ,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1 ,3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, particularly preferred examples of a “heteroaryl” include pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), or pyrimidinyl.

[0149] As used herein, the term “carbocyclyl” refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless defined otherwise, “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl. As used herein, the term “heterocyclyl” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl. “Heterocyclyl” may, for example, refer to an oxadiazolyl or a piperazinyl group.

[0150] As used herein, the term “halogen” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).

[0151] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl” may, e.g., refer to -CF3, -CHF2, - CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A preferred “haloalkyl” group is fluoroalkyl. A particularly preferred “haloalkyl” group is -CF3.

[0152] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context. The term “bond” may also refer to a dative covalent bond or coordinate bond, particularly when describing the interactions between a chelator and a metal such as in complexes. As used herein, a “coordinate bond” preferably refers to a shared pair of electrons between two atoms, wherein one atom supplies both electrons to the pair, e.g. wherein a nitrogen atom provides both electrons when bonded to a metal atom. As used herein, a “covalent bond” preferably refers to a shared pair of electrons between two atoms, wherein each atom supplies one electron to the pair, e.g. the bond between a carbon atom and hydrogen atom.

[0153] As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0154] Various groups are referred to as being “optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted. If one or more substituents is present, each substituent is preferably independently selected from H, Ci-s alkyl, C2-8 alkenyl, C2-8 alky nyl, C1-8 haloalkyl, halogen, -O-(Ci-e alkyl), -NH2, -NH(Ci-s alkyl), -N(Ci-s alkyl)2, -SH, -S-(Ci-s alkyl), (Co-3)-carbocyclyl, and (Co-3)-heterocyclyl.

[0155] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I).

[0156] As used herein, unless otherwise indicated, the term “group” or “moiety” refers to a chemical entity that is monovalent (i.e., has one terminus that can be covalently bonded to other chemical species), divalent, or polyvalent (i.e., has two or more termini that can be covalently bonded to other chemical species).

[0157] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

[0158] As used herein, the term “about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated.

[0159] As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower meanings of “consisting essentially of’ and “consisting of’. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of ‘A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0160] It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the invention specifically relates to each combination of meanings (including general and / or preferred meanings) for the various groups and variables comprised in formula (I), (II) and (Ila).

[0161] I n this specification, a number of documents including patent applications and scientific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0162] The reference in this specification to any prior publication (or information derived therefrom) is not and should not be taken as an acknowledgment or admission or any form of suggestion that the corresponding prior publication (or the information derived therefrom) forms part of the common general knowledge in the technical field to which the present specification relates.

[0163] The invention is also illustrated by the appended figures.

[0164] Fig 1 Attachment receptor used by PIV3. A) Schematic view of the glycan array protocol used with the laboratory strain (ATCC) and two clinical isolates of PIV3 (2017 and 2021 ). Full viruses were incubated overnight at 4°C on a glycan array that has 100 different glycans. Created with Biorender.com. B) Images of glycan array after PIV3 ATCC or EV68 incubation. Each glycan on the array is expressed by 4 dots in a row. The green dots on the bottom right are the positive control for each subarray.

[0165] Fig 2 A) Glycan array results with the three different PIV3 strains used. Intensities of fluorescence are express relative to the fluorescence of the positive control and background. B) The structures of the hits found in the glycan array are shown. C) A549 with a lack of sialic acid transporter (A549 SA KO) were infected by PIV3 and EV68. After immunostaining, the level of infectivity was evaluated by tetramethyl benzidine. This experiment was performed by Dr. Valeria Cagno. **** P< 0.0001.

[0166] Fig 3 Synthesis and characterization of CD-SLNT A) Representation of CD-MUS. B) Synthesis reactions for CD-SLNT based on a previous article [O. Kocabiyik et al, Adv Sci 2020, 8(3), 2001012], CD-3’SLN and CD-SA were synthetized by a similar method. N-hydroxysuccinimide (NHS) 1-Ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC-HCI) 4-dimethylaminopyridine pyridine (DMAP) triethylamine (TEA). C) Representation of CD-SLNT. D) Representation of CD- 3’SLN and CD-SA. E) HPLC of CD-SLNT 0.15 with an XBridge BEH Amide column with 10mM ammonium formate and acetonitrile. F) The different peaks present in the HPLC data can be differentiated by their MS profile corresponding to their major mass over charge peak (1834, 1568, or 1914 m / z).

[0167] Fig 4 Schematic view of the biological assays. A) Inhibition and B) virucidal experiments were performed with three different strains of PIV3 (ATCC, 2017, 2021) as described previously [S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318].

[0168] Fig 5 Antiviral activity of CD-MUS. A, B, C) Inhibition and D, E, F) virucidal of CD-MUS were performed against PIV3 ATCC (A, D) and the two clinical isolates: 2017 (B, E) and 2021 (C, F). Virucidal experiments were done with incubation of 1 hour at 37°C. Virucidal experiment with 10 pg / mL against 2021 PIV3 was done only once. * P< 0.0332.

[0169] Fig 6 Antiviral activity of CD-SLNT. A, B, C) Inhibition of CD-SLNT and LSTd against PIV3 ATCC (A) and the two clinical isolates (B, C) were performed with different equivalences (0.15, 0.3, 0.6, 1.2 i.e amount of LSTd grafted onto the modified p-cyclodextrin). The pre-incubation was done for 1 hour at 37°C or 4°C. Experiments with ATCC at 37°C (0.6 and 1.2) and 4°C (0.15, 0.6,1 .2), with 2017 at 37°C (1 .2) and 4°C (0.6, 1 .2) and with 2021 at 37°C (0.6, 1 .2) were done only once. Inhibition of LSTd was done only once. D, E, F) Virucidal experiments were done with 300 pg / mL of CD-SLNT 0.15 against PIV3 ATCC (D), 2017 (E) and 2021 (F) with incubation of 2 hours at 37°C. * P< 0.0332.

[0170] Fig 7 Antiviral activity of CD-3’SLN and CD-SA. A, B, C) Inhibition of CD-3’SLN and D, E, F) CD- SA was performed against ATCC (A, D), 2017 (B, E), and 2021 (C, F) PIV3 strains. Experiments with CD-3’SLN were performed only once.

[0171] Fig 8 Structural analysis of HN protein of PIV3. A) List of mutations observed after sequencing the HN protein of PIV3 of the three different strains used. Their position according to MF987836 and their location according to UniProt are mentioned. B) Homology modeling with SwissModel was used to model HN of ATCC, 2017, and 2021 PIV3 strains using 6c0m.1.A as a template. The red circle refers to one of the sialic acid binding pockets of HN involved in viral attachment. The green and black circles highlight the conformational and electronegativity changes induced by the mutation of amino acids 501 and 556 respectively. Fig 9 Toxicity assay ex vivo with CD-MUS and CD-SLNT. Toxicity on MucilAir was assessed by MTS (A), LDH release (B), IL-6 (C), and IL-1 p (D). CD-MUS and CD-SLNT were added daily to the apical side of MucilAir. Daily apical washes were performed and used for evaluation of LDH, IL-6, and IL-1 p release. On the last day, MTS was done on the apical side and an untreated tissue was treated with Tween 20 1% as control. Only one CD-MUS-treated tissue was used in the ex vivo toxicity assay. * P<0.0332, ** P<0.0021 .

[0172] Fig 10 Ex vivo activity of CD-MUS and CD-SLNT. A) We used a human upper respiratory tract model to test the activity of CD-MUS and CD-SLNT. For this purpose, we used different types of administration Created with BioRender.com. B,C) In the pre-treatment, we incubated 2021 PIV3 with 100 pg / mL or 300 pg / mL of CD-MUS or CD-SLNT respectively for 1 hour at 37°C. Tissues were infected for 3 hours at 33°C. A daily apical wash was done and the level of PIV3 released was quantified by RT-qPCR (B). IL-6 release was quantified on the apical wash of day 3 and 4 post-infection (C). D) In post-treatment, tissues were infected and treated 24hpi. 30 / CD-MUS (333.33 g / mL) and CD-SLNT (1 mg / mL) were applied apically every day. Level ofPIV3 in the apical washes was quantified by RT-qPCR (D). *P < 0.0332, **** P<0.0001.

[0173] Fig 11 Resistance against CD-MUS and CD-SLNT. A) PIV3 2021 strains were passaged several times with increasing concentrations of CD-MUS and CD-SLNT. B) Cytotoxicity of CD-MUS and CD-SLNT was performed on LLCMK2 cells. Modified p-cyclodextrins were left on the cells for 5 days at 37°C before evaluation of the toxicity by MTT. C, D) After the 3rdpassage, the antiviral activity of CD-SLNT 0.15 against untreated and CD-SLNT 0.3 treated viruses (C) or CD-MUS against untreated and CD-MUS treated viruses (D) were performed.

[0174] Fig 12 Combination assays using CD-MUS and CD-SLNT. CD-MUS and CD-SLNT were mixed at different concentrations and incubated for 1 hour at 37°C with ATCC, 2017, or 2021 PIV3 strains before the infection of LLCMK2 cells. Inhibition percentages were calculated by plaque assay and then evaluated with SynergyFinder 3.0 [A. Ivanevski et al, Nucleic Acids Res, 2022, 50(W1), W739-W743]. The reference algorithms (HSA, Loewe, Bliss, and ZIP) were applied. Green, white, and red areas indicate antagonistic, additive, and synergistic areas respectively.

[0175] Fig 13 Broad spectrum activity of CD-MUS and CD-SLNT. Inhibition assays of CD-SLNT and CD- MUS were performed against H5N1 IAV (A) and EV68 (B). Antiviral (C, E) and virucidal (D, F) activity of CD-MUS was also assessed against TBEV (C, D) and MPX (E, F).

[0176] Fig 14 Schematic representation of modified P-cyclodextrins. Schemes of the different CD with the respective ligands. These drawings do not consider the possible configurations the substituents can adopt on the primary face of the cyclodextrin, but only the type of substituents. Fig 15 Antiviral activity of CD-MUS and CD-SLNT against hPIV3. Inhibition (A, B) and virucidal activity (C, D) of CDs. Inhibition was performed by incubating 1 h at 37°C laboratory and clinical strains of hPI V3 with CD-MUS (A) or CD-SLNT (B) before infection on cells. Antiviral activity was assessed by plaque assay counted manually. Data represent mean ± SEM of two (A - ATCC), three (A - clinical #1 , B), and six (A - clinical #2) independent experiments. Nonlinear regression with variable Hill slope and constraints for the bottom and top (0 and 100 respectively) were performed to compute ECso. (C, D) Virucidal experiments were done by incubating viruses for 1 hour with 100 pg / mL CD-MUS (C) or 2 hours with 300 pg / mL CD-SLNT (D) at 37°C. The virus-drug mix was then serially diluted. Viral titer was assessed by plaque assay counted manually. Data represent mean ± SEM of two independent (C, D) experiments. Two-tailed t-tests between untreated and treated conditions were performed. Limit Of Detection (LCD)* P< 0.0332, *** P<0.0002, **** P<0.0001.

[0177] Fig 16 Resistance to CD-SLNT / SO3-. PIV3 (A) and IAV H1 N1 (B) viruses were passaged 10 times in the presence of an increasing concentration of CD-SLNT / SO3-. At the final passage, the antiviral activity of CD-SLNT / SO3- against the untreated and treated viruses was assessed. Resistant plaque-purified IAV H1 N1 viruses were obtained (B). Data represent mean ± SEM of two (B-Plaque purified resistant CD-SLNT / SO3- passage 10), three (B-Untreated passage 10, CD-SLNT / SO3- passage 10) or four (A) independent experiments. Each independent experiment with untreated or treated virus at passage 10 was carried out using the two independent virus replicates. Nonlinear regression with variable Hill slope and constraints for the bottom and top (0 and 100 respectively) were performed to compute ECso.

[0178] Fig 17 Ex vivo activity of CD-SLNT / SO3-. HPIV3 (A), SARS-CoV-2 (B), RSV (C), or IAV H1 N1 (D) were incubated with 300 pg / mL of CD-SLNT / SO3- for 1 hour at 37°C. Human upper respiratory tract models (n = 2 (A, C, D) or 6 (B) per group) were then infected at 33°C. The inoculum was removed after 3h. A daily apical wash was performed, and the level of viruses released was quantified by RT-qPCR. Data represent mean ± SEM. Area under the curve followed by a two- tailed t-test was performed. ** P<0.0021 , *** P<0.0002, **** P<0.0001. Cartoon created with biorender.com.

[0179] Fig 18 In vivo activity of CD-SLNT / SO3-. (A, B) Zebrafish larvae were infected with IAV H1 N1 . CD- SLNT / SO3- was co-injected at the same time at a concentration of 100 pg / mL. At 7 hpi and each day, 10 larvae are lysed for viral RNA quantification by RT-qPCR. Data represents mean ± SEM of four independent experiments. (C, D, E) Mice (n = 10 per group) were infected with RSV. (C) Mice were either treated with 5 mg / kg of CD-SLNT / SO3- 10 minutes before infection (pre-treatment) with a daily dose until 4 days post-infection (dpi) or with 10 mg / kg of CD- SLNT / SO3- starting 1 dpi (post-treatment). (D, E) RSV replication was assessed by luciferase activity at 2 (D) and 4 (E) dpi. Data represents mean ± SEM of a single experiment. (Two-tailed Mann-Whitney tests were performed to compare untreated and treated conditions. * P< 0.0332, ** P<0.0021 , *** P<0.0002. Schematic view created with biorender.com.

[0180] Fig 19 Use of sialic acid and heparan sulfate for hPIV3 infection. (A) A549 with sialic acid transporter knockout (A549 SA KO) were infected with hPI V3 and EV68. After immunostaining, the level of infectivity was evaluated by tetramethyl benzidine. Data represent mean ± SEM of three independent experiments. Two-tailed t-tests were performed to compare WT and SA KO data for each virus. (B) LLCMK2 cells were passaged in the presence or not of 30 mM sodium chlorate (NaCIOs). They were then infected with hPIV3 or RSV-GFP. Infectivity was assessed by plaque assay for hPI V3 and number of infectious units for RSV-GFP. Data represent mean ± SEM of two independent experiments. Two-tailed t-tests were performed to compare untreated and treated for each virus. * P< 0.0332, ** P<0.0021 , *** P<0.0002, **** P<0.0001.

[0181] Fig 20 Assessing the optimal composition of glycan on p-cyclodextrin. (A) Antiviral activity of CD- SLNT with different equivalences (0.15, 0.3, 0.6, 1.2 i.e amount of SLNT grafted onto the modified p-cyclodextrin), CD-3’SLN, CD-SA, or SLNT alone against Human Parainfluenza virus 3 (hPIV-3) clinical #2 were performed. (B) Sulfated versions of these cyclodextrins (CD-SA / SO3- , CD-3’SLN / SO3-, CD-SLNT / SO3- with two different equivalences of SLNT), CD-MUS or CD- 503- (cyclodextrin synthesized similarly to CD-SLNT / SO3- without SLNT) were tested against hPIV-3 clinical #2.(C) CD-SLNT and its respective sulfated version (CD-SLNT / SO3-), CD-MUS and CD-SO3- were tested against RSV-GFP. (D-E) CD-SA, CD-3’SLN, CD-SLNT and their respective sulfated versions (CD-SA / SO3-, CD-3’SLN / SO3-, CD-SLNT / SO3- respectively), CD- MUS and CD-SO3- were tested against Influenza A H5N1 (D) or H1 N1 (E) viruses. The preincubation was done for 1 hour at 37°C before infection on LCCMK2 cells for hPIV-3 clinical #2 (A-B), or RSV-GFP (C) and on MDCK-Siat for Influenza A H5N1 (D) or H1 N1 (E) viruses. Data represents mean ± SEM of two (A - CD-SA, CD-3’SLN, CD-SLNT (0.6, 1.2), SLNT; B - CD- SA / SO3-, CD-3’SLN / SO3-; C - CD-SLNT, CD-SLNT(0.28) / SO3-, CD-SO3-, CD-MUS; D - CD- SA, CD-SA / SO3-, CD-3’SLN / SO3-, CD-SLNT(0.28) / SO3-, CD-MUS, CD-SO3-; E - CD- 3’SLN / SO3-, CD-SLNT, CD-MUS), three (A -CD-SLNT (0.15, 0.3); C- CD-SLNT (0.15) / SO3- batch#2, CD-SLNT (0.15) / SO3- batch#3; D - CD-SLNT (0.15) / SO3- batch#2, CD-3’SLN, E - CD-SA, CD-3’SLN, CD-SO3-), four (B - CD-SLNT(0.28) / SO3-; C - CD-SLNT (0.15) / SO3- batch#1 ; D - CD-SLNT, E - CD-SA / SO3-, CD-SLNT (0.15) / SO3- batch#3, CD- SLNT(0.28) / SO3-), five (B - CD-SO3-, CD-SLNT (0.15) / SO3- batch#1; E - CD-SLNT (0.15) / SO3- batch#1, #2) or six (B - CD-MUS) independent experiments. Nonlinear regression with variable Hill Slope and constraint bottom and top (0 and 100 respectively) were performed to compute ECso. Fig 21 Toxicity of modified P-cyclodextrin. Toxicity of CD-MUS, CD-SLNT, and CD-SLNT / SO3- was assessed in vitro and ex vivo. CDs were incubated for 1 h (A) or 5 days (B) on LLCMK2. Cell viability was quantified five days post-exposure by MTT. Data represents mean ± SEM of two (A, B - CD-SLNT) or five independent experiments (B - CD-MUS, CD-SLNT / S03-). Nonlinear regression with variable Hill slope and constraints for the bottom and top (0 and 100 respectively) were performed to compute CCso. (C, D) CDs were administered apically in human respiratory airways daily (n = 2 for each condition). (C) Viability was assessed by MTS 4 days after the first exposure. Data represents mean ± SEM. A two-tailed t-test was performed. (D) LDH was quantified on the daily apical of the human respiratory airway. Data represents mean ± SEM. The statistical analysis was performed by calculating the area under the curve followed by a two-tailed t-test.

[0182] Fig 22 Antiviral activity of CD-SLNT / SO3- against IAV H1 N1. IAV H1 N1 with MOI between 1 and 0.01 were incubated with CD-SLNT / SO3- at different concentrations for 1 hour at 37°C. Virus and CD-SLNT / SO3- mix was then added on MDCK-Siat for one hour at 37°C before removal. Infectivity was assessed by immunofluorescence one day post-infection. Data represents mean ± SEM of three independent experiments. Nonlinear regression with variable Hill Slope and constraint bottom and top (0 and 100 respectively) were performed to compute ECso, and with F equal to 1 for EC99.

[0183] Fig 23 Virucidal activity of CD-SLNT / SO3-. HPIV3 (A), Influenza A H1 N1 (B), Influenza A H5N1 (C), Influenza B (D), RSV (E) or SARS-CoV-2 (F) were incubated with 300 pg / mL of CD-SLNT / SO3- for 1 hour at 37°C. Viral titers were then quantified. Data represents mean ± SEM of two (A, C, E, F) or three (B, D) independent experiments. Two-tailed t-tests were performed to compare untreated and treated conditions. * P< 0.0332, ** P<0.0021 , *** P<0.0002, **** P<0.0001.

[0184] Fig 24 Virucidal kinetics activity of CD-SLNT / SO3-. IAV H1 N1 (A), IAV H5N1 (B) or hPI V3 (C) were incubated with 300 pg / mL of CD-SLNT / SO3- for 0, 10, 30, or 60 minutes at 37°C. Viral titers were then quantified. Data represents mean ± SEM of two independent experiments. One-way ANOVA with Dunnett’s multiple comparisons compared to 0’ Untreated was performed to compare the different conditions. (D) Octadecyl rhodamine B chloride (R18) was incubated with IAV H1 N1 followed by being diluted in DMEM and CD-SLNT / SO3- (300 pg / mL). Fluorescence was quantified at 30, 60, 120 and 180 minutes. Data represents mean of fold change compared to 30 minutes untreated condition ± SEM of three independent experiments. Area under the curved followed by One-way ANOVA and Dunnett’s multiple comparisons test was performed to compared conditions. ** P<0.0021 , **** P<0.0001 , DES: diethylstilbestrol.

[0185] Fig 25 Chromatographs of different batches of CD-SLNT / SO3-. High-performance liquid chromatography coupled with mass spectrometry was performed with the different produced batch of CD-SLNT / S03-. Arrows identified pics for which mass spectrometry was confident with a type of species that can be synthesized. The analysis showed that batches that mix SLNT and Taurine generate both species with SO3- alone that elute before 20 minutes with this method, and species with SLNT and differing number of taurine groups. Centered around 30 min are the species with 1 SLNT that we hypothesize to be the most potent, between 40-45 minutes species with 2 SLNT and different amounts of SO3- and between 50-55 minutes species with 3 SLNT and different amounts of SO3-.

[0186] Fig 26 Ex vivo activity of CD-SLNT / SO3-. Influenza A H1 N1 (A) or SARS-CoV-2 (B) were incubated with 300 pg / mL of CD-SLNT / SO3- for 1 hour at 37°C. Human upper respiratory tract models (n = 2 (A) or 6 (B) per group) were then infected at 33°C. The level of infectious viruses released were titered on MDCK-Siat (A) or Vero E6 (B) cells with the apical wash performed at 48 and 96 hpi. Data represent mean ± SEM. Two-tailed t-test was performed for each time point. (C) CD-SLNT / SO3- (300 pg / mL) was mixed with hPIV3 and directly added on the apical side of the human upper respiratory tract model (n = 3) without pre-incubation. The airways were then infected at 33°C. A daily apical wash was performed, and the level of viruses released was quantified by RT-qPCR. Data represent mean ± SEM. Area under the curve followed by a two- tailed t-test was performed. * P< 0.0332, ** P<0.0021 , *** P<0.0002, **** P<0.0001.

[0187] Fig 27 In vivo activity of CD-SLNT / SO3-. Mice (n = 5 (A), 10 (B, C, D) per group) were infected with RSV-Luc. Mice were either treated with 5 mg / kg of CD-SLNT / SO3- 30 minutes before infection (pre-treatment) with a daily dose until 4 days post-infection. (A) RSV replication was assessed by luciferase activity on day 4 for the initial experiment. During a subsequent experiment (B, C, D), infected mice were pre-treated similarly as initially or with 10 mg / kg of CD-SLNT / SO3- starting 1-day post-infection (post-treatment) until 4 days post-infection. Mice weights were measured every day (B). RSV replication was assessed by luciferase activity on day 4 in the lungs (C) and nose (D). Data represents mean ± SEM of one experiment. Two-tailed Mann- Whitney tests were performed to compare untreated and each condition. * P< 0.0332, ** P<0.0021 , *** P<0.0002, **** P<0.0001 , non significant (ns) Examples

[0188] Nomenclature

[0189] The following nomenclature is used throughout the examples

[0190] CD-MUS (Fig 3A): 11-mercapto-1 -undecanesulfonate (MUS)-modified p-cyclodextrin (CD)

[0191] CD-SLNT (Fig 3C): Neu5Aca(2,3)Galp(1 ,4)GlcNAcp(1,3)Galp(1,4)Glcp1-4-modified p-cyclodextrin (CD) CD-3'SLN (Fig 3D): 3-sialyllactosamine (6'SLN)-modified p-cyclodextrin (CD)

[0192] CD-SA (Fig 3D): Sialic acid-modified p-cyclodextrin (CD)

[0193] CD-SLNT / Taurine (Fig 15): Neu5Aca(2,3)Galp(1 ,4)GlcNAcp(1 ,3)Galp(1,4)Glcp1-4-modified and taurine- modified p-cyclodextrin (CD)

[0194] CD-SLNT / SO3- (Fig. 15): Neu5Aca(2,3)Galp(1 ,4)GlcNAcp(1 ,3)Galp(1 ,4)Glcp1-4-modified p-cyclodextrin (CD) with one or more SOr bearing substituents

[0195] Material and Methods

[0196] Cell and viruses

[0197] LLCMK2 (ATCC CCL-7), A549 (ATCC CRM-CCL-185), MDCK (ATCC CCL-34), A549 SLC35A1 KO, and Vero E6 (ATCC CRL-1586) cells were maintained in Dulbecco’s Modified Eagle Medium (DMEM) (Gibco) with 10% Fetal Bovine Serum (FBS) (Pan Biotech) and 1 % penicillin / streptomycin (Gibco) at 37°C and 5% CO2.

[0198] PIV3 was purchased on ATCC and two clinical samples were isolated from clinical specimens. H5N1 IAV, Enterovirus D68 (EV68), and Tick Born Encephalitis Virus (TBEV) were donated. MPX was isolated from a clinical sample.

[0199] Glycan Array

[0200] The 100 glycan array was purchased from ZBiotech (ref 10601 -8S). The array was initially blocked for 1 hour at room temperature with 1 % Bovine Serum Albumin (BSA) (AppliChem) and 0.05% Tween-20 (Sigma). PIV3 and EV68 were added onto the subarray overnight at 4°C. The array was then washed three times with 0.05% Tween 20 in Phosphate-buffered saline (PBS) (Bischel) before fixation with 4% formaldehyde. Anti-Parainfluenza (1 :10) (Light Diagnostics) and anti-Enterovirus (1 : 200) (Invitrogen) were used for 1 hour at 37°C. The glycan array was washed three times. Anti-mouse AlexaFluor 488 (1 :1500) (Invitrogen) was added for 1 hour at 37°C. After three washes with 0.05% Tween-20, the array was disassembled and immerged in the wash solution for 10 minutes. Deionized water was used for the last wash before drying the glycan array. The array was visualized with Leica DMi 8 and the intensities of the different positive spots were quantified with Imaged.

[0201] Sialic acid Knock out cells

[0202] A549 and A549 SLC35A1 KO cells (16’000 cells / well) were seeded in a 96-well plate. Cells were infected with PIV3 and EV68 with a dilution 1 :10 from the viral stock in DMEM 0% with 200 ng / mL TPCK Trypsin (Sigma) and DMEM 2.5% respectively. After 1 hour at 37°C, infected cells were incubated for 1 day at the same temperature. After fixation with methanol, cells were blocked with 1 % BSA and 0.05% Tween- 20 for 20 minutes at room temperature. Anti-Parainfluenza (1 :10) and anti-Enterovirus (1 :500) were used for 1 hour at 37°C followed by extensive washes and anti-mouse horseradish peroxidase (HRP) (1 : 1000) (Cell Signaling) for 1 hour at 37°C. Tetramethyl Benzidine (Invitrogen) was added to stained cells and HCI (CHUV) was used to stop the reaction. Absorbance was read at 450nm with a Microplate reader.

[0203] Example 1 : Synthesis of modified P-cyclodextrin

[0204] CD-MUS was made as described previously [S. T. Jones et al., Sc / . Adv. 2020, 6, eaax9318]. For modified P-cyclodextrin with sialic acid-based glycans (CD-SLNT, CD-3’SLN, CD-SA), they were synthetized following similar reactions as done previously [O. Kocabiyik et al, Adv Sci 2020, 8(3), 2001012], Briefly, Heptakis-(6-deoxy-6-mercapto)-p-cyclodextrin and 11 -dodecenoic acid were dissolved in DMSO and linked under ultraviolet overnight. N-hydroxysuccinimide, 1 -Ethyl-3-(3- dimethylaminopropyl) carbodiimide and 4-dimethylaminopyridine pyridine were added and mixed overnight. This reaction was washed with cold water, acetonitrile and diethyl ether. For CD-SA, CD-3’SLN and CD-SLNT, Neu5Ac-a-ethylamine, Neu5Aca(2,3)-Galp(1-4)-GlcNAcp-ethylamine and Neu5Aca(2,3)Galp(1,4)GlcNAcp(1,3)Galp(1,4)Glcp1- 4 propylamine (Asparia) were added respectively with triethylamine. The reaction was stirred overnight. For CD-SLNT / Taurine, taurine was also added. Modified p-cyclodextrin were dialyzed for several days and then filtered and freeze dried. Modified p-cyclodextrins were characterized with1H, DOSY Nuclear Magnetic Resonance (NMR), and High-Performance Liquid Chromatography - Mass Spectrometry (HPLC-MS) studies. An XBridge BEH Amide 5pm 4.6x250mm was used for HPLC characterization (Table 1).

[0205] Table 1: Method used for HPLC characterization. Percentages of water with 10mM Ammonium Formate or acetonitrile are shown according to time with a constant flow of 1 mL / min. Example 2: Dose-response against modified P-cyclodextrin

[0206] Inhibition assays against PIV3, TBEV, MPX, H5N1 IAV, and EV68 were done based on previously described experiments [S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318].

[0207] For PIV3, modified p-cyclodextrins were serially diluted in DMEM supplemented with 200 ng / mL TPCK Trypsin for PIV3 from an initial concentration of 300 pg / mL CD-SA, CD-3’SLN, CD-SLNT, and CD- SLNT / Taurine or 100 pg / mL CD-MUS. Two hundred plaque-forming units of viruses were added. Virus and p-cyclodextrin were incubated for 1 hour at 37°C or 4°C. LLCMK2 (70’000 cells / well) previously seeded in 24 well plate and were infected with 200 pl of virus / p-cyclodextrin mix. After 1 hour at 37°C, the virus inoculum was removed. An overlay of 0.5% Methylcellulose (MTC) (Sigma) in DMEM 0% FBS with 200ng / mL TPCK Trypsin was added onto the cells. Infected cells were incubated for 3, 4, or 5 days at 37°C for PIV3 ATCC, 2017 and 2021 respectively. Crystal violet (Sigma) was used to fix and stained cells. Plaques were quantified manually.

[0208] For TBEV, modified p-cyclodextrins were serially diluted in DMEM 0% or with 2.5% FBS from an initial concentration of 100 pg / mL CD-MUS. Two hundred plaque-forming units of viruses were added. Virus and p-cyclodextrin were incubated for 1 hour at 37°C. A549 (100’000 cells / well) previously seeded in 24 well plate were infected with 200 pl of virus / p-cyclodextrin mix. After 1 hour at 37°C, the virus inoculum was removed. An overlay of 0.6% Avicel gp3515 (Selectchemie) in DMEM 2.5% FBS was added onto the cells. Infected cells were incubated for 3 days at 37°C. Crystal violet was used to fix and stained cells. Plaques were quantified manually.

[0209] For MPX, modified p-cyclodextrins were serially diluted in DMEM from an initial concentration of 100 pg / mL CD-MUS. Two hundred plaque-forming units of viruses were added. Virus and p-cyclodextrin were incubated for 1 hour at 37°C. Vero E6 (100’000 cells / well) previously seeded in a 24 well plate were infected with 200 pl of virus / p-cyclodextrin mix. After 1 hour at 37°C, the virus inoculum was removed. An overlay of 0.5% MTC in DMEM 2.5% FBS was added onto the cells. Infected cells were incubated for 2 days at 37°C. Crystal violet was used to fix and stained cells. Plaques were quantified manually.

[0210] For H5N1 IAV, modified p-cyclodextrins were serially diluted in DMEM supplemented with 200 ng / mL TPCK Trypsin for PIV3 from an initial concentration of 300 pg / mL CD-3’SLN and CD-SLNT or 100 pg / mL CD-MUS. An MOI of 0.01 was used. Virus and p-cyclodextrin were incubated for 1 hour at 37°C. MDCK (13’000 cells / well), seeded in a 96 well plate and were infected with 10Oul. After 1 hour at 37°C, the virus inoculum was removed. DMEM was added onto the cells. Infected cells were incubated for one day at 37°C. Methanol (Sigma) was used to fix the 96 well plate. Blocking buffer (1 % BSA, 0.05% Tween-20) was added for 20 min at room temperature. Anti-Influenza (1 :100) (Light Diagnostics) was added for 1 hour at 37°C. After washing with 0.05% Tween 20, anti-mouse HRP (1 :1000) was added for 1 hour at 37°C. 3, 3'-D iami no benzid i ne solution (Sigma) was added on cells for the staining. The number of infected cells was counted manually. For EV68, modified p-cyclodextrins were serially diluted in DMEM supplemented with 200 ng / mL TPCK Trypsin for PIV3 from an initial concentration of 300 pg / mL CD-3’SLN and CD-SLNT or 100 pg / mL CD- MUS. An MOI of 0.01 was used. Virus and p-cyclodextri n were incubated for 1 hour at 37°C. HeLa (16’000 cells / well) seeded in a 96 well plate were infected with 10Oul. After 1 hour at 33°C, the virus inoculum was removed. DMEM was added onto the cells. Infected cells were incubated for one day at 33°C. Methanol was used to fix the 96 well plate. Blocking buffer (1 % BSA, 0.05% Tween-20) was added for 20 min at room temperature. Anti-Enterovirus (1 :500) was added for 1 hour at 37°C. After washing with 0.05% Tween 20, anti-mouse HRP (1 :1000) was added for 1 hour at 37°C. 3,3'-Diaminobenzidine solution was added on cells for the staining. The number of infected cells was counted manually.

[0211] Example 3: Virucidal experiment against modified P-cyclodextri n

[0212] For PIV3, 105pfu of viruses were incubated with 100 or 300 pg / mL of modified p-cyclodextri n for 1 hour or 2 hours at 37°C. Viruses were serially diluted in DMEM with 200 ng / mL TPCK Trypsin. LLCMK2 (70’000 cells / well) in a 24 well plate were infected for 1 hour at 37°C. Viruses were removed and 0.5% MTC in DMEM with 200ng / mL TPCK Trypsin was added onto the cells. Cells were incubated for 3, 4, or 5 days at 37°C for PIV3 ATCC, 2017 and 2021 respectively. At the end of the incubation, cells were fixed and stained with crystal violet. The number of plaques was quantified manually to determine the titer.

[0213] For TBEV, 105pfu of viruses were incubated with 10 or 100 pg / mL of CD-MUS for 1 hour at 37°C. Viruses were serially diluted in DMEM 0% or 2.5% FBS. A549 (100’000 cells / well) in a 24 well plate and were infected for 1 hour at 37°C. Viruses were removed and 0.6% Avicel gp3515 in DMEM 2.5% FBS was added onto the cells. Cells were incubated for 3 days at 37°C. At the end of the incubation, cells were fixed and stained with crystal violet. The number of plaques was quantified manually to determine the titer.

[0214] For MPX, 105pfu of viruses were incubated with 100 of CD-MUS for 1 hour at 37°C. Viruses were serially diluted in DMEM. Vero E6 (100’000 cells / well) in a 24 well plate and were infected for 1 hour at 37°C. Viruses were removed and 0.5% MTC in DMEM 2.5% FBS was added onto the cells. Cells were incubated for 2 days at 37°C. At the end of the incubation, cells were fixed and stained with crystal violet. The number of plaques was quantified manually to determine the titer.

[0215] RT-PCR and RT-qPCR

[0216] PIV3 was lysed with TRK Lysis buffer and total RNA was extracted with E.Z.N.A total RNA extraction (Omega Bio-Tek) according to the manufacturer’s protocol. Reverse transcriptase was done with Maxima H Minus First Strand cDNA Synthesis Kit (ThermoFisher) using random primers. PCR was performed with Platinum II Taq Hot-Start DNA Polymerase (ThermoFisher) using two sets of primers for HN (Fwd 5’- GGAAGCAYACCAAYCAC-3’ with Rev 5’-GCCTTTGTARTATATCCCTGG-3’ and Fwd 5’- CTAGCACTCCTAAAYACAGATG-3’ with Rev 5’-GCCATTGTTAGATTCAGTGTCC-3’) and two others for F (Fwd 5’-CTCCCTTTATTAACYAGRCTGC-3’ with Rev 5’-GTGRTTGGTRTGCTTCC-3’ and Fwd 5’- GGAGTTGGGAAAATCAAACAATGG-3’ with Rev 5’-GCTCCACCTAGAAATGC-3’). PCR fragments were confirmed by gel electrophoresis and sequenced by Sanger method by Microsynth. RT-qPCR was done with TaqPath 1 -Step RT-qPCR Master Mix using Vi06439670_s1 (ThermoFisher) as primers and probe mix.

[0217] Example 4: Ex vivo human upper respiratory tract experiments

[0218] MucilAir Nasal with a pool of donors were purchased from Epithelix and were maintained according to the manufacturer’s protocol. For pre-administration, CD-SLNT (300 pg / mL) and CD-MUS (100 pg / mL) were incubated with PIV3 for 1 hour at 37°C before infection. MucilAir were washed with PBS with calcium and magnesium (PBS++) (Gibco) for 45 min at 37°C. PIV3 from the 2021 clinical isolate produced on MucilAir were used to infect MucilAir for 3 hours at 33°C on the apical side. MucilAir were washed twice with PBS++ and maintained at 33°C. For post-infection, treatment started one-day post infection once per day by adding 30 pl of 1 mg / mL of CD-SLNT or 333 pg / mL of CD-MUS. Every day, 200 pl of MucilAir medium was added at the apical side for 20 minutes at 33°C. On the last day, MucilAir were fixed with 4% formaldehyde.

[0219] Example 5: Toxicity assays in vitro and ex vivo

[0220] LLCMK2 were seeded in 96 well plate with 10’000 cells / well. Modified p-cyclodextrin (CD-MUS and CD- SLNT) were serially diluted in DMEM 0% FBS with 1 :10’000 TPCK Trypsin from 1 mg / mL and added to the cells. Cells were incubated for 5 days at 37°C. After incubation, cells were washed once with DMEM 0% FBS. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma) was added to the cells with a concentration of 0.5 mg / mL in DMEM 0% FBS for 3 hours. DMSO was used to lyse cells and solubilize MTT. Absorbance at 570 nm was quantified with a Microplate reader.

[0221] MucilAir were treated daily once with 30 pl of CD-SLNT (1 mg / mL) and CD-MUS (333.3 pg / mL) and maintained at 33°C. Apical washes were done every day with 200 pl of MucilAir medium for 20 min at 33°C. The basal medium was replaced every day. On the last day, 1 % Tween-20 was added on the apical side to induce cytotoxicity as a positive control. CyQUANT LDH Cytotoxicity Assay (ThermoFisher), Lumit Interleukin (IL) 6, and Lumit IL-1 p (Promega) were used according to the manufacturer’s protocol on apical washes. CellTiter 96 Aqueous Cell Proliferation Assay (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, MTS) (Promega) was performed on the apical side of MucilAir according to manufacturer’s protocol.

[0222] Example 6: Resistance against modified P-cyclodextrin

[0223] LLCMK2 were seeded on a 6 well plate (300’000 cells / well). Clinical PIV3 was used to infect LLCMK2 with an MOI of 0.01 . After 1 hour at 37°C, the virus inoculum was removed. CD-SLNT (50 pg / mL) or CD- MUS (1 pg / mL) were added onto cells diluted in DMEM 0% FBS with 1 :10’000 TPCK trypsin. After 5 days post-infection, the supernatant was collected and centrifuged at 2’000 rpm for 5 min. Viruses were titered on LLCMK2. Subsequent passages were performed with the previous virus (MOI 0.01) and modified 0- cyclodextrin concentrations were doubled.

[0224] 3D representation

[0225] HN was sequenced as described above. Sequences were aligned with MF987836 with Geneious Prime. HN sequence was then translated into amino acid with Expasy (Swiss Institute of Bioinformatics). The 3D model was built with SwissModel [A. Waterhouse et al, Nucleic Acids Res, 2018, 46(W1), W296- W303] using 6c0m.1.A [M. Pascolutti et al, ACS Chem Biol, 2018, 13(6), 1544-1550] as a template before being visualized with Chimera X version 1.4rc202205290614.

[0226] Statistics

[0227] In vitro experiments were performed in duplicate with at least two independent experiments unless otherwise indicated. Ex vivo experiments were performed with at least two MucilAir in independent experiments unless otherwise indicated. Results are shown as the mean and standard error of the mean. Half maximal effective concentration (ECso) and 50% cytotoxicity concentration (CCso) were calculated with GraphPad Prism version 9.1. One orTwo-way ANOVA followed by multiple comparison analysis was used as statistical tests to compare grouped analysis. An unpaired f-test was used to compare two different conditions. The area under the curve analysis followed by one-way ANOVA was done to compare curves.

[0228] Example 7: Identification of glycans used as attachment

[0229] Before entering the host cell, viruses must attach to the host cells. Inhibition of this interaction allows to stop the life cycle of viruses. We assessed the attachment receptors used by PIV3 (Figure 1). Therefore, we used a glycan array containing 100 different sugars incubated overnight at 4°C with a laboratory strain (ATCC) and two clinical samples (2017 and 2021) of PIV3 (Figure 1A). After quantifying the fluorescence of the positive spots in the array (Figure 1 B), we found that heparin octasaccharide and (LS- tetrasaccharide d) LSTd were common hits among the three strains (Figure 2A, B). Sialyl Lewis x Pentasaccharide and Manose-9 were also found for the ATCC strain.

[0230] To confirm the need for sialic acid by our different strains of PIV3, we infected A549 cells deficient in the expression of sialic acid on their surface by solute carrier family 35 member A1 (SLC35A1) knockout (Figure 2C). All three strains of PIV3 used showed a significant reduction in infectivity in knockout cells, comparable to EV68 used as a positive control.

[0231] Example 8: Synthesis and characterization of newly modified P-cyclodextrin

[0232] It has been shown previously that modified p-cyclodextrin can be synthetized to mimic attachment receptors. We synthetized these macromolecules to mimic the two hits of our glycan array. CD-MUS (Figure 3A), synthesized as previously described [S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318], harbors a negative charge due to a sulfonate at its end and thus mimics the negative charges of heparin octasaccharide and of heparan sulfate [S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318]. Modified 0- cyclodextrins with LSTd at their end have never been synthetized before. We used the same process as the recently published CD-3’SLN [0. Kocabiyik et al, Adv Sci 2020, 8(3), 2001012.] (Figure 3B). LSTd was grafted onto a p-cyclodextrin with an 11 -carbon linker with different equivalences (1.2, 0.6, 0.3, 0.15, i.e amount of glycan relative to the available position on the activated p-cyclodextrin) and will be named CD-SLNT (Figure 3C) in the following text. To identify the minimal motif for effective antiviral activity, we add as modified p-cyclodextrin, macromolecules with shorter glycan of LSTd at their ends. CD-3’SLN as synthetized previously [O. Kocabiyik et al, Adv Sci 2020, 8(3), 2001012] represents the intermediate motif while CD-SA has only sialic acid at its end (Figure 3D).

[0233] Characterization of the modified p-cyclodextrin was performed by High-Performance Liquid Chromatography (HPLC) with Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR). HPLC- MS was done with CD-SLNT 0.15 and showed three peaks with 30, 45, and 54 min as retention time (Figure 3E). These peaks had different MS profiles with major peaks at 1834, 1568, and 1914 m / z (Figure 3F). This suggests that modified p-cyclodextrins have 1 , 2, or 3 LSTd respectively at their end. Unfortunately, NMR studies require more material and solubility issues limited the starting material of HPLC-MS data.

[0234] Example 9: Synthesis of cyclodextrin derivatives.

[0235] Cyclodextrin Core p-cyclodextrin(-S-C11-COOH)7 (M. Amonsen etal, Journal of Virology, 2007, 81 , 8341- 8345; N. Lee et al, PLoS One, 2018, 13, e0195525): All reagents were dried before use under -2.5x10- 2mbar at room temperature for 48 hours; dry solvents were purchased and used as received. Potassium tert-butoxide (tBUOK, 82.47 mmol: 8.7g, Sigma) and 12-mercaptododecanoic acid (35.28 mmol: 8.2 g, Sigma) were dissolved in 100 mL of dry DMF under an argon atmosphere and the mixture was stirred at room temperature using a mechanical stirrer, 300rpm. Heptakis-(6-deoxy-6-iodo)-p-Cyclodextrin (4.2 mmol: 8 g, Arachem) was added to the mixture after one hour, the mixture was placed in an oil bath at 70°C and the reaction proceeded overnight (12 hours). The crude, was precipitated into 1 L of diethyl ether (Et20) and vacuum filtered with a fritted disk funnel (POR 3). The solid on the filter was collected (25 g), dissolved in 190 mL of distilled water. Then 380 mL of ACN was added to the aqueous solution creating an off-white homogeneous suspension. This mixture was vacuum filtered (POR4) - the crude was allowed to percolate through the filter by gravity: once a flow of solvent was observed by gravity alone, the vacuum assisted filtration was turned on and the filtration went smoothly. -12 grams of an off-white solid was collected and dried. It was again dissolved in 200mL of pure water and precipitated into 0.1 M HCI, to obtain the protonated species as a white powder, collected via centrifugation in 45mL Falcon tubes, followed by decantation. 1 H NMR (400 MHz, TFA-d) 5 5.37 (d, J = 3.6 Hz, 1 H, glucose H-1), 4.35 (t, J = 9.0 Hz, 1 H, glucose H-3), 4.28 (t, J = 7.4 Hz, 1 H, glucose H-5), 4.10 (dd, J = 9.9, 3.4 Hz, 1 H, glucose H- 2), 3.88 (t, J = 9.3 Hz, 1 H, glucose H-4), 3.48 (d, J = 12.8 Hz, 1 H, glucose H-6a), 3.24 (dd, J = 13.5, 7.6 Hz, 1 H, glucose H-6b), 3.00-2.84 (m, 2H, S-CH2-CH2), 2.64 (t, J = 7.6 Hz, 2H, CH2-COOH), 1.86 (q, J = 7.4 Hz, 4H, CH2-CH2-COOH, S-CH2-CH2), 1.53 (m, 14H, S-C-C-CH2-CH2-CH2-CH2-CH2-CH2-CH2- C-C-C00). HRMS (nanochip-ESI / LTQ-Orbitrap) m / z: [M-3H]3- Calcd for

[0236] C126H221042S73- 877.5133; Found 877.1148.

[0237] Activated p-cyclodextrin(-S-CD-NHS)7 (M. Amonsen et al, Journal of Virology, 2007, 81 , 8341-8345; N. Lee et al, PLoS One, 2018, 13, eO195525): |3-CD-(-S-C11-COOH)7 (0.377 mmol: 10 g) was dissolved in 100 mL DMSO under magnetic stirring until a transparent homogeneous solution formed. Then, N- hydroxysuccinimide (5.317 mmol: 1.03 g, Sigma Aldrich) was added followed by the addition of 1-Ethyl- 3-(3-dimethylaminopropyl)carbodiimide (9.53 mmol: 1.85 g Sigma Aldrich), and 4-Dimethylaminopyridine (1 .22 mmol: 150 mg Sigma Aldrich) and stirred for 12 hours. The crude was washed with cold acidic water (500|j L of 1 M HCI into 2L of MilliQ Water kept at 4°C) and centrifuged at 5500 rpm at 4°C for 5 minutes inside 45mL falcon tubes. Generally, four falcon tubes were filled with 30mL of the acidic water. Then, 10mL of the crude was added into the 30mL of acidic water into per tube, forming a white precipitate. The dispersion was centrifuged at 5500 rpm, the supernatant discarded, another 30mL of the acidic water added, followed by the crude, repeating the procedure until the pellet became too large for the falcon tube. The procedure was started using a new falcon tube to complete all the 100mL of crude. Once the solid was collected, additional washes with acidic washes were performed, aiming at 5 washes per pellet. The pellets were redispersed using a sonicator bath in alternation with vigorous shaking and vortexing. As the number of washes progressed, the time of centrifugation was extended to 10 or 15min as needed to sediment all the visible solid material. Then, Acetonitrile (ACS grade, Sigma Aldrich) was used to wash the white crude. Sonication and vigorous agitation with the aid of a vortex was used to completely redisperse the crude in Acetonitrile and centrifuge it down at 5500 rpm and 4°C. This was repeated until a cloudy white supernatant that could not be further sedimented under these conditions was formed. This translucent (opaque) off-white supernatant was discarded and the wash was finished using Diethyl Ether (ACS grade, Fisher Scientific). The crude was dispersed in Et20 using vigorous agitation, vortexing and sonication when needed. The Et20 washed were done 5 times to completely remove the acetonitrile The final pellets were dried inside a desiccator under high vacuum for 12 hours and collected as a dry powder (~12 grams).

[0238] Characterization of relevant batches using HPLC-MS. HPLC-MS (Agilent 1260 6470 LC / TQ) using a Hilic Amide column (Waters, XBridge BEH Amide 5pm, 4.6x250mm) following the gradient below was performed for each sample.

[0239] Despite the promising results, the synthesis of the macromolecule presents challenges, as it yields CDs with complex mixtures of substitution levels and ligand positions, rather than single, well-defined chemical entities. However, various batches of CD-SLNT / SO3- tested against IAV H1 N1 and RSV revealed consistent antiviral activity (Figure 20C, E). Characterization via HPLC-MS indicated that the most abundant species is CD with one single SLNT and multiple sulfonate groups (Figure 25), this is in line as well with the reduced activity of batches with higher degrees of substitution (Figure 20B, D, E). Although each batch demonstrates reproducible antiviral activity, this heterogeneity must be considered when interpreting structure-activity relationships. These findings also highlight that developing multivalent materials does not necessarily lead to higher potency.

[0240] Table 2: Method used for HPLC characterization. A is MilliQ water with 10mM of ammonium formate, pH 3 and B is mass grade Acetonitrile.

[0241] Example 10: In vitro efficacy of CD-MUS and CD-SLNT against PIV3

[0242] To test the antiviral activity of the newly synthesized modified p-cyclodextrin, we incubated the laboratory and clinical strains of PIV3 with CD-SLNT and CD-MUS (Figure 4A). As an alternative to CD-SLNT, to find the minimal motif that allows antiviral activity, we tested as well CD-3’SLN [0. Kocabiyik et al, Adv Sci 2020, 8(3): 2001012] and CD-SA.

[0243] CD-MUS showed ECso of 2.5, 1.5, and 0.16 pg / mL (0.8, 0.5 pM, and 52.6 nM) for the ATCC, 2017 and 2021 strains respectively (Figure 5A, B, C). The activity against the ATCC strain was similar to the previous study that tested CD-MUS against PIV3 (1.198 pg / mL) [S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318]. We confirmed that CD-MUS is also potent against the clinical isolates.

[0244] CD-SLNT showed antiviral activity with the least substituted modified p-cyclodextrin (0.15) with an ECso of 65.87 and 38.31 pg / mL (13.6 and 8 pM) for 2017 and 2021 clinical PIV3 respectively (Figure 6A-C). CD-SLNT with 0.15 equivalence showed a mixed composition of 1 , 2, and 3 LSTd grafted onto modified P-cyclodextrin (Figure 3E-F). Interestingly, this correlated with the number of sialic acid binding regions present on the HN protein. CD-SLNT 0.3 also showed high efficacy, especially for 2017 (ECso of 22.79 pg / mL). In contrast, with the 0.6 or 1.2 equivalence that probably presents 5 to 7 LSTd grafted on the macromolecule, we observed no antiviral activity against the three strains of PIV3. This excess of LSTd might produce steric hindrance. Since they would have no space available to bind, it will result in a repulsive force that is counterproductive for inhibition. These data underline the importance of multivalency that correlate with the number of binding pockets available to achieve inhibition. As confirmation, LSTd alone had an ECso of 90.6 pg / mL (85.8 pM) against PIV3 ATCC (Figure 6A) while did not show antiviral activity against clinical isolates of PIV3 (Figure 6B-C).

[0245] Interestingly, when the incubation between CD-SLNT and PIV3 was performed at 4°C (i.e., the same temperature of the glycan array), higher potency was observed with CD-SLNT 0.3 (ECso of 14.89, 8.26, and 5.53 pg / mL against PIV3 ATCC, 2017 and 2021 respectively) (Figure 6A-C). At this temperature, the conformational stability of HN could be increased and thus allow better interaction with CD-SLNT. This temperature could also allow more stability of the modified p-cyclodextri n resulting in fewer conformational clashes between the macromolecule and HN. However, CD-SLNT 0.15 against clinical isolate did not follow the same rule which could be due to a decreased solubility of this macromolecule at this temperature. Against PIV3 ATCC, however, CD-SLNT 0.15 showed higher potency at 4°C underling a possible combined effect of stability of modified p-cyclodextri n / HN and solubility of CD-SLNT.

[0246] CD-3’SLN and CD-SA, two modified p-cyclodextri n with reduced length of LSTd, showed no antiviral activity (CD-3’SLN) or reduced potency (CD-SA) expect for PI v3 ATCC that had an ECso of 59.18 pg / mL (Figure 7). 3’SLN and SA were not observed in the positive hits of the glycan array. Therefore, the HN protein might have a specific preference for LSTd and not for reduced sialic acid glycans.

[0247] Modified p-cyclodextri ns showed virucidal activity against various viruses [S. T. Jones et al., Sc / . Adv. 2020, 6, eaax9318]. This effect is the result of forces on the virus surface created by the linker between the p-cyclodextri n and the ligand [V. Cagno et al, Nat Mater, 2018, 17(2), 195-203]. This linker must be sufficiently long [S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318], hydrophobic [O. Kocabiyik et al, Adv Sci 2020, 8(3), 2001012], and slightly flexible [S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318; O. Kocabiyik et al, Adv Sci 2020, 8(3), 2001012], We, therefore, tested if CD-MUS and CD-SLNT have virucidal activity against the different PIV3s used (Figure 4B). We incubated for 1 hour or 2 hours at 37°C with CD-MUS and CD-SLNT respectively 105plaque-forming units of PIV3. We then diluted the reaction at non-i n hi bitory concentrations of the molecules to assess if the virus was irreversibly inhibited. CD-MUS induced a complete loss of infectivity with ATCC and the 2021 clinical isolate of PIV3 while a significant 1.34 log decrease in the 2017 clinical isolate was observed (Figure 5D-F). CD-SLNT, instead, showed a 1.79 log and 0.74 log decrease in infectivity with 2017 and 2021 clinical isolates respectively (Figure 6D-F). Although CD-MUS had better virucidal activity, CD-SLNT showed as well virucidal effect on PIV3 clinical isolates. An higher dose of CD-SLNT could have a similar virucidal activity than CD-MUS.

[0248] Example 11 : Structural analysis of HN

[0249] To understand the differences in antiviral activity between the different strains of PIV3, we sequenced the HN protein of PIV3. We hypothesized that the modified p-cyclodextri ns bind HN since this protein is responsible for binding sialic acid on the cell triggering fusion. We identified 20 amino acid differences in the HN protein among the three PIV3 strains used (Figure 8A). The majority of mutations are located on the virion's surface. We then modeled the resulting protein by homology modeling using SwissModel between amino acids 142 and 572 showing the head of the HN protein (Figure 8B). Two regions near the sialic acid binding site (red circle) are of interest. The first one is in the region of the amino acid 501 in PI V32021 (S501 L) (green circle) which changes the surface of the protein. This could potentially change the binding of the modified P-cyclodextrin in this region. The second, near the dimer interface represented by a black circle, showed a higher electronegativity due to residue 556 in PIV3 ATCC (N556D) which could result in a lower ability to bind with CD-MUS. These results correlate with the ECsos of CD-MUS suggesting a favorable impact of S501 L while the opposite for N556D. To understand the impact of these mutations on CD-SLNT, additional experiments such as in silico modeling between HN and the different CD-SLNT are needed.

[0250] Example 12: Efficacy of CD-MUS and CD-SLNT on ex vivo respiratory tract

[0251] To test the efficacy of modified p-cyclodextrin against PIV3 in a human derived reliable model, we used a human upper respiratory tract pseudostratified epithelium (MucilAir). This ex vivo tissue has an air-liquid interface and has been used in different studies with respiratory viruses This model presents the different cell types of the respiratory tract: basal, goblet, and ciliated cells. Overall, this pseudostratified human respiratory tissue represents one of the best current models to study respiratory viruses in their natural tropism.

[0252] We evaluated the toxicity on MucilAir with once-daily administration of CD-MUS and CD-SLNT by cell viability with lactate dehydrogenase (LDH) release, MTS, and cytokine (IL-1 and IL-6) release. Both modified p-cyclodextrin (CD-MUS and CD-SLNT) did not show a reduction in cell viability (Figure 9A). Although CD-SLNT did not show LDH release similarly to what was observed with a similar modified p- cyclodextrin [0. Kocabiyik et al, Adv Sci 2020, 8(3), 2001012], LDH release on the apical side increased significantly after 4 administrations of CD-MUS (Figure 9B) and not on the basal side (data not shown) in line with a previous study [S. T. Jones et al., Sci. Adv. 2020, 6, eaax9318]. This highlights apical toxicity that did not involve the entire tissue. IL-6, a pro-inflammatory cytokine, was not released after CD-MUS and CD-SLNT treatments compared to untreated (Figure 9C). Whereas CD-SLNT and untreated showed similar apical release of IL-1 p, another pro-inflammatory cytokine, we observed an overall higher level with CD-MUS (Figure 9D). Moreover, we observed a decreasing trend in released IL-1 p for each condition which could be due to stress adaptation of MucilAir after the alteration of their air-liquid interface.

[0253] To test the efficacy ex vivo, we used the original clinical sample of PIV3 2021 that was never grown on LLCMK2. First, we incubated viruses with CD-MUS or CD-SLNT 0.15 with the highest concentration used in vitro (100 or 300 g / mL respectively) (Figure 10A). After 1 hour at 37°C, MucilAir were infected at 33°C and the inoculum was removed. Levels of daily apically release PIV3 were assessed by RT-qPCR. Under this condition, we observed that CD-MUS and CD-SLNT limit the infection (Figure 10B). No increase in apically released PIV3 was observed after pre-incubation with CD-SLNT indicating that the virus did not grow. This result is also consistent with the absence of increased IL-6 expression (Figure 10C). However, although delayed, PIV3 replicated in the CD-MUS treated condition. The level of IL-6 was similar or higher with CD-MUS than untreated even if PIV3 in the apical wash did not reach a similar level as untreated. This effect could be mainly due to the growth of the virus since IL-6 was not induced by CD-MUS treatment alone (Figure 9C). Overall, CD-SLNT showed a better inhibition profile since PIV3 infection and cytokine release were limited.

[0254] Example 13: Resistance against CD-MUS and CD-SLNT

[0255] To evaluate the barrier to resistance of our modified p-cyclodextrins, we passaged 2021 clinical isolate of PIV3 with increasing concentrations of CD-MUS and CD-SLNT (Figure 11 A). CD-MUS induced cytotoxicity with a CCso of 87.91 g / mL after 5 days limiting the final concentration that can be used while it was not observed for CD-SLNT (Figure 11 B). After three passages, we evaluated the efficacy of CD- MUS (Figure 11 C) and CD-SLNT 0.15 (Figure 11 D) with the untreated virus and the virus passaged with CD-MUS and CD-SLNT 0.3. At passage 3, CD-MUS and CD-SLNT still showed antiviral activity against the different viruses similarly or with increased sensitivity compared to the original clinical PIV3 isolate.

[0256] Example 14: Combination antiviral studies with CD-MUS and CD-SLNT

[0257] CD-MUS showed high efficacy but induced toxicity in vitro and ex vivo. Conversely, CD-SLNT showed lower efficacy but no impact on cytotoxicity in the two models used. Both molecules limited or delayed the infection in the human upper respiratory tract. Therefore, we tested the combination of these two drugs against PIV3 to see if we could combine the positive features of both macromolecules. We mixed CD- MUS and CD-SLNT 0.15 and incubated with the different strains of PIV3 for 1 hour at 37°C. Synergy scores were then obtained with SynergyFinder 3.0 (Figure 12) [A. Ivanevski et al, Nucleic Acids Res, 2022, 50(W1), W739-W743],

[0258] For PIV3 ATCC, results showed a clear antagonism between CD-MUS and CD-SLNT. This is probably due to the poor activity of CD-SLNT against this laboratory strain (Figure 6A). However, CD-SLNT could potentially still bind HN and reduced the accessibility of the binding site of CD-MUS. On the opposite, for PIV3 clinical isolates, synergy scores are at the limit of antagonism and additivity (i.e -10). All the different scores to evaluate synergism (Highest single agent (HAS), Loewe, Bliss, or Zero interaction potency (ZIP) ( B. Yadav et al, Comput Struct Biotechnol J, 2015, 13, 504-513 (2015); J. Tang, et al, Front Pharmacol, 2015, 6, 181; C. I. Bliss, Annals of Applied Biology, 1939, 26, 585-615; S. Loewe et al, Naunyn- Schmiedebergs Archiv fur experimentelle Pathologie und Pharmakologie, 1926, 114, 313-326; S. Loewe, Ergebnisse der Physiologie, 1928, 27, 47-187; A. H. C. Vlot et al, Drug Discovery Today, 2019, 24, 2286- 2298), were concordant with the antagonistic effect (Table 3). A direct interaction or different but closed binding sites between CD-MUS and CD-SLNT which would block the binding of modified p-cyclodextrins could explain this effect. Nevertheless, we observed a common area of synergism with a high concentration of CD-SLNT and low concentration of CD-MUS against clinical isolates of PIV3. Virus HSA Loewe Bliss ZIP

[0259] Table 3: Synergy score of combination CD-MUS & CD-SLNT.

[0260] This antagonist effect was investigated by a computational approach. SLNT was docked on site I of the sialic acid pocket previously described in the hemagglutinin-neuraminidase (HN) protein (M. Porotto et al, J Virol, 2007, 81 , 3216-3228; P. Yuan et al, Structure, 2005, 13, 803-815; Crennell, T. et al, Nat Struct Biol, 2000, 7, 1068-1074) (PDB 5B2D (M. Kubota et al, Proc Natl Acad Sci U S A, 2016, 113, 11579- 11584). The sialic acid was stabilized by a complex of three arginines. SLNT was not possible to dock on site II at the dimer interface (M. Porotto et al, J Virol, 2007, 81 , 3216-3228; M. Porotto et al, J Biol Chem, 2012, 287, 778-793; T. C. Marcink et al, mBio, 2020, 11). Molecular dynamics of 500 ns were performed with 10 CD-MUS around the hemagglutinin-neuraminidase protein (PDB 4MZA (R. Xu et al, mBio, 2013, 4, e00803-00813)). Most of the amino acids with which CD-MUS interacts by hydrogen bonds, water bridges, or ionic interactions are lysines (30.7%), asparagines (19.5%), threonines (16.5%) and arginines (12.7%) due to their polarity. Although they showed to bind mainly distal locations to the sialic acid binding site, interactions were observed in and around the site I sialic acid binding pocket, including with the arginines interacting with SLNT. These data support the antagonism observed experimentally since the binding of one CD could prevent the interaction of the other.

[0261] To better investigate the possible synergism without the structural interaction among modified 0- cyclodextrins that might lead to the antagonism, we synthetized a modified p-cyclodextrin with LSTd and sulfonate as active ligands (Figure 14). During the synthesis of CD-SLNT 0.15, we added taurine to add a sulfonate group to the free site on the p-cyclodextrin. This represents a combination of CD-MUS and CD-SLNT on the same p-cyclodextrin which could overcome the antagonism and increase the overall solubility of the molecule. We, therefore, tested CD-SLNT / taurine against PIV3. We observed an increase in potency compared to the original CD-SLNT against 2017 PIV3 (ECso 14.4 pg / mL compared to 65.9 pg / mL) and against 2021 PIV3 (ECso 27.6 pg / mL compared to 38.3 pg / mL) (Table 4). This result shows that the combination of these ligands on the same modified p-cyclodextrin could be beneficial against PIV3 and gives a broad-spectrum inhibitory activity (Table 4) against multiple respiratory viruses: influenza H1 N1 , influenza H5N1 , respiratory syncytial virus and SARS-CoV-2.

[0262] Furthermore, CD-SLNT / SO3- was tested against PIV3. We observed a further increase in potency compared to the original CD-SLNT against 2017 PIV3 (ECso 0.19 pg / mL compared to 65.9 pg / mL) and a similar potency against 2021 PIV3 (ECso 0.6 pg / mL compared to 38.3 pg / mL) (Figure 20). This result shows that the combination of these ligands on the same modified p-cyclodextrin could be especially beneficial against PIV3 and gives a broad-spectrum inhibitory activity against multiple respiratory viruses: influenza H1 N1, influenza H5N1, respiratory syncytial virus and SARS-CoV-2. In summary, an initial combination of the sulfonated CD-MUS and the sialylated CD-SLNT was explored against hPI V3, a virus known to use sialic acid and heparan sulfate as attachment receptors (Figure 2A, Figure 19) (M. Porotto et al, J Virol, 2007, 81 , 3216-3228; T. C. Marcink et al, Sci Adv, 2023, 9, eade2727). Both macromolecules showed antiviral and virucidal activity independently against hPIV3 due to their structural features (Figure 15) (S. T. Jones et al, Sci Adv, 2020, 6, eaax9318; O. Kocabiyik et al, Advanced Science, 2021, 8, 2001012). However, the combination of both CDs resulted in antagonism, which was explored with an in silico approach, showing the potential interference of the two macromolecules by binding to the residues close or within the sialic acid binding region. A similar antagonism is expected as well for other viruses such as IAV H1 N1. Indeed, lysine, asparagine, threonine, and arginine, the key interacting residues with CD-MUS, are locally present in the sialic acid binding region on the hemagglutinin of IAV (W. Zhang et al, J Virol, 2013, 87, 5949-5958; R. M. DuBois et al, J Virol, 2011, 85, 865-872; R. Xu et al, J Virol, 2012, 86, 982-990) and could interact with the glycans mediating the interference.

[0263] Example 15: Potential broad spectrum activity of CD-MUS and CD-SLNT

[0264] CD-MUS and CD-SLNT have the potential to have a broad-spectrum activity against different viruses because they mimic common attachment receptors. CD-SLNT was therefore tested against other sialic acid-dependent viruses: H5N1 IAV (Figure 13A) and EV68 (Figure 13B). Against the avian strain of IAV, CD-SLNT showed high efficacy similar to CD-3’SLN [O. Kocabiyik et al, Adv Sci 2020, 8(3), 2001012], The 0.15 equivalence showed a lower ECso than 0.3 (0.145 versus 1.48 g / mL) indicating that less substituted modified p-cyclodextrin is also preferred against H5N1 IAV.

[0265] Example 16: Pan- activity of the dual active molecule against respiratory viruses in vitro

[0266] To overcome the antagonism of the two cyclodextrins, a new CD with SLNT and sulfonate as active epitopes on the primary face was synthesized: CD-SLNT / SO3- (Figure 14). CD-SLNT / SO3- showed lower ECso on clinical isolates of hPIV3 if compared to CD-SLNT (Table 4). Additionally, molecular dynamics support the biological results, confirming that SLNT can bind to the sialic acid pocket while the sulfate can interact with other residues without interference.

[0267] More importantly, this dual-active molecule can mimic simultaneously heparan sulfate and sialic acid and has a broader antiviral activity. CD-SLNT / SO3- was therefore tested against a panel of viral pathogens with an MOI of 0.001 (hPIV3, SARS-CoV-2, HSV-2), 0.008 (IAV H1 N1 , IAV H5N1 , IBV) and 0.01 (RSV, IAV H7N1). The macromolecule showed activity against IAV (H1 N1), IBV, SARS-CoV-2, RSV, and HSV- 2 and also against two different avian strains of IAV (H5N1 and H7N1) (Table 4) in the low micromolar to nanomolar range. To evaluate the variation of EC50 in presence of different viral amounts, a dose response assay at different MOIs was performed against IAV H1 N1 (Figure 22). The results, evidence, as expected by the mechanism of action, a shift in the EC50. However, even at MO1 1 CD-SLNT / SO3- has a ECso of 66.62 nM. Virus CD-MUS (EC50) CD-SLNT (EC50) CD-SLNT / SO3- Virucidal [pg / mL] [pg / mL] (EC50) [pg / mL] CD-SLNT / SO3- hPIV3 Clinical #1+ 1.54 65.59 0.19 Y

[0268] (506.28 nM) (18'469.74 nM) (47.76 nM) RSV 0.74 >300 2.29 Y

[0269] (242.62 nM) (576.69 nM) IAV HlNlt 6.11 0.13 0.051 Y

[0270] (2'007.39 nM) (36.32 nM) (12.82 nM) IAV H5N1 54.86 0.15 0.55 Y

[0271] (18'035.61 nM) (39.62 nM) (138.27 nM) HSV-2 1.11 >300 20.14 n.a (364.92 nM) (5'063.02 nM)

[0272] Table 4: Antiviral activity of CD-MUS, CD-SLNT, and CD-SLNT / SO3-. Effective concentration inhibiting 50% of vims infection (ECso). Molarities were calculated considering the main synthesized macromolecule, n.a: not assessed, t Viruses for which CD-SLNT / S03- is more potent than both CD-MUS and CD-SLNT.

[0273] Virucidal activity of CD-SLNT / S03- was confirmed against hPIV3, RSV, IAV, and differently than CD- MUS, against SARS-CoV-2 as well. The assay was performed with approximately 105infectious viruses at a dose of 300 pg / mL (75.42 pM) corresponding to the EC99 at a high viral load (Table 4, Figure 22, Figure 23). Importantly, the investigation of virucidal kinetics on IAV and hPIV3 revealed rapid inactivation, even without preincubation for IAV (Figure 24A, B) or after only 10 minutes of exposure for h PI V3 (Figure 24C). Additionally, the virucidal activity was evaluated in the presence of varying amounts of IAV (Figure 23B), showing— as expected— a more pronounced effect at lower viral loads, but still a sustained reduction with a mean of 2.38 log units in infectivity. Moreover, the virucidal activity was validated using an octadecyl rhodamine B chloride (R18) release assay (A. C. Zwygart et al, C J Med Virol, 2024, 96, e70101 ; Y. Zhu et al, Pharmaceutics, 2023, 15), which assesses membrane integrity by measuring the release of a fluorescent dye. As expected, an increase in fluorescence was observed in the presence of 1 % Triton X-100 (positive control) and CD-SLNT / S03-, indicating membrane disruption. In contrast, no increase was seen with diethylstilbestrol (DES), which was previously reported to bind hemagglutinin and prevent viral entry without disrupting the membrane (Franzi, G. et al, Int J Mol Sci, 2023, 24) (Figure 24D). Characterization of CD-SLNT / S03- by high-performance liquid chromatography coupled with mass spectrometry showed, as expected, a mixture of CDs (Figure 25) with a prevalent species being a CD harboring one SLNT and multiple sulfonate groups. Different batches were synthesized to assess the reproducibility of the synthesis, and the different batches showed consistent activity against IAV H1 N1 and RSV (Figure 20C, E). Furthermore, for viruses dependent on sialic acid (hPIV3, IAV), an increase of SLNT grafted at the surface of CD-SLNT / SO3- reduced the potency of the macromolecule as also shown for CD-SLNT against h PI V3 (Figure 20B, D, E) while the effect was not observed for RSV which does not depend on sialic acid (Figure 20C).

[0274] Example 17: Resistance to CD-SLNT / SO3-

[0275] To investigate the barrier to resistance of CD-SLNT / S03-, hPIV3 clinical #2 and IAV H1 N1 were passaged 10 times in the presence of an increasing concentration of the macromolecule. After the last passage, the antiviral activity of CD-SLNT / SO3- was assessed against the virus passaged 10 times in the presence or absence of the macromolecule. After 10 passages, no resistance of hPIV3 to the macromolecule was detected (Figure 16A). However, regarding IAV H1 N1, the antiviral potency of CD-SLNT / SO3- was reduced by 28 times against treated viruses compared to the untreated virus for which the macromolecule already lost 10 times its antiviral activity after 10 passages (Figure 16B). Two CD-SLNT / SO3- resistant IAV variants were purified by plaque assay (Figure 16B) and the whole genome was sequenced to determine whether specific mutations were present. Several mutations were identified (Table 5), two of which, K154E and G155E, are located close to the sialic acid binding site of the hemagglutinin. In the GISAID database, they are observed to be present in less than 1 % of the sequenced Influenza viruses (Table 5).

[0276] In summary, the barrier to resistance of CD-SLNT / SO3- was evaluated against hPIV3 and IAV H1 N1. While for hPIV3, no signs of resistance were observed (Figure 16A), IAV H1 N1 revealed a reduction in potency after ten passages (Figure 16B). Although cell adaptation might already alter the efficacy of CD- SLNT / SO3-, additional mutations were identified on two different resistant viruses that may abolish the antiviral activity of the macromolecule (Table 5): in the hemagglutinin gene, K154E and G155E mutations are located near the sialic acid binding site, supporting the mechanism of action. Gene Mutation Frequency in

[0277] GISAID

[0278] Table 5: Influenza A H1N1 mutations after resistance to CD-SLNT / SO3-. showing bold HA mutations are closed to the sialic acid binding pocket of the protein. #1, #2 Mutations present in the resistant plaque-purified Influenza A H1N1 viruses #1 or#2 respectively. * Mutations present in one replicate of untreated virus t V479 is the natural amino acid of Influenza A H1N1 hemagglutinin. Example 18: Broad-spectrum activity of CD-SLNT / S03- ex vivo.

[0279] The efficacy of CD-SLNT / S03- was then evaluated in a more relevant model for viral infections: human- derived, pseudostratified airway epithelium from the upper respiratory tract. This model allows the study of clinical strains without cell adaptation and enables the assessment of receptor usage and true viral tropism, as the primary target cells for these viruses are predominantly ciliated cells. HPIV3, SARS-CoV- 2, RSV, or IAV H1 N1 were pre-incubated for 1 hour at 37°C with 300 pg / mL of CD-SLNT / SO3- (75.42 pM) to assess whether CD-mediated viral inactivation was sufficient to delay viral replication. Human respiratory airways were then infected and maintained at 33°C for 4 days without further addition of the macromolecule. Apical washes were collected every day, and the viruses were quantified by RT-qPCR. In all infected tissues treated with CD-SLNT / SO3-, a significant reduction of apically released viruses was observed (Figure 17). The infectivity of apically released IAV H1 N1 and SARS-CoV-2 viruses was also evaluated at two different time points, showing a significant reduction in infectious virus at 48 hpi for both respiratory viruses (Figure 26A, B). Additionally, an experiment with treatment at the time of infection, without pre-incubation, was performed with hPIV3, showing a significant reduction in apically released viruses under this condition as well (Figure 26C). CD-SLNT / SO3- did not show ex vivo toxicity by the measurement of cell viability or LDH release even with daily addition of the macromolecule (30 pg - 7.54 nmol) (Figure 21 C, D).

[0280] I n summary, the activity of CD-SLNT / SO3- was verified in ex vivo human respiratory tissues, which proved to be relevant for respiratory viruses (73-76), the macromolecule reduced apically released hPIV3, RSV, IAV H1 N1 , and SARS-CoV-2 (Figure 17 and Figure 26A, B).

[0281] Example 19: Activity in vivo of CD-SLNT / SO3-

[0282] The antiviral activity of CD-SLNT / SO3- was assessed against IAV H1 N1 in a zebrafish larvae model. This model has previously been shown to express sialic acid, support IAV infection, and has been used by various research groups to study the host response and pathogenicity of IAV (K. A. Gabor et al, Dis Model Meeh, 2014, 7, 1227-1237; B. L. Soos et al, Viruses, 2024, 16; M. Goody et al, PLoS Curr, 2017, 9). Furthermore, a known antiviral molecule, baloxavir acid, is able to inhibit virus replication, demonstrating that the model is suitable for testing antivirals. IAV H1 N1 and 100 pg / mL CD-SLNT / SO3- (25.14 pM) were co-injected into the swim bladder of zebrafish larvae without further addition of the macromolecule (Figure 18A). A pool of 10 zebrafish were harvested at different time points to quantify the amount of viral RNA. The addition of CD-SLNT / SO3- during infection inhibited the replication of IAV H1 N1 virus by 1.68 log (Figure 18B). No signs of toxicity or locomotor impairment (J. Van Dycke et al, Nat Protoc, 2021, 16, 1830-1849) were observed by the addition of CD-SLNT / SO3-, in comparison to DMSO-treated control.

[0283] The antiviral activity of CD-SLNT / SO3- was further evaluated against RSV in vivo in a mouse model. Mice were infected with an RSV strain harboring a luciferase reporter gene. This infection model has been extensively used to test antiviral efficacy (V. Cagno et al, Nature Materials, 2018, 17, 195-203; S. M. Sake et al, Nat Commun, 2024, 15, 1173). The bioluminescence measured during the experiment has been shown to be a reliable marker of viral load in the lungs and therefore reflects the infection in real time (M. A. Rameix-Welti et al, Nat Commun, 2014, 5, 5104). Mice were treated with 5 mg / kg / day of CD- SLNT / SO3- 10 min before infection with RSV and daily for 3 days (Figure 18C). The luciferase activity in the nose and lungs of mice was measured at days 2 and 4 post-infection. CD-SLNT / SO3- treatment was shown to inhibit RSV replication at days 2 and 4 post-infection (Figure 18D, E). These results were reproduced in an independent experiment (Figure 27A). No loss of weight was observed by the administration of CD-SLNT / SO3- in mice (Figure 27B).

[0284] Finally, the therapeutical activity of CD-SLNT / SO3- was also evaluated by treating RSV-infected mice starting 1-day post-infection with 10 mg / kg / day of CD-SLNT / SO3- (Figure 18C). In this setting, a comparable global reduction in viral replication was observed (Figure 18D, E). For both types of administration, a significant 0.3 log reduction of infection in the lungs of treated mice was observed (Figure 29C) and in the nose of pre-treated mice at day 4 post-infection (Figure 27D).

[0285] In summary, a dual-active CD was designed and synthesized that incorporates SLNT and sulfonate groups on its primary face, referred to as CD-SLNT / SO3-, providing a unique strategy to simultaneously target viruses using either or both receptors (Figure 14). the macromolecule was inhibiting and had virucidal activity against major respiratory viruses (IAV H1 N1 , IBV, SARS-CoV-2, RSV, and hPIV3) and against two avian strains of IAV (H5N1 and H7N1) (Table 4, Figure 22, 23, 24). While CD-SLNT / SO3- showed improved antiviral efficacy compared to either CD-MUS or CD-SLNT for each virus tested, the dual-active material demonstrated superior potency against a clinical isolate of hPIV3, IAV H1 N1 , and SARS-CoV-2 compared to both single active CD (Table 4) suggesting that the mixture of ligands confers to the material additional chemical properties. Indeed, the dual-active macromolecule has better efficacy than previous attachment inhibitors. For example, CD-SLNT / SO3- showed nanomolar activity against SARS-CoV-2 and IAV H1 N1 while other virucidal attachment inhibitors designed with a similar approach but with a different scaffold than p-cyclodextri n resulted in a micromolar activity (Y. Zhu et al, ACS Cent Sci, 2024, 10, 1012-1021). Additionally, CD-SLNT / SO3- has virucidal activity against SARS-CoV-2 in contrast to CD-MUS (Figure 23F)(M. Gasbarri et al,. Microorganisms, 2020). Furthermore, the kinetics of virucidal activity observed against IAV suggested a faster inactivation by CD-SLNT / SO3- (Figure 24A, B) than previously developed CD (S. T. Jones et al, Sci Adv, 2020, 6, eaax9318).

[0286] Conclusion

[0287] To find new antivirals against PIV3, a virus causing severe respiratory symptoms, especially in young children, we designed attachment inhibitors. We first identified glycans bound by PIV3: heparin octasaccharide and LSTd. Modified p-cyclodextri ns previously shown to have antiviral and virucidal activity were used as potential attachment inhibitors. We used a previously synthesized molecule, CD- MUS, and synthesized a new one, CD-SLNT, to mimic heparin octasaccharide and LSTd respectively. We observed that both molecules have antiviral and virucidal activity against PIV3, especially against clinical isolates without showing resistance so far. These molecules were also effective in limiting PIV3 infection in a human upper respiratory tract model and show broad-spectrum activity. Although CD-MUS and CD-SLNT seem to have an antagonistic activity, a novel modified p-cyclodextrin containing both ligands could be used to increase the potency of the attachment inhibitors. Furthermore, this dual active molecule shows inhibitory activity against several major human respiratory pathogens: namely PIV3, RSV, SARS-CoV-2 and different strains of Influenza virus.

Claims

CLAIMS1 . A compound comprising a core and at least one moiety L which is attached to the core, wherein the moiety L is a moiety of formula (I):wherein the compound includes up to 5 moieties -L of formula (I), preferably wherein the compound includes from 1 to 5 moieties -L, more preferably from 1 to 3 moieties -L; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the core is a macrocyclic core, preferably wherein the macrocyclic core is selected from a cyclodextrin (alpha, beta and gamma), a modified cyclodextrin, a cyclic biotin, a crown ether, a pillararene, a calixarene, a corrole, a phthalocyanine, a cucurbituril, a porphyrin, a macrocyclic peptide, a macrocyclic glycopeptide, a carbohydrate containing macrocycle, including Ipomomeassin F, glucolipsin A, forsytheenthoside A, clemahexapetoside A, clemahexapetoside B, clemoarmanoside A and tricolorin A, a macrocyclic lactone, including macrolides, a macrocyclic drug, including bacitracin, dactinomycin, geldanamycin, azithromycin, vancomycin, clarithromycin, roxithromycin, telithromycin, dirithromycin, carbomycin, josamycin, kitasamycin, midecamycin, oleandomycin, solithromycin, spiramycin, leucomycin, amphotericin B, simeprevir, lorlatinib, epothilone B, alisporivir, pacritinib, grazoprevir, paritaprevir, glecaprevir, sanglifehrin A, and cyclosporine, and macrocycle-based PROTAC, more preferably wherein the macrocyclic core is selected from a-cyclodextrin, 0- cyclodextrin and y-cyclodextrin, even more preferably wherein the macrocyclic core is 0- cyclodextrin.

3. The compound of claim 1 or 2, represented by formula (II):wherein x is 6, 7 or 8; each occurrence of each R’ and R” is independently selected from H, -(CH2)yi-COOH, and - (CH2)yi-SO3H, wherein each occurrence of y1 is independently an integer from 4 to 20; each occurrence of R is independently selected from -(CH2)y2-SO3-, -(CH2)y2-NH-(CH2)y3-L, - (CH2)y2-COOH, -(CH2)y2-CONH-(CH2)y3-L, and -(CH2)y2-CONHCH2CH2SO3H; each occurrence of Z is independently selected from -S-, -NH-, -N(Ci-s alkyl)-, -NH-C(=O)-, -N(Ci- 8 alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(Ci-e alkyl)-, -O-C(=O)-, -C(=O)-O-, -C(=O)-, and -O-; each occurrence of Y2 is independently an integer from 8 to 14; each occurrence of y3 is independent an integer from 2 to 5; provided that at least one R is either -(CH2)y2-NH-(CH2)y3-L or -(CH2)y2-CONH-(CH2)y3-L, preferably wherein at least one R is -(CH2)y2-NH-(CH2)y3-L; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein x is 7.

5. The compound of claim 3 or 4, wherein each R’ is H and each R is H.

6. The compound of any one of claims 3 to 5, wherein at least one instance of R is selected from - (CH2)y2-SO3-, -(CH2)y2-COOH, and -(CH2)y2-CONHCH2CH2SO3H, preferably wherein one or more R is -(CH2)y2-NH-(CH2)y3-L and each of the remaining instances of R is -(CH2)y2-SO3’.

7. The compound of any one of claims 3 to 6, wherein each occurrence of y2 is an integer from 6 to 10, preferably wherein each occurrence of y2 is 8.

8. The compound of any one of claims 3 to 7, wherein each occurrence of y3 is independently an integer from 2 to 4, preferably wherein each occurrence of y3 is 4.

9. The compound of any one of claims 3 to 8, wherein each occurrence of Z is independently selected from -S-, -NH-, N(CI-3 alkyl)-, and -O-, preferably wherein each occurrence of Z is S.

10. The compound of any one of claims 3 to 9, wherein at least one R is -(CH2)8-NH-(CH2)4-L, preferably wherein exactly one R is -(CH2)s-NH-(CH2)4-L and each of the remaining instances of R is -(CH2)8-SO3_.11 . The compound of any one of claims 3 to 10, wherein the compound of formula (II) is a compound of formula (Ila):or a pharmaceutically acceptable salt thereof, wherein x, Z, R, R’ and R” are as defined in any one of claims 3 to 10.

12. A pharmaceutical composition comprising the compound of any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. The compound of any one of claims 1 to 11 or the pharmaceutical composition of claim 12 for use as a medicament.

14. The compound of any one of claims 1 to 12 or the pharmaceutical composition of claim 12 for use in treating and / or preventing a viral infectious disease, preferably wherein the viral infectious disease is caused by a virus that binds to sialic acid and / or sulfonated / sulfated group, more preferably wherein said virus is a respiratory virus, sexually transmitted virus or vector transmitted virus, most preferred is a viral infectious disease selected from Paramyxoviridae family (such as PIV1 , PIV2, PIV3, PIV4, Nipah, Hendra virus or mumps), Orthomyxoviridae (such as influenza A virus H5N1 , H1 N1 or H3N2 or influenza B virus), Pneumoviridae (such as Respiratory Syncytial Virus and Human Metapneumovirus), Coronaviridae (such as SARS-CoV-2, MERS-CoV, , Human Coronavirus OC43), Herpesviridae (such as Herpes Simplex Virus (HSV) 1 , HSV2, cytomegalovirus), Caliciviridae (such as norovirus), Reoviridae (such as rotavirus), Papillomaviridae, Polyomaviridae, Adenoviridae and Flaviviridae (such as Zika virus, Dengue virus, West Nile Virus and Tick Borne Encephalitis Virus) and Poxviridae (such as Monkeypox).

15. The compound of any one of claims 1 to 11 for use in disinfection and / or sterilization.

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