WO2024200861A1

WO2024200861A1 - Heteromultivalent polymers and antiviral applications thereof

Info

Publication number: WO2024200861A1
Application number: PCT/EP2024/058879
Authority: WO
Inventors: Rainer Haag; Sumati Bhatia; Michael Schirner
Original assignee: Freie Universität Berlin
Priority date: 2023-03-30
Filing date: 2024-04-02
Publication date: 2024-10-03

Abstract

The invention relates to heteromultivalent polymers comprising a linear polymer backbone, wherein said backbone is substituted with at least one hemagglutinin binding moiety and at least one neuraminidase binding moiety, pharmaceutical compositions comprising the same and their medical use, in particular for viral infections.

Description

Heteromultivalent polymers and antiviral applications thereof

Description

Influenza A viruses (IAV) regularly challenge public health globally by causing seasonal influenza and sporadic pandemics leading to 3-5 million cases of severe illness and an estimated 290,000 to 650,000 deaths per year worldwide (https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal). World Health Organization. Influenza (Seasonal)). The unpredictable patterns of IAV antigenic drift and shift make the annual adaptation of vaccines challenging. Also, recent studies have illustrated that influenza A virus co-infection may enhance the severity of concomitant COVID-19 (Bai, L. et al. Cell Res 2021, 31 (4), 395-403; Cuadrado-Payan, E. et al. Lancet 2020, 395 (10236), e84; Stowe, J. et al., Int J Epidemiol 2021, 50 (4), 1124-1133.).

The IAV is an enveloped RNA virus whose membrane anchors two surface proteins, the homotrimeric hemagglutinin (HA) that binds to sialic acid (SA) on cell surfaces and the tetrameric neuraminidase (NA) which is a sialidase responsible for cleaving sialoside bonds between HA and SA . (de Vries, E. et al. Trends Microbiol 2020, 28 (1), 57-67. Vahey, M. D.; Fletcher, et al. Elife 2019, 8. Hamming, P. H. et al. Chem Sci 2020, 11 (1), 27-36. McAuley, J. L.; et al. Front Microbiol 2019, 10.) The process of IAV binding to host cell receptors is highly dynamic, and before ultimately being internalized, virus particles move along the host cell membrane.⁹ This process is facilitated by the multivalent attachment of multiple noncovalent HA-SA bonds that in turn can be cleaved by NA, resulting in a directional movement.^10-12

The NA also allows virions to move through the host mucus layer which is rich in sialylated glycoproteins. These sialylated glycoproteins otherwise could inhibit viral entry into the host system.¹³ Overall, the balance of HA receptor-binding and NA receptor-cleaving activity is pivotal for virus replication and transmission. Commercial anti-influenza drugs such as Oseltamivir and Zanamivir are NA inhibitors that can prevent the cleavage of sialoside bonds with HA proteins, thus able to interfere with the mobility as well as the release of newly formed virions from the host cell and consequently, the propagation of viral infection.¹⁴ The emergence of stable and transmissible drug resistance in IAV strains can render these drugs ineffective as suggested by oseltamivir and zanamivir-resistant IAVs.¹⁵ Neuraminidase binding drugs like Tamiflu are being used prophylactically or at the early stage of an influenza infection in high dosage of 30 mg (in patients with body weight <15 kg) to 75 mg (body weight >40 kg) daily for at least two weeks in high-risk patients by oral intake. The use of high dosage of this drug is also one of the reasons for development of Tamiflu-resistant viruses in patients infected with influenza.

Inhibiting the infection at an early step by targeting the HA to prevent binding and subsequent entry of the virus into the target cell is a promising approach. Multivalent sialoside-based polymers,¹⁶ dendrimers,¹⁷ nanoparticles,¹⁸’¹⁹ nanogels,²⁰’²¹ and proteins²² have overcome the low binding affinity (Kd ~ 2-4 mM)²³ of monovalent SA to HA through a multivalent effect and have shown significant inhibition of IAV binding to the host cells. However, due to the rather high amino acid sequence and structural variability of the HA binding pocket of different strains, broad activity with high efficacy is still elusive for most polysialylated inhibitors.²⁴’²⁵ Replacing SA with 6'-sialyllactose (SL), which mimics the natural receptor more closely, extended the activity against some IAV strains; high potency, however, remained a bottleneck.²⁴

E.g., Papp et al. describes the inhibition of influenza viruses by hyperbranched polyglycerol derivatives (Papp, I et al. ChemBioChem 2011, 12, 887-895). Furthermore, Whitesides et al. and Matrosovich et al. reported on polyacrylamide sialosides, which were found to be efficient showing Ki values in lower nanomolar range, but serious concerns were raised about the toxicity of the polymers.

Erberich et al. describes, amongst others, a linear polyglycerol carrying 2-Acetylamino-2-deoxy-3,4,6- tri-O-acetyl -D-glucose residues as substituents [17],

WO 2009/032605 A2 describes bi-functional polymer-attached inhibitors of influenza virus.

WO 2017/129781 Al describes linear polyglycerol derivatives, a method for manufacturing and applications.

Chuanxiong Nie et al., Angew. Chem. 2020, 132, 1-6 describes certain heteromultivalent nanoparticlebased inhibitors and effects on IAV hemagglutinin and neuraminidase. The exact reference is Bhatia S. et al., Adaptive Flexible Sialylated Nanogels as Highly Potent Influenza A Virus Inhibitors, Angew. Chem. Int. Ed.2020, 59, 12417-12422, https://doi.org/10.1002/ange.202006145

Chuanxiong Nie et al., Nie et al., Sci. Adv. 2021; 7: eabd3803 describes Heteromultivalent topology- matched nanostructures as influenza A virus inhibitors. Detailed description of the invention

The present inventors have overcome the issues known from the prior art by developing the compounds of the present invention, which are disclosed herein in further detail. It is an object of the present invention to provide novel substances that can be used, in particular, as antiviral drugs.

This object is achieved by providing heteromultivalent polymers according to the present invention. These show for the first time marked synergistic effects against both the binding and release of viruses, in particular influenza.

An aspect of the present invention is a heteromultivalent polymer comprising a linear polymer backbone, wherein said backbone is substituted with at least one hemagglutinin binding moiety and at least one neuraminidase binding moiety.

In certain embodiments of the invention, the linear polymer backbone is comprised of a biocompatible hydrophilic polymer.

In certain embodiments of the invention, the linear polymer backbone is selected from the group comprising polyglycerol, PEG, PAMAM, polyoxazoline, chitosan, cellulose, and callose, particularly polyglycerol.

In certain embodiments of the invention, the linear polymer backbone is a linear polyglycerol, particularly consisting of 1,2-linked or 1,3 -linked glycerol units, more particularly 1,3 -linked glycerol units.

In certain embodiments of the invention, the linear polymer backbone has a molecular weight from 1.000 to 100.000 Da, particularly from 2.000 to 20.000 Da, particularly from 4.000 to 15.000 Da, particularly from 7.500 to 12.500 Da, particularly about 10.000 Da.

In certain embodiments of the invention, the backbone is substituted with a multitude of hemagglutinin binding moieties and a multitude of neuraminidase binding moieties.

In certain embodiments of the invention, the degree of substitution of said backbone with hemagglutinin binding moieties is from 5% to 70%, particularly from 10% to 65%, particularly from 15% to 65%, particularly from 25% to 65%, particularly from 30% to 60%, particularly from 35% to 50%, particularly from 40% to 50%, particularly about 40%. In certain embodiments of the invention, the degree of substitution of said backbone with neuraminidase binding moieties is from 5% to 70%, particularly from 10% to 65%, particularly from 15% to 65%, particularly from 25% to 65%, particularly from 30% to 60%, particularly from 40% to 60%, particularly from 35% to 50%, particularly about 40%, or particularly from 10% to 60%, particularly from 20% to 60%.

In certain embodiments of the invention, the degree of substitution of said backbone with neuraminidase binding moieties and hemagglutinin binding moieties (i.e. the degree of substitution with the total of neuraminidase binding moieties and hemagglutinin binding moieties) is from 10% to 100%, particularly from 15% to 90%, particularly from 20% to 95%, particularly from 30% to 90%, particularly from 40% to 85%, particularly from 40% to 80%, particularly from 50% to 80%, particularly from 70% to 90%, particularly from 75% to 85%, particularly about 80%.

In certain embodiments of the invention, the ratio of neuraminidase binding moieties and hemagglutinin binding moieties are from 5: 1 to 1:5, particularly from 4: 1 to 1:4, particularly from 3: 1 to 1:3, particularly from 2: 1 to 1 :2, and particularly about even (meaning 1 : 1).

In certain embodiments of the invention, the total number of neuraminidase binding moieties is from 1 to 65, particularly 5 to 60, particularly 10 to 55, particularly 13 to 54, particularly about 13 or about 54.

In certain embodiments of the invention, the total number of hemagglutinin binding moieties is from 1 to 65, particularly 5 to 60, particularly 10 to 55, particularly 25 to 55, particularly 40 to 55, particularly 45 to 55, particularly about 54.

In certain embodiments of the invention, the neuraminidase binding moieties are selected from the group comprising small molecules, peptides, proteins, nucleic acids, and glycans, particularly neuraminic acid or derivatives thereof.

In certain embodiments of the invention, the neuraminidase binding moieties are a neuraminidase inhibitor with a molecular weight of less than 2.000 g/mol, particularly from 200 to 1.500 g/mol, particularly from 250 to 1.000 g/mol, particularly from 275 to 750 g/mol, particularly from 300 to 500 g/mol, particularly from 300 to 400 g/mol, particularly from 300 to 350 g/mol.

In certain embodiments of the invention, the neuraminidase binding moieties are selected from the group comprising zanamivir, laninamivir, oseltamivir, peramivir, Neuraminidase-IN-5, Neuraminidase-IN-8, Neuraminidase-IN-1, Neuraminidase-IN-6, Neuraminidase-IN-4, Neuraminidase-IN-10, Neuraminidase-IN-7, Ganoderic acid TR, Theaflavin, Massarilactone H, Yadanziolide B, Neuraminidase-IN-9, Neuraminidase-IN-11, Neuraminidase-IN-3, Glyasperin C, 2,3 -Dehydro-2 - deoxy-N-acetylneuraminic acid, Neu5Ac2en, Emodin-l-O-P-D-glucopyranoside, Aurintricarboxylic acid, Ganoderic acid T-N, BCX-1898, 4-O-Methylepisappanol and derivatives thereof, particularly, zanamivir, laninamivir, oseltamivir, peramivir, particularly zanamivir.

In certain embodiments of the invention, the hemagglutinin binding moieties are selected from the group comprising small molecules, peptides, proteins, nucleic acids, and glycans, particularly small molecules, peptides and glycans, more particularly Oleanolic acid, Aureonitol, Neoechinulin B, N- cyclohexyltaurine, sialic acid, sialyllactose and derivatives thereof or a peptide having from 8 to 40 amino acids, comprising a sequence Xl-X2-X3-Tyr-Asp-X5-X6-X7 (SEQ ID No. 3), wherein XI is selected from the group consisting of Leu, His, He, Trp, Asp, Glu, Gly, Lys, Asn, Pro and Arg, X2 is selected from the group consisting of Leu, Pro, Gin, Arg, Cys, Asp, Glu, He, Lys, Met and Ser, X3 is selected from the group consisting of Tyr, Gly, Phe, Gly, Gin, Thr, Trp and Leu, X4 is selected from the group consisting of He, Ala, Cys, Asp, Glu, Leu, Met, Pro, Vai and Thr, X5 is selected from the group consisting of Pro, Gin, Asp, Glu, Arg, X6 is selected from the group consisting of Ala, Asp, Pro, Cys, Glu, Lys, Gin, Gly and Thr, and X7 is selected from the group consisting of Phe, Asn, Cys, Asp, Glu, Met, Pro, Leu, Thr, Trp and Ser, more particularly sialic acid and 6 '-sialyllactose, particularly 6 - sialyllactose.

In certain embodiments of the invention, the neuraminidase binding moieties are selected from the group comprising zanamivir, laninamivir, oseltamivir, peramivir and derivatives thereof, particularly zanamivir, laninamivir, particularly zanamivir and wherein the hemagglutinin binding moieties are selected from the group comprising sialic acid, sialyllactose and derivatives thereof, particularly sialic acid and 6 '-sialyllactose, particularly 6 '-sialyllactose.

In certain embodiments of the invention, the neuraminidase binding moieties and/or hemagglutinin binding moieties are bound to the linear polymer backbone directly or via a linker group.

In certain embodiments of the invention, the neuraminidase binding moieties and/or hemagglutinin binding moieties are bound to the linear polymer backbone via a linker group selected from the group comprising Ci-ioAlkyl, particularly Ci-eAlkyl, wherein one or more methylene groups are optionally replaced by a unit independently selected from the group comprising O, S, NH, NH-0, C(O)NH, NHC(O) and CH2(CCHNNN), or by a group -X-Y-, wherein X = S and Y = CH2, (CH2)3O, or CH₂(CCHNNN), or X = O and Y = NHCH₂ or X = NH and Y = COCH₂, preferably X = S and Y = (CH₂)₃OCH₂ or X = S and Y = (CH₂)₃O.

In certain embodiments of the invention, the heteromultivalent polymer has efficacy against at least one, particularly at least two, particularly at least three hemagglutinin serotypes, particularly in influenza, selected from the group comprising Hl, H3, H5 and H7 and/or, particularly and, at least two neuraminidase serotypes selected from the group comprising Nl, N3 and N9.

In certain embodiments of the invention, the heteromultivalent polymer has efficacy against one or more virus strains selected from the group comprising A/Aichi/2/68 (H3N2), A/NewYork/55/2004 (H3N2), A/Victoria/210/2009 (H3N2), A/Puerto Rico/8/1934 (H1N1), A/Vietnam/ 1203/2004 (H5N1), A/Mute swan/Germany/R901/06 K3141 (H7N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm) A/Bremen/5/2017 (H3N2), A/Asian/2013 (H7N9), and A/Califomia/7/2009 (HINlpdm), particularly A/Bremen/5/2017 (H3N2), A/PR/8/34 (H1N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm), and A/Califomia/7/2009 (HINlpdm).

Another aspect of the present invention is a heteromultivalent polymer according to the present invention for use as a medicament.

Another aspect of the present invention is a heteromultivalent polymer according to the present invention for use in the treatment of a subject infected with a vims having hemagglutinin and neuraminidase, particularly with an ortho- or paramyxovirus, particularly with an orthomyxovirus, particularly with a vims selected from the group comprising influenza, parainfluenza and mumps, particularly with an influenza vims, more particularly with a vims selected from the group comprising influenza type A and type B, more particularly with influenza type A.

In certain embodiments of the invention, the treatment is of a subject infected with a vims as defined herein above, wherein the infection is with a neuramidase inhibitor-resistant vims.

In certain embodiments of the invention, in the treatment is of a subject infected with a vims according to item 24, wherein the infection is with a vims selected from the group comprising influenza strains selected from the group comprising hemagglutinin serotypes Hl, H3, H5 and H7, particularly selected from the group comprising A/Aichi/2/68 (H3N2), A/NewYork/55/2004 (H3N2), A/Victoria/210/2009 (H3N2), A/Puerto Rico/8/1934 (H1N1), A/Vietnam/ 1203/2004 (H5N1), A/Mute swan/Germany/R901/06 K3141 (H7N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2),

A/Bayem/63/2009 (HINlpdm) A/Bremen/5/2017 (H3N2), and A/Califomia/7/2009 (HINlpdm), particularly A/Bremen/5/2017 (H3N2), A/PR/8/34 (H1N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm), and A/Califomia/7/2009 (HINlpdm). Another aspect of the present invention is a heteromultivalent polymer according to the present invention for use in preventing virus transmission from one subject to another, particularly transmission of a virus as defined herein.

Another aspect of the present invention is a pharmaceutical composition comprising the heteromultivalent polymer according to the present invention.

In certain embodiments of the invention, the pharmaceutical composition furthermore comprises at least one excipient.

In certain embodiments of the invention, the pharmaceutical composition is in an aerosol form, particularly formulated for nasal and/or pulmonal administration.

Surprisingly, the heteromultivalent polymers of the present invention show a better antiviral effect than homomultivalent polymers or heteromultivalent nanoparticles known from the prior art. This can be seen from the data provided herewith.

As used herein, “homomultivalent” refers to compounds or particles comprising moieties that can all interact with the same target, e.g. hemagglutinin OR neuraminidase. As an example, see WO 2017/129781 Al. In contrast, “heteromultivalent” refers to compounds or particles comprising moieties that can interact with different targets, e.g. hemagglutinin AND neuraminidase (i.e. hemagglutinin binding moieties AND neuraminidase binding moieties).

The term “about” as used herein with respect to numbers, values, figures, ranges and/or amounts is preferably meant to mean “circa” and/or “approximately”. The meaning of those terms is well known in the art and particularly includes a variance, deviation and/or variability of the respective number, figure, range and/or amount of plus/minus the typical variance, deviation and/or variability occurring in typical methods of determining such numbers, values, figures, ranges and/or amounts, particularly plus/minus 15%, particularly plus/minus 10%, particularly plus/minus 5%.

As used herein, the term "effective amount" includes a dosage sufficient to produce a desired result with respect to the indicated disorder, condition, mental state, or the like. The desired result may comprise a subjective or objective improvement in the recipient of the dosage.

As used herein, the term "administering" includes activities associated with providing a subject an amount of a compound or composition of the present invention. Administering includes providing unit dosages of compounds or compositions of the present invention to a subject. In particular embodiments, administering includes providing effective amounts of compounds or compositions of the present invention for a specified period of time, e.g. for about 6, 9, 12, 15 or more hours, or about 1, 2, 3, 4, 5 or more days.

The term “treating” or “treatment” means an alleviation of symptoms associated with a disease, disorder or condition, or halt of further progression or worsening of those symptoms. Depending on the disease and condition of the subject, the term “treatment” as used herein may include one or more of curative, palliative and prophylactic treatments. Treatment can also include administering a compound or composition of the present invention in combination with other therapies.

Herein, a “subject” is particularly a subject in need of treatment or prevention of a disorder, condition, mental state, or the like, and particularly of having administered a compound or composition of the present invention. In particular embodiments, said subject is a patient, particularly a human patient. In other particular embodiments, said subject is a non-human subject, such as a mammal, or such as an avian.

“Pharmaceutically acceptable” means suitable for use in a subject.

Testing of the compounds of the present invention in cell culture models have shown that the range between the therapeutic concentration and the toxic concentration is extremely high, in fact toxicity has so far not yet been observed at the tested concentrations of up to 10 pM. Therefore the range between the therapeutic concentration and the toxic concentration is expected to usually be in the range of a factor of about 1000 or even higher. Thus, an embodiment of the invention related to compounds of the invention that are non-toxic for humans or animals, in particular non-toxic for humans and non-human mammals, in particular rodents, particularly with a toxic concentration being at least a factor of about 1000, particularly a factor of about 1000, greater than a therapeutic concentration.

The heteromultivalent polymers of the present invention can be described with a general formula PBxHAMyNAM_z, with the following meanings: PB = polymer backbone, x = MW in kDa, HAM = hemagglutinin binding moiety, NAM = neuramidase binding moiety, y,z = degree of substitution (e.g. 0.10 stands for a degree of substitution of about 10%). In these general formulae, PB, HAM and NAM may be replaced by specific groups, like LPG for a linear polyglycerol backbone, SA for a sialic acid moiety, SL for a 6'-sialyllactose moiety, or ZA for a zanamivir moiety.

Favorably, the polymer for the backbone has high water solubility, cytocompatibility, scalability, and good in vivo clearance in subjects, such as human subjects.

In certain embodiments, the backbone is a linear Polyglycerol, which consists of linearly linked glycerol units (LPG).

In certain embodiments, the backbone is 10 kDa LPG; particularly 1,3-linked.

In an embodiment, the polymer backbone, in particular the polyglycerol backbone additionally carries at least one further substituent in the nature of a covalently bound residue chosen from the group consisting of buffering agents, amines and sulfates. Thus, the backbone can be substituted by one or more buffering agents, one or more amines and/or by one or more sulfates along with the hemagglutinin binding moieties and neuraminidase binding moieties.

In certain embodiments, the hemagglutinin binding moieties are sialic acid derivatives according to general formulae (I) or (II), wherein a covalent bond is formed between a carbon atom of the backbone and residue Y of the sialic acid derivative:

wherein in formula (I)

Ri = H or CH₃,

R₂ = H, F, Cl, Br, or NHC(NH)NH₂,

R₃ = H, OH, F, Cl, or Br,

R4 = NHCH₂COOH, SCH₂COOH, NHCO(CH₂)nCH₃, or SCO(CH₂)_nCH₃,

Rs = H, OH, F, Cl, Br, OCONH₂, or OCONH(CH₂)_nCH₃,

Re = H, OH, F, Cl, Br, OCONH₂, or OCONH(CH₂)_nCH₃,

R₇ = H, OH, F, Cl, Br, OCONH₂, or OCONH(CH₂)_nCH₃, and

X = S and Y = CH₂, (CH₂)₃O, or CH₂(CCHNNN), or

X = O and Y = NHCH₂, and n = 0 to 10, independently from other variables n in the same molecule or in other molecules and in formula (II)

Ri = H or CH₃,

R₂ = H, OH, or F,

R₃ = H, F, or NHC(NH)NH₂,

R» = H, OH, F, Cl, Br,

Rs = NHCH₂COOH, SCH₂COOH, NHCOCH₂OH, NHCO(CH₂)_nCH₃, or SCO(CH₂)_nCH₃,

Re = H, OH, F, Cl, Br, OCONH₂, or OCONH(CH₂)_nCH₃,

R₇ = H, OH, F, Cl, Br, OCONH₂, or OCONH(CH₂)_nCH₃, and

X = S and Y = CH₂, (CH₂)₃O, or CH₂(CCHNNN), or

X = NH and Y = COCH₂, and n = 0 to 10, independently from other variables n in the same molecule or in other molecules, wherein the bond between the C2 atom and the C3 atom in formula (II) can be a single bond or a double bond.

According to formula (I), a linkage of the sialic acid derivative residue to the backbone is formed via the C-2 atom of the sialic acid derivative residue.

According to formula (II), a linkage of the sialic acid derivative residue to the backbone is formed via the C-7 atom of the sialic acid derivative residue.

In an embodiment, R₂ and R₃ in formula (I) both mean F so that the sialic acid derivative is a difluorosialic acid derivative. In an embodiment, R₃ and R4 in formula (II) both mean F so that the sialic acid derivative is a difluorosialic acid derivative.

In certain embodiments, the hemagglutinin binding moieties correspond to formula (I), wherein Ri = H, R₂ = H, R₃ = OH, R4 = NHCOCH3, R₅ = OH, Re = OH, R₇ = OH, X = S and Y = (CH₂)₃O. In certain embodiments, Ri = H, R₂ = H, R₃ = OH, R₄ = NHCOCH₃, R₅ = OH, R₆ = OH, R₇ = OH, X = S and Y = CH₂(CCHNNN).

In certain embodiments, the hemagglutinin binding moieties correspond to formula (II), wherein Ri = H, R₂ = H, R₃ = H, R4 = OH, R₅ = NHCOCH₃, Re = OH, R₇ = OH, X = S and Y = (CH₂)₃O. In certain embodiments, Ri = H, R₂ = H, R₃ = H, R4 = OH, R₅ = NHCOCH₃, Re = OH, R₇ = OH, X = S and Y = CH₂(CCHNNN)CH₂-.

The residue CH₂(CCHNNN) is a cyclic residue that can also be represented by the following formula (III):

Therein, dashed lines indicate bonds that will be formed to neighboring residues or molecule parts.

In an embodiment, the hemagglutinin binding moieties correspond to the following formulae (IV), (V), (VI) or (VII):

Thereby, residues Ri to R7 can have the general meanings explained in connection to formulae (I) and (II) or the specific meanings indicated just above.

6'-sialyllactose has the following structure (shown as its Na-salt):

In certain embodiments, the hemagglutinin binding moieties are peptides selected from the peptides disclosed as the invention of European patent No. EP 3023435 Al, in particular

1. a peptide having from 8 to 40 amino acids, comprising a sequence Xl-X2-X3-X4-Asp-X5- X6-X7 (SEQ ID NO:2), wherein XI to X7 are selected from Ala, Asn, Asp, Arg, Cys, Gin, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Vai, and wherein SEQ ID NO:2 has at least 62.5% sequence identity and at most 87.5% sequence identity with the sequence Phe-Tyr-Asp-Tyr-Asp-Val-Phe-Tyr (SEQ ID NO: 1); particularly, wherein the sequence is Xl-X2-X3-Tyr-Asp-X5-X6-X7 (SEQ ID NO:3); particularly, wherein the sequence is Xl-X2-X3-Tyr-Asp-Val-X6-X7 (SEQ ID NO:4) or XI- Tyr-X3-Tyr-Asp-X5-X6-X7 (SEQ ID NO:5); particularly, wherein the sequence is Xl-Tyr-X3-Tyr-Asp-Val-X6-X7 (SEQ ID NO:6), Xl-Tyr- X3-Tyr-Asp-X5-Phe-X7 (SEQ ID NO:7) or Xl-X2-X3-Tyr-Asp-Val-Phe-X7 (SEQ ID NO:8); particularly, wherein the sequence is selected from a group consisting of Phe-Tyr-X3-Tyr-Asp- Val-X6-X7 (SEQ ID NO:9) Xl-Tyr-X3-Tyr-Asp-Val-Phe-X7 (SEQ ID NO: 10), Phe-X2-X3- Tyr-Asp-Val-Phe-X7 (SEQ ID NO: 11), and Phe-Tyr-X3-Tyr-Asp-X5-Phe-X7 (SEQ ID NO: 12); particularly, wherein at least one of XI is selected from the group consisting of Leu, His, He, Trp, Asp, Glu, Gly, Lys, Asn, Pro and Arg; X2 is selected from the group consisting of Leu, Pro, Gin, Arg, Cys, Asp, Glu, He, Lys, Met and Ser; X3 is selected from the group consisting of Tyr, Gly, Phe, Gly, Gin, Thr, Trp and Leu; X4 is selected from the group consisting of lie, Ala, Cys, Asp, Glu, Leu, Met, Pro, Vai and Thr; X5 is selected from the group consisting of Pro, Gin, Asp, Glu, Arg; X6 is selected from the group consisting of Ala, Asp, Pro, Cys, Glu, Lys, Gin, Gly and Thr; and X7 is selected from the group consisting of Phe, Asn, Cys, Asp, Glu, Met, Pro, Leu, Thr, Trp and Ser; particularly, wherein the peptide further comprises an N-terminally flanking sequence Ala-Arg- Asp and/or a C-terminally flanking sequence Tyr- Ala-Met- Asp; particularly, wherein the peptide further comprises an oligo lysine (Lys)n with 2 < n < 6; particularly, wherein the peptide has less than 30, preferably less than 25, more preferably less than 20, most preferred less than 15 amino acids; particularly, wherein at least a part of the peptide is cyclized by forming a ring generated by a covalent bond linking an N-terminal moiety and a C-terminal moiety, an N-terminal moiety and a side chain moiety, a C-terminal moiety and a side chain moiety, or two side chain moieties of the peptide; particularly, wherein the peptide comprises at least one D-amino acid.

Herein, the terms “degree of substitution” and “degree of functionalization” are used interchangeably with respect to the degree to which the polymers backbones are substituted with hemagglutinin binding moieties and/or neuraminidase binding moieties. The degree of substitution can be determined e.g. by NMR.

In an embodiment relating to a in the linear polyglycerol backbone, the median carbon atom of a first glycerol unit in the linear polyglycerol backbone (C2 atom) is linked to one of the two terminal carbon atoms in a second glycerol unit (C 1 atom) via an ether. Thereby, a 1 ,2-linkage between adj acent glycerol units in the linear polyglycerol compound is formed. It can also be denoted as 2,1-linkage. In an embodiment, the terminal carbon atom of a first glycerol unit in the linear polyglycerol compound (C 1 or C3 atom) is linked to one of the two terminal carbon atoms in a second glycerol unit (C 1 or C3 atom) via an ether. Thereby, a 1,3 -linkage between adjacent glycerol units in the linear polyglycerol compound is formed. It can also be denoted as 3,1-linkage. In an embodiment, the glycerol units of the claimed compounds are either exclusively 1,2-linked or 1,3 -linked to each other.

The general formulae of such 1,2-linked and 1,3 -linked polyglycerol compounds are depicted below, wherein the meanings of the indicated residues in an embodiment are also indicated:

1 ,2-linked linear polyglycerol 1 ,3-linked linear polyglycerol

with n = 5 to 1500, particularly 5 to 1350, particularly 5 to 1000, particluarly 10 to 750, particularly 25 to 500, particularly 50 to 250, particularly 75 to 200, particularly 100 to 150, particularly about 135,

X, Y = independently from each other any organic residue with a functional group chosen from the group consisting of alcohol, amine, thiol, azide, alkyne, alkene, carboxylic acid, aldehyde, ketone, halogen, isocyanate, isothiocyanate, Michael acceptor/donor group,

Z = independently from other residues Z is OH or the point of attachment of a hemagglutinin binding moiety and at least one neuraminidase binding moiety.

The hemagglutinin binding moieties and neuraminidase binding moieties are covalently bound to the backbone, in certain embodiments via a linker.

For the avoidance of doubt, the hemagglutinin binding moieties and neuraminidase binding moiety are moieties which are suitable for binding with viral hemagglutinin and neuraminidase glycoproteins, respectively. The hemagglutinin binding moieties and neuraminidase binding moiety are typically moieties which are derived from a parent compound known to have hemagglutinin or neuraminidase binding activity, particularly inhibiting activity, and which are, where needed, modified for covalent attachment to the polymer backbone, wherein covalent attachment may be directly to the backbone and/or via linker group. The neuraminidase binding moieties and/or hemagglutinin binding moieties are bound to the linear polymer backbone directly means typically that they are bound to the linear polymer backbone via one of their C, O, N, or S atoms. Linker groups are described herein.

The molecular weight of the heteromultivalent polymers of the invention and/or the polymer backbone, in particular in the case of a polyglycerol backbone can be determined as a number average molecular weight, in particular determined by gel permeation chromatography. As an example, a gel permeation chromatography method for use with the present invention can be found O. in Dragostin, L. Profire, 5 - Molecular weight of polymers used in biomedical applications, Editor(s): Maria Cristina Tanzi, Silvia Fare, Characterization of Polymeric Biomaterials, Woodhead Publishing, 2017, Pages 101-121, ISBN 9780081007372, https://doi.org/10.1016/B978-0-08-100737-2.00005-4.

Molecular weight of the backbone and/or heteromultivalent polymers is typically expressed as number average molecular weight M_n.

For the avoidance of doubt, when the molecular weight of the polymer backbone is reference herein, this typically refers to the molecular weight of the unmodified, unsubstituted polymer backbone.

In an embodiment, the heteromultivalent polymer (backbone plus substituents) has a number average molecular weight (M_n) of 7.000 to 700.000 Da, particularly from 14.000 to 140.000 Da, particularly from 28.000 to 105.000 Da, particularly from 52.500 to 87.500 Da, particularly about 70.000 Da.

Molecular weight distribution of polymers (Mw and M_n) is determined by gel permeation chromatography (GPC) as typically applied for this purpose by a person skilled in the art, for example by using a GPC instrument from Agilent (Santa Clara, USA) equipped with a refractive index detector, Agilent 1100 pump, and columns using water as mobile phase at a flow rate of 1 mL/min. The molecular weight calibration is e.g. performed using the pullulan standard. Other generally suited methods for determining M_n are matrix-assisted laser desorption/ionization - time of flight mass spectroscopy (MALDI-TOF) and multi angle light scattering (MALS) leading to approximately the same results as GPC.

Thereby, a combination of the before mentioned molecular weight ranges with a degree of substitution of 50 % to 80 % is particularly well suited. Thus, in an embodiment, the compound might have a number average molecular weight (M_n) of 30 kDa to 70 kDa and a degree of substitution of 50 % to 80 %. In another embodiment, the compound might have a number average molecular weight (M_n) of 30 kDa to 70 kDa and a degree of substitution of 50 % to 80 %.

In certain embodiments, the linear polymer backbone is terminally substituted, e.g. with a benzyl group. LPG typically has terminal OH groups, which may be unsubstituted or substituted to form an ether or ester.

In particular embodiments, the heteromultivalent polymers according to the present invention have a linear polyglycerol (LPG) backbone substituted with zanamivir (ZA) and 6'-sialyllactose (SL) moieties or derivatives thereof; more particularly the backbone has a molecular weight of about 10 kDa; more particularly the backbone is an LPG; more particularly the degree of substitution is about 40% for the zanamivir (ZA) and 6'-sialyllactose (SL) moieties, respectively.

In an embodiment, the heteromultivalent polymer is used as a medicament, namely as prophylactic or therapeutic agent. Suited areas of application are antiviral therapy (post infection) and prophylactic treatments of individuals to avoid a viral infection. Thus, the instant invention relates to method of treating a human or an animal (in particular a non-human mammal) in need thereof with a prophylactic or therapeutic agent comprising a heteromultivalent polymer according to the invention.

In an embodiment, the heteromultivalent polymer is used as an antiviral agent, an antibacterial agent or an anti-inflammatory agent. Thus, the instant invention relates to method of treating a human or an animal (in particular a non-human mammal) in need thereof with an antiviral agent, an antibacterial agent or an anti-inflammatory agent comprising a heteromultivalent polymer according to the invention.

In an embodiment, the heteromultivalent polymer is used against Orthomyxoviridae, in particular influenza type A virus, influenza type B virus, and/or influenza type C virus, in particular influenza A.

In certain embodiments, pharmaceutical compositions of the present invention may comprise one or more excipients, such as for instance diluents, extenders, or carriers, binding agents, fillers, lubricants, disintegrants, wetting agents, solvents, propellants, and the like. Pharmaceutical compositions of the present invention may furthermore comprise one or more items from the group comprising packaging, instructions to the subject and/or physician treating the subject and a leaflet. In certain embodiments, pharmaceutical compositions of the present invention are formulated as ready-to-use formulation or as a freeze dried composition. Medical applications of the compounds of the present invention may be disclosed herein as said compound for the use as a medicine and/or for a use in the prevention and/or treatment of certain medical conditions. They equally relate to the use of such compound of the present invention for the manufacture of a medicament and/or for the manufacture of a medicament for use in the prevention and/or treatment of certain medical conditions. They equally relate to the use of a pharmaceutical composition comprising such compound of the present invention for the prevention and/or treatment of certain medical conditions. They equally relate to the use of such compound of the present invention for the prevention and/or treatment of certain medical conditions. They equally relate to a method of treatment of a subject in need thereof, in particular for the prevention and/or treatment of certain medical conditions in a subject suffering therefore, said method comprising administering to said subject a therapeutically effective amount of such compound of the present invention. In certain embodiments, such subjects are mammals, particularly human, particularly human patients.

In certain embodiments, the medical applications of the compounds of the present invention involve that the compound is to be administrated in an aerosol form, particularly formulated for nasal and/or pulmonal administration.

In an embodiment, the aforementioned use is a use in antiviral prophylaxis or therapy. In a further embodiment, the antiviral prophylaxis or therapy is directed against influenza virus.

In particular embodiments, preventing virus transmission from one subject to another may include the infection of a subject with said virus, and/or the release of said virus from cells of a subject that are infected with said virus and/or release of said virus from a subject infected with said virus.

Described herein is a method for manufacturing a certain heteromultivalent polymers of the invention which comprise linear polyglycerols. This method comprises the following steps: a) providing a linear polymer, wherein the polymer is selected from the polymers described herein as the polymer backbone, particularly a polymer comprising a backbone of linearly linked glycerol residues, said polymer bearing hydroxyl groups or other functional groups chosen from the group consisting of allyl, azides, alkynes, alkenes, thiols, halogens, primary or secondary amines, carboxylic acids, aldehydes, ketons and any Michael donor or acceptor for conjugation of anionically charged entities, and b) causing a reaction of at least some of said hydroxyl groups or said other functional groups of the linear polymer provided in step a) with a compound able to introduce a substituent chosen from the group described herein for the hemagglutinin binding moiety, and causing a reaction of at least some of said hydroxyl groups or said other functional groups of the linear polymer provided in step a) with a compound able to introduce a substituent chosen from the group described herein for the neuraminidase binding moiety. The hemagglutinin binding moieties and the neuraminidase binding moiety can be introduced in the same or different steps.

In step a) allyl and azide are particularly suited functional groups. The reaction partners used in step b) might carry a thiol group or a thiopropargyl group to allow for formation of a covalent bond.

A method of producing an LPG for the backbopne ist via assembly of pentaglycerin units, particularly via Anionic ring-opening polymerization of protected glycidol. (Anja Thomas, et al. Biomacromolecules 2014, 15 (6), 1935-1954)

Typically, in the production of the compounds of the present invention, the backbone is synthesized first, and then substituted.

All embodiments of the heteromultivalent polymer according to the invention, their uses and the disclosed methods can be combined in any desired way and are transferable to any other or same category of subject-matter that is herein disclosed (i.e. from the compound to a method or from a method to a use or from a use to a method of from the compound to the combined preparation etc.).

Description of the Figures

FIG 1 shows inhibitory effect of compounds tested against IAV subtype strains. The inhibitor constant Ki(HAI) was calculated and presented as log 10 Ki(HAI) for better visualization. The Ki(HAI) reflects the lowest inhibitor concentration necessary to achieve full inhibition of virus-induced hemagglutination. The graph shows the mean and standard deviation (SD) of three independent experiments with each virus, p-values were determined using ANOVA with multiple testing (Kruskal- Wallis test and Dunn’s test). For avoidance of doubt, for each compound values are listed from left to right for A/X31/H3N2; A/Panama/2007/2009 (H3N2); A/Califomia/7/2009 (HINlpdm); A/Bayem/63/2009 (HINlpdm).

FIG 2 shows representative fluorescent images for infected cells being treated with the inhibitors. The cells were infected by IAV A/X31 (H3N2) for 45 min and then cultured in the medium containing 10 nM inhibitors for 24 hours. Scale bar: 50 pm. Immunostaining was done for the viral nucleoprotein (NP). FIG 3 shows shows inhibition of ex vivo human lung tissue influenza A virus A/Panama/2007/1999 (H3N2) propagation with compounds of the invention and comparator compounds. IAV replication was compared to the replication after treatment with (A) LPG10SL0.50, LPG10ZA0.10 or LPG10ZA0.40SL0.40; (B) physical mixture of LPG10SL0.50 + LPG10ZA0.10 and LPG10ZA0.40SL0.40 or; (C) zanamivir.

FIG 4 shows a reduction in virus titers of different strains (additionally including A/Bremen/5/2017 (H3N2) and A/PR/8/34 (H1N1)) at 10 nM of the compound using homomultivalent ZA and SA compounds as well as the physical mixture of homomultivalent LPG to compare to covalently bound heteromultivalent ligands. Only the location names are used to refer to the different strains for clarity. All data represent three independent experiments in duplicates. For avoidance of doubt, for strain, values are listed from left to right for untreated; LPG10OH; LPG10ZA0.10SA0.40; LPG10ZA0.10 + LPG10SA0.40; LPG10ZA0.10; LPG10SA0.40.

Particular embodiments of the invention are enumerated in the following items:

1. Heteromultivalent polymer comprising a linear polymer backbone, wherein said backbone is substituted with at least one hemagglutinin binding moiety and at least one neuraminidase binding moiety.

2. Heteromultivalent polymer according to item 1, wherein the linear polymer backbone is comprised of a biocompatible hydrophilic polymer.

3. Heteromultivalent polymer according to item 1 or 2, wherein the linear polymer backbone is selected from the group comprising polyglycerol, PEG, PAMAM, polyoxazoline, chitosan, cellulose, and callose, particularly poly glycerol.

4. Heteromultivalent polymer according to any of the preceding items, wherein the linear polymer backbone is a linear polyglycerol, particularly consisting of 1,2-linked or 1,3 -linked glycerol units, more particularly 1,3-linked glycerol units.

5. Heteromultivalent polymer according to any of the preceding items, wherein the linear polymer backbone has a molecular weight from 1.000 to 100.000 Da, particularly from 2.000 to 20.000 Da, particularly from 4.000 to 15.000 Da, particularly from 7.500 to 12.500 Da, particularly about 10.000 Da. Heteromultivalent polymer according to any of the preceding items, said backbone is substituted with a multitude of hemagglutinin binding moieties and a multitude of neuraminidase binding moieties. Heteromultivalent polymer according to any of the preceding items, wherein the degree of substitution of said backbone with hemagglutinin binding moieties is from 5% to 70%, particularly from 10% to 65%, particularly from 15% to 65%, particularly from 25% to 65%, particularly from 30% to 60%, particularly from 35% to 50%, particularly from 40% to 50%, particularly about 40%. Heteromultivalent polymer according to any of the preceding items, wherein the degree of substitution of said backbone with neuraminidase binding moieties is from 5% to 70%, particularly from 10% to 65%, particularly from 15% to 65%, particularly from 25% to 65%, particularly from 30% to 60%, particularly from 40% to 60%, particularly from 35% to 50%, particularly about 40%, or particularly from 10% to 60%, particularly from 20% to 60%. Heteromultivalent polymer according to any of the preceding items, wherein the degree of substitution of said backbone with neuraminidase binding moieties and hemagglutinin binding moieties (i.e. the degree of substitution with the total of neuraminidase binding moieties and hemagglutinin binding moieties) is from 10% to 100%, particularly from 15% to 90%, particularly from 20% to 95%, particularly from 30% to 90%, particularly from 40% to 85%, particularly from 40% to 80%, particularly from 50% to 80%, particularly from 70% to 90%, particularly from 75% to 85%, particularly about 80%. Heteromultivalent polymer according to any of the preceding items, wherein the ratio of neuraminidase binding moieties and hemagglutinin binding moieties are from 5: 1 to 1:5, particularly from 4:1 to 1:4, particularly from 3 : 1 to 1:3, particularly from 2: 1 to 1:2, and particularly about even (meaning 1: 1). Heteromultivalent polymer according to any of the preceding items, wherein the total number of neuraminidase binding moieties is from 1 to 65, particularly 5 to 60, particularly 10 to 55, particularly 13 to 54, particularly about 13 or about 54. Heteromultivalent polymer according to any of the preceding items, wherein the total number of hemagglutinin binding moieties is from 1 to 65, particularly 5 to 60, particularly 10 to 55, particularly 25 to 55, particularly 40 to 55, particularly 45 to 55, particularly about 54. Heteromultivalent polymer according to any of the preceding items, wherein the neuraminidase binding moieties are selected from the group comprising small molecules, peptides, proteins, nucleic acids, and glycans, particularly neuraminic acid or derivatives thereof. Heteromultivalent polymer according to any of the preceding items, wherein the neuraminidase binding moieties are a neuraminidase inhibitor with a molecular weight of less than 2.000 g/mol, particularly from 200 to 1.500 g/mol, particularly from 250 to 1.000 g/mol, particularly from 275 to 750 g/mol, particularly from 300 to 500 g/mol, particularly from 300 to 400 g/mol, particularly from 300 to 350 g/mol. Heteromultivalent polymer according to any of the preceding items, wherein the neuraminidase binding moieties are selected from the group comprising zanamivir, laninamivir, oseltamivir, peramivir, Neuraminidase-IN-5, Neuraminidase-IN-8, Neuraminidase-IN-1, Neuraminidase-IN-6, Neuraminidase-IN-4, Neuraminidase-IN-10, Neuraminidase-IN-7, Ganoderic acid TR, Theaflavin, Massarilactone H, Yadanziolide B, Neuraminidase-IN-9, Neuraminidase-IN-11, Neuraminidase-IN-3, Glyasperin C, 2,3- Dehydro-2-deoxy-N-acetylneuraminic acid, Neu5Ac2en, Emodin- 1-O-P-D-glucopyranoside, Aurintricarboxylic acid, Ganoderic acid T-N, BCX-1898, 4-O-Methylepisappanol and derivatives thereof, particularly, zanamivir, laninamivir, oseltamivir, peramivir, particularly zanamivir. Heteromultivalent polymer according to any of the preceding items, wherein the hemagglutinin binding moieties are selected from the group comprising small molecules, peptides, proteins, nucleic acids, and glycans, particularly small molecules, peptides and glycans, more particularly Oleanolic acid, Aureonitol, Neoechinulin B, N-cyclohexyltaurine, sialic acid, sialyllactose and derivatives thereof or a peptide having from 8 to 40 amino acids, comprising a sequence Xl-X2-X3-Tyr-Asp-X5-X6-X7 (SEQ ID No. 3), wherein XI is selected from the group consisting of Leu, His, He, Trp, Asp, Glu, Gly, Lys, Asn, Pro and Arg, X2 is selected from the group consisting of Leu, Pro, Gin, Arg, Cys, Asp, Glu, He, Lys, Met and Ser, X3 is selected from the group consisting of Tyr, Gly, Phe, Gly, Gin, Thr, Trp and Leu, X4 is selected from the group consisting of He, Ala, Cys, Asp, Glu, Leu, Met, Pro, Vai and Thr, X5 is selected from the group consisting of Pro, Gin, Asp, Glu, Arg, X6 is selected from the group consisting of Ala, Asp, Pro, Cys, Glu, Lys, Gin, Gly and Thr, and X7 is selected from the group consisting of Phe, Asn, Cys, Asp, Glu, Met, Pro, Leu, Thr, Trp and Ser, more particularly sialic acid and 6 '-sialyllactose, particularly 6 '-sialyllactose. Heteromultivalent polymer according to any of the preceding items, wherein the neuraminidase binding moieties are selected from the group comprising zanamivir, laninamivir, oseltamivir, peramivir and derivatives thereof, particularly zanamivir, laninamivir, particularly zanamivir and wherein the hemagglutinin binding moieties are selected from the group comprising sialic acid, sialyllactose and derivatives thereof, particularly sialic acid and 6 '-sialyllactose, particularly 6 '-sialyllactose. Heteromultivalent polymer according to any of the preceding items, wherein the neuraminidase binding moieties and/or hemagglutinin binding moieties are bound to the linear polymer backbone directly or via a linker group. Heteromultivalent polymer according to any of the preceding items, wherein the neuraminidase binding moieties and/or hemagglutinin binding moieties are bound to the linear polymer backbone via a linker group selected from the group comprising Ci-ioAlkyl, particularly Ci-eAlkyl, wherein one or more methylene groups are optionally replaced by a unit independently selected from the group comprising O, S, NH, NH-O, C(O)NH, NHC(O) and CH2(CCHNNN), or by a group -X-Y-, wherein X = S and Y = CH2, (CTb O, or CH₂(CCHNNN), or X = O and Y = NHCH₂ or X = NH and Y = COCH₂, preferably X = S and Y = (CH₂)₃OCH₂ or X = S and Y = (CH₂)₃O . Heteromultivalent polymer according to any of the preceding items, wherein said heteromultivalent polymer has efficacy against at least one, particularly at least two, particularly at least three hemagglutinin serotypes, particularly in influenza, selected from the group comprising Hl, H3, H5 and H7 and/or, particularly and, at least two neuraminidase serotypes selected from the group comprising Nl, N3 and N9. Heteromultivalent polymer according to any of the preceding items, wherein said heteromultivalent polymer has efficacy against one or more virus strains selected from the group comprising A/Aichi/2/68 (H3N2), A/NewYork/55/2004 (H3N2), A/Victoria/210/2009 (H3N2), A/Puerto Rico/8/1934 (H1N1), A/Vietnam/ 1203/2004 (H5N1), A/Mute swan/Germany/R901/06 K3141 (H7N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm) A/Bremen/5/2017 (H3N2), A/Asian/2013 (H7N9), and A/Califomia/7/2009 (HINlpdm), particularly A/Bremen/5/2017 (H3N2), A/PR/8/34 (H1N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm), and A/Califomia/7/2009 (HINlpdm). Heteromultivalent polymer according to any of the preceding items, for use as a medicament. Heteromultivalent polymer according to any of items 1 to 21 for use in the treatment of a subject infected with a virus having hemagglutinin and neuraminidase, particularly with an ortho- or paramyxovirus, particularly with an orthomyxovirus, particularly with a virus selected from the group comprising influenza, parainfluenza and mumps, particularly with an influenza virus, more particularly with a virus selected from the group comprising influenza type A and type B, more particularly with influenza type A. Heteromultivalent polymer for use in the treatment of a subject infected with a virus according to item 23, wherein the infection is with a neuramidase inhibitor-resistant virus. Heteromultivalent polymer for use in the treatment of a subj ect infected with a virus according to item 24, wherein the infection is with a virus selected from the group comprising influenza strains selected from the group comprising hemagglutinin serotypes Hl, H3, H5 and H7, particularly selected from the group comprising A/Aichi/2/68 (H3N2), A/NewYork/55/2004 (H3N2), A/Victoria/210/2009 (H3N2), A/Puerto Rico/8/1934 (H1N1), A/Vietnam/1203/2004 (H5N1), A/Mute swan/Germany/R901/06 K3141 (H7N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm) A/Bremen/5/2017 (H3N2), and A/Califomia/7/2009 (HINlpdm), particularly A/Bremen/5/2017 (H3N2), A/PR/8/34 (H1N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm), and A/Califomia/7/2009 (HINlpdm). Heteromultivalent polymer according to any of items 1 to 21 for use in preventing vims transmission from one subject to another, particularly transmission of a vims as defined in any of items 23 to 25. Pharmaceutical composition comprising the heteromultivalent polymer according to any of items 1 to 21. Pharmaceutical composition according to item 27, furthermore comprising at least one excipient. Pharmaceutical composition according to any of items 27 to 28, which is in an aerosol form, particularly formulated for nasal and/or pulmonal administration. Examples

Example 1 - Synthesis of compounds of the invention

Materials

All the solvents and reagents are of analytical grades purchased from commercial suppliers and used without further purification. The progress of the reactions in case of small molecules is monitored by Merck silica gel 60 F254 pre-coated TLC (thin layer chromatography) plates and the spots on TLS are visualized by staining in 5% H2SO4 in ethanol and ceric solution. Silica gel 100-200 mesh is used for column purification of small molecules. The polymers are purified by dialysis against water using benzoylated membrane of MW cut off 2000 Da. Linear polyglycerol (M_n = 9.9 kDa, PDI = 1.24) was dried at 50 °C overnight under vacuum prior to use.

NMR, IR, GPC, mass, and zeta potential analysis

^JH and ¹³C NMR were recorded on Bruker AMX 500 MHz and 125 MHz, respectively, using solvent residual peak as internal standard, where the values of chemical shift are shown on 8 scale and coupling constant (J) are in Hz. Infrared (IR) transmission spectra were recorded on Nicolet AVATAR 320 FT- IR 5 SXC with a DTGS detector from 650 to 4000 cm"¹ (Thermo Fisher Scientific, Waltham, MA, USA) and the ESI was measured using a TSQ 7000 (Finnigan Mat) instrument. The molecular weight distribution of polymers (M_w and M_n) was determined using the GPC instrument from Agilent (Santa Clara, USA) equipped with refractive index detector, Agilent 1100 pump, and columns using water as mobile phase at a flow rate of 1 mE/min. The molecular weight calibration was performed using the pullulan standard. The zeta potential measurements were done using DES (Malvern Instruments Corp.) at 25 °C PB (10 mM, 7.4 pH) at 1 mg/mL particle concentration.

General synthesis of LPGs substituted with SA or SL and ZA

As an example, the modification of ZA and SL for attachment to the polymer backbone is shown. Methods of modifying compounds for attachment to polymers via various reactive groups and/or via linkers are well-known to the skilled person.

Scheme 1. (A) Synthesis of ZA-alkyne. (B) Synthesis of SL-alkyne as reported earlier in literature (M. N. Stadtmueller, et al. Journal of Medicinal Chemistry 2021, 64, 12774.) (C) Synthesis ofZA, SA, and SL-functionalized linear polyglycerol polymers. (D) Structures of SA and SL functionalized linear polyglycerols as reported earlier in literature (S. Bhatia et. al., Biomaterials 2017, Biomaterials 2017, 138, 22-34 and M. N. Stadtmueller, et al. Journal of Medicinal Chemistry 2021, 64, 12774 respectively)

Synthesis of ZA-alkyne

The key intermediate SI, required for the synthesis of ZA-alkyne was prepared from per-O-acetylated sialic acid with a moderate yield as described previously (Jian Li et al.,

Bioorg. Med. Chem. Lett., 2006, 16, 5009-5013).

Synthesis of compound S2

To a solution of amine SI (20 g, 46.5 mmol) and 1,3 -di -Boc-2 -methylisothiourea (17.4 g, 60 mmol) in anhydrous DCM (500 mL), triethylamine (14 g, 140 mmol) was added, and the mixture was cooled to 0 °C. This was followed by addition of HgCL (16 g, 60 mmol) in small amounts in 30 min. Subsequently, the suspension was allowed to warm at room temperature for overnight. After the disappearance of the starting material as monitored by TLC, the reaction mixture was diluted with ethyl acetate and filtered through celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and the obtained residue was purified by silica gel column chromatography to afford the desired fully protected zanamivir S2 as a white solid (25 g, 80% yield). ’H NMR (500 MHz, CDCh): 8 = 1.49 (s, 18H), 1.88 (s, 3H), 2.05, 2.07, 2.12 (3 x _s, 12H), 3.79 (s, 3H), 4.14 (dd, 1H, J= 12.4, 7.1 Hz), 4.27 (m, 2H), 4.64 (dd, 1H, J = 12.4, 2.4 Hz), 5.30 (m, 1H), 5.43 (d, 1H, J = 5.2 Hz), 5.87 (d, 1H, J = 2.3 Hz); ¹³C NMR (125 MHz, CDCh): 8 = 20.94, 21.00, 21.06, 23.22, 28.14, 28.28, 48.06, 49.78, 52.67, 62.34, 67.78, 71.19, 77.96, 84.90. 108.82, 145.70, 152.58, 156.70, 161.75, 170.25, 170.28, 170.77, 171.15. HRMS (ESI): m/z calculated for C29H44N4O14: 695.2746 [M+Na⁺], found 695.2743. Synthesis of compound S3

A solution of fully protected zanamivir S2 (10 g, 14.9 mmol) in methanol (250 mL) was treated with a catalytic amount of methanolic sodium methoxide. The solution was stirred at room temperature for 4 h. After consumption of starting material, the reaction mixture was adjusted to pH 7 using an acidic ionexchange resin Dowex-50WX8. After filtration and washing the resin with methanol, the solvent was removed under reduced pressure. The crude product obtained was dried over high vacuum and purified by column chromatography using 3% methanol in DCM to get a white solid (6.4 g, 79% yield). ¹ H NMR (500 MHz, CD₃OD): 8 = 1.48 (s, 9H), 1.49 (s, 9H), 2.00 (s, 3H), 3.43 (bs, 1H), 3.58 (dd, 1H, J = 8.9, 3.6 Hz), 3.75 (s, 3H), 3.84-3.91 (m, 2H), 3.98-4.03 (m, 2H), 4.22 (d, 1H, J = 10.6 Hz), 5.17 (d, 1H, J = 4.0 Hz), 5.25 (td, 1H, J= 9.5, 2.2 Hz), 5.77 (d, 1H, J= 2.4 Hz), 8.25 (d, 1H, J= 6.8 Hz), 8.58 (d, 1H, J = 7.9 Hz), 10.36 (s, 1H); ¹³C NMR (125 MHz, CD₃OD): 8 = 22.93, 28.12, 28.28, 48.28, 50.79, 52.57, 64.23, 69.00, 69.63, 78.21, 80.61, 84.50, 107.95, 146.28, 152.71, 157.32, 162.40, 174.02. HRMS (ESI): m/z calculated for C23H38N4O11: 569.2429 [M+Na⁺], found 569.2450.

Synthesis of compound S4

A solution of compound S3 (5 g, 9. 15 mmol) in dry acetone (150 mL) was treated with triflic acid (200 pL) at room temperature for 4 h. The reaction mixture was then neutralized with triethylamine (1 mL) and concentrated in vacuo. The obtained residue was purified by column chromatography using 1% methanol in DCM to afford the desired product S4 as a white solid (4.2 g, 78% yield). ’H NMR (500 MHz, CDCh): 8 = 1.35 (s, 3H), 1.40 (s, 3H), 1.48 (s, 9H), 1.49 (s, 9H), 1.99 (s, 3H), 3.48 (dd, 1H, J = 8.2, 4.3 Hz), 3.77 (s, 3H), 3.92-3.97 (m, 1H), 4.01 (d, 1H), 4.07 (dd, 1H, J= 8.8, 4.8 Hz), 4.15 (dd, 1H, J = 8.7, 6.2 Hz), 4.36-4.40 (m, 1H), 5.16 (bs, 1H), 5.24 (d, 1H, J= 4.0 Hz), 5.78 (d, 1H, J = 2.3 Hz), 8.03 (bs, 1H), 8.65 (d, 1H, J= 5.8 Hz), 11.35 (s, 1H); ¹³C NMR (125 MHz, CDCh): 8 = 23.07, 25.34, 27.19, 28.11, 28.29, 48.70, 52.00, 52.51, 67.54, 69.79, 74.12, 78.60, 80.61, 84.72, 106.65, 109.26, 147.05, 152.72, 157.52, 162.05, 174.09. HRMS (ESI): m/z calculated for C26H42N4O11: 609.2742 [M+Na⁺], found 609.2771.

Synthesis of ZA-alkyne

Compound S4 (5 g, 8.52 mmol), DMAP (2.07 g, 17 mmol) and pyridine (50 mL) were taken in 250 mL flask. The mixture was stirred at room temperature and 4-nitrophenylvhloroformate (3.42 g, 17 mmol) was added after 30 min. The solution was then stirred overnight at room temperature. After consumption of starting material as monitored by TLC, the reaction mixture was diluted with acetonitrile (50 mL) and subsequently, propargylamine (2.24 mL, 35 mmol) was added and stirred again for 3 h. The reaction mixture was concentrated under reduced pressure and the obtained crude was dissolved in DCM and washed with 2M HC1 (2 x 100 mL). The organic phase was dried over anhydrous MgSCfi. concentrated, and purified by column chromatography using 1% methanol in DCM to give ZA-alkyne as a white solid (4.5 g, 79% yield). ³H NMR (500 MHz, CDCI3): 8 = 1.32 (s, 3H), 1.36 (s, 3H), 1.45 (s, 18H), 1.88 (s, 3H), 2.22 (s, 3H), 3.76 (s, 3H), 4.01 (m, 2H), 4.10 (dd, 1H, J= 8.5, 6.6 Hz), 4.14 (m, 1H), 4.34 (m, 2H), 5.12 (t, 1H, J= 5.5 Hz), 5.19 (m, 2H), 5.86 (d, 1H, J= 2.4 Hz), 6.10 (d, 1H, J= 9.1 Hz), 8.43 (d, 1H, J = 8.5 Hz), 11.36 (s, 1H); ¹³C NMR (125 MHz, CDC1₃): 8 = 23.17, 25.47, 26.61, 28.10, 28.30, 31.18, 48.26, 49.09, 52.48, 65.98, 70.36, 71.77, 74.75, 77.58, 79.58, 79.77, 83.81, 109.01, 109.91, 145.24, 152.77, 155.24, 156.97, 161.97, 162.97, 170.89. HRMS (ESI): m/z calculated for C30H45N5O12: 690.2957 [M+Na⁺], found 690.2975.

Synthesis of 6'-SL-alkyne

6’-Sialyllactose alkyne (SL-alkyne) was prepared in two consecutive steps by following the procedure as reported earlier in literature (M. N. Stadtmueller, et al. Journal of Medicinal Chemistry 2021, 64, 12774.

The loading of ZA and SA or SL ligands was determined by 1H NMR analysis and the zeta potential (negative or positive charge in mV) of polymer conjugates was measured using the dynamic light scattering technique as discussed earlier in literature (S. Bhattachaijee Journal of Controlled Release 2016, 235, 337-351) (Malvern Instruments Corp.) at 25 °C PB (10 mM, 7.4 pH) at 1 mg/mL particle concentration. The results are shown in Table 1.

Exemplary NMR method for functionalized polyglycerols: The degree of functionalization of SL and ZA conjugated to linear polyglycerols was analyzed by correlating the integrals specific to sugar residues at 2.01 ppm to the integrals of the linear polyglycerol backbone at 3.25-4.54 ppm. Based on the degree of functionalization, the total molecular weight of the sugar residues was added to the number average molecular weight of linear polyglycerol obtained by GPC. This led to the determination of the number average molecular weight of SA/SL and ZA functionalized linear polyglycerols.

Synthesis of ZA, SA and SL-functionalized linear polyglycerols

Synthesis of multivalent compound LPGIQZAQ.IQ

LPG-N3 (10 kDa) having degree of functionalization (DF) = 0.15 (100 mg, 1.35 mmol per monomer unit) was dissolved in 10 mL of DMF. To this solution, ZA-alkyne (108 mg, 0.243 mmol, 1.2 equiv. per azide group (10% functionalization)) was added and stirred well. Then each CUSO4.5H2O (7 mg, 0.2 equiv. per azide) and sodium ascorbate (16 mg, 0.4 equiv. per azide) was dissolved in 0.5 mL of water separately and mixed well. The resulting mixture was added to the solution of LPG-N3 and ZA-alkyne. The overall reaction mixture was degassed with argon for 30 min and allowed to stir at 50 °C for 48 h under argon atmosphere. After completion of reaction as monitored by IR, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 2M NaOH (10 mL) and stirred for 5 h at room temperature. Then the solution was neutralized with 2M HC1 and lyophilized to dryness. The dry residue was taken in 10 mL DCM/TFA (1: 1) and continued stirring for further 5 h at room temperature. Solvents were removed under high vacuum, dissolved in distilled water and dialyzed against water and aqueous EDTA for 3 days (changing the solvent thrice a day). The dialyzed solution was lyophilized to yield the purified product as a white foamy solid (82% yield). ^XH NMR (500 MHz, D₂O): 8 = 2.00 (s, 3H, -NHCOCH₃), 3.51-4. 14 (m, 40H, LPG and sugar backbone), 4.46-4.58 (m, 3H), 5.76 (s, 1H, -C=CH of ZA), 8.10 (bs, 1H, triazole). M_n (NMR analysis) ~ 16,000 g/mol; GPC (H₂O): M_n = 10,208 g/mol, M_w = 15,912 g/mol, PDI = 1.55.

Synthesis of multivalent compound LPG10ZA0.40

Compound LPG10ZA0.40 was synthesized by similar procedure as used for the synthesis of compound LPG10ZA0.10 by using compound LPG-N3 (DF = 0.80) (100 mg, 1.06 mmol per monomer unit), ZA- alkyne (341 mg, 0.51 mmol, 1.2 equiv. per azide (40% functionalization)), CuSC>4.5H₂O (21 mg, 0.2 equiv. per azide) and sodium ascorbate (84 mg, 1.0 equiv. per azide). The desired compound was obtained as a white foamy solid (78% yield) by following the same deprotection and purification procedure as reported for LPGi₀ZA₀.i₀. ‘H NMR (500 MHz, D₂O): 8 = 1.99 (s, 3H, -NHCOCH3), 3.50- 4.14 (m, 16H, LPG and sugar backbone protons), 4.47-4.54 (m, 4H), 5.77 (s, 1H, -C=CH ofZA), 8.12 (bs, 1H, triazole). M_n (NMR analysis) ~ 34,000 g/mol; GPC (H₂O): M_n = 15,634 g/mol, M_w = 26,855 g/mol, PDI = 1.70.

Synthesis of multivalent compound LPG10ZA0.10SA0.40

LPG-N3 (10 kDa) having DF = 0.80 (100 mg, 1.06 mmol per monomer unit) was dissolved in 10 mL of DMF. Then ZA-alkyne (86 mg, 0.13 mmol, 1.2 equiv. per azide group (10% functionalization)), SA- alkyne (272 mg, 0.50 mmol, 1.2 equiv. per azide group (40% functionalization)) were added and stirred well. Then CuSC>4.5H₂O (26 mg, 0.2 equiv. per azide to be functionalized) and sodium ascorbate (42 mg, 0.4 equiv. per azide to be functionalized) each were dissolved in 0.5 mL of water separately and mixed well. The resulting mixture was added to the solution of LPG-N3, SA-alkyne and ZA-alkyne. The overall reaction mixture was degassed with argon for 30 min and allowed to stir at 50 °C under argon atmosphere. After 48 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 2M NaOH (5 mL) and stirred for 5 h at room temperature. Then the solution was neutralized with 2M HC1 and lyophilized to dryness. The dry residue was taken in 10 mL DCM/TFA (1: 1) and continued stirring for further 5 h at room temperature. Then, solvents were removed under high vacuum, dissolved in distilled water and dialyzed against water and aqueous EDTA for 3 days (changing the solvent thrice a day). The dialyzed solution was lyophilized to yield the purified product as a white foamy solid (80% yield). ’H NMR (500 MHz, D₂O): 8 = 1.70-1.79 (m, 4H, SA axial proton), 2.05 (s, 15H, -NHCOCH3), 2.78 (bs, 4H, SA equatorial proton), 3.58-4.39 (m, 90H, LPG, SA and ZA backbone), 5.64 (s, 1H, -C=CH of ZA), 7.95 (bs, 5H, triazole). M_n (NMR analysis) ~ 37,000 g/mol; GPC (H₂O): M_n = 13,669 g/mol, M_w = 21,064 g/mol, PDI = 1.54.

Synthesis of multivalent compound LPGIOZAO.IOSLQ.4O

LPG-N3 (10 kDa) having DF = 0.80 (100 mg, 1.06 mmol per monomer unit) was dissolved in 10 mL of DMF. Then ZA-alkyne (86 mg, 0.13 mmol, 1.2 equiv. per azide group (10% functionalization)), SL- alkyne (356 mg, 0.50 mmol, 1.2 equiv. per azide group (40% functionalization)) were added and stirred well. Then CuSCLAFLO (26 mg, 0.2 equiv. per azide to be functionalized) and sodium ascorbate (42 mg, 0.4 equiv. per azide to be functionalized) each were dissolved in 0.5 mL of water separately and mixed well. The resulting mixture was added to the solution of LPG-N3, SL-alkyne and ZA-alkyne. The overall reaction mixture was degassed with argon for 30 min and allowed to stir at 50 °C under argon atmosphere. After 48 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 2M NaOH (5 mL) and stirred for 5 h at room temperature. Then the solution was neutralized with 2M HC1 and lyophilized to dryness. The dry residue was taken in 10 mL DCM/TFA (1: 1) and continued stirring for further 5 h at room temperature. Then, solvents were removed under high vacuum, dissolved in distilled water and dialyzed against water and aqueous EDTA for 3 days (changing the solvent thrice a day). The dialyzed solution was lyophilized to yield the purified product as a white foamy solid (78% yield). ^JH NMR (500 MHz, D₂O): 8 = 1.69 (bs, 4H, SA axial proton), 1.93-2.21 (m, 27H, -NHCOCH3), 2.67 (bs, 4H, SA equatorial proton), 3.50-3.84 (m, 154H, LPG, SL and ZA backbone), 4.39 (m, 18H), 5.53 (s, 1H, -C=CH of ZA), 7.41-7.98 (m, 6H, triazole and amide). M_n (NMR analysis) ~ 56,000 g/mol.

Synthesis of multivalent compound LPG10ZA0.40SL0.40

LPG-N3 (10 kDa) having DF = 0.80 (100 mg, 1.06 mmol per monomer unit) was dissolved in 10 mL of DMF. Then ZA-alkyne (334 mg, 0.50 mmol, 1.2 equiv. per azide group (40% functionalization)), SL- alkyne (356 mg, 0.50 mmol, 1.2 equiv. per azide group (40% functionalization)) were added and stirred well. Then CUSO4.5H2O (42 mg, 0.2 equiv. per azide to be functionalized) and sodium ascorbate (67 mg, 0.4 equiv. per azide to be functionalized) each were dissolved in 0.5 mL of water separately and mixed well. The resulting mixture was added to the solution of LPG-N3, SL-alkyne and ZA-alkyne. The overall reaction mixture was degassed with argon for 30 min and allowed to stir at 50 °C under argon atmosphere. After 48 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 2M NaOH (5 mL) and stirred for 5 h at room temperature. Then the solution was neutralized with 2M HC1 and lyophilized to dryness. The dry residue was taken in 10 mL DCM/TFA (1: 1) and continued stirring for further 5 h at room temperature. Then, solvents were removed under high vacuum, dissolved in distilled water, and dialyzed against water and aqueous EDTA for 3 days (changing the solvent thrice a day). The dialyzed solution was lyophilized to yield the purified product as a white foamy solid (80% yield). ’H NMR (500 MHz, D₂O): 8 = 1.74-2.24 (m, 40H, SL axial proton, - NHCOCH3), 2.72 (bs, 4H, SL equatorial proton), 3.55-3.94 (m, 138H, LPG, SL and ZA backbone), 4.46 (m, 39H), 8.00 (bs, 8H, triazole). M_n (NMR analysis) ~ 67,000 g/mol.

Biological assays

The nomenclature of polymers is as described above. LPGxOH refers to the unsubstituted LPG backbone, e.g. LPG10OH to 10 kDa LPG; comparator polymers have only HA or NA binding moieties, i.e. are homosubstituted, hence y or z has a value of 0; the respective groups are thus omitted in the formula.

Example 2 - Neuraminidase inhibition activity

NA inhibition activity of compounds of the present invention and comparator compounds was tested against A/X31 (H3N2) virus in a standard fluorescence-based assay using 2'-(4-Methylumbelliferyl)-a- D-A'-accty 1 neuraminic acid (MUN ANA). The cleavage of MUNANA by neuraminidase releases the fluorescent product methylumbelliferone. The amount of fluorescence therefore directly relates to the amount of enzyme activity. The results are shown in Table 1.

Table 1. Characterization of compounds tested against A/X31 (H3N2) virus.

Compound DF (%) SA, SL & ZA per ^-potential NA inhibition polymer ±SD [mV] ICso±SD [nM|

[ZA]^e

LPG10OH - - -2.7 ±1.66 1775 ± 592

LPGIOSA_O.4O SA = 44 SA = 60 -30.8 ±2.58 1579 ± 336

LPGioSLo so SL = 50 SL = 67 -18.6 ±1.72 >10 000

Zanamivir . . . 0.97 ± 0.16

LPGioZAo.io ZA = 10 ZA = 13 -3.3 ±1.40 2.10 ± 0.41

(27.3)

LPG10ZA0.40 ZA =40 ZA = 54 -17.4 ±3.48 1.27 ± 0.24

(68.58)

LPG10ZA0.10SA0.40 ZA = 13, SA = 40 ZA = 20, SA = 54 -29.5 ±4.34 0.07 ± 0.01

(1-4)

LPG10ZA0.10SL0.40 ZA = 10, SL = 40 ZA = 13, SA = 54 -22.4 ±3.66 19.58 ± 4.76

(255)

LPG10ZA0.40SL0.40 ZA = 40, SL = 40 ZA = 54, SL = 54 -15.9 ±4.95 4.86 ±1.25

(262)

DF: degree of functionalization as determined by ¹HNMR analysis.

“SA, SL & ZA per polymer”: Number of sialic acid, 6'-sialyllactose, and/or zanamivir moieties per polymer, calculated from DF determined by ¹HNMR. Zeta ©-potential was measured in aqueous phosphate buffer (10 mM, 7.4 pH) at 1 mg/mL of concentration.

IC50 values were obtained by MUNANA assay with A/X31 (H3N2) virus. Values are expressed as mean ±SD, n=6. Values in brackets are in terms of ZA concentration (of ZA moieties conjugated with the polymer backbone).

The homomultivalent ZA compounds (LPG10ZA0.10 and LPG10ZA0.40), as well as heteromultivalent compounds of the present invention (LPG10ZA0.10SA0.40, LPG10ZA0.10SL0.40 and LPG10ZA0.40SL0.40) show IC50 values in the nanomolar range. Interestingly, heteromultivalent compounds LPG10ZA0.10SL0.40 and LPG10ZA0.40SL0.40, showed comparably weaker NA inhibition than LPG10ZA0.10SA0.40.

The control compounds LPG10OH and sialic acid-based inhibitors LPG10SA0.40 and LPG10SL0.40 did not show any inhibition of NA activity.

Example 3 - Test of inhibition of virus-cell binding; HAI assay

The hemagglutination inhibition (HAI) assay was performed with different compounds using influenza A viruses A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Califomia/7/2009 (HINlpdm) and A/Bayem/63/2009 (HINlpdm). In the HAI assay is that IAV inhibitors will prevent the attachment of the virus to RBC. Therefore, hemagglutination is inhibited when inhibitors are present. Using different dilution of compounds, lowest inhibitory concentrations of compounds is evaluated. The Ki(HAI) reflects the lowest inhibitor concentration necessary to achieve full inhibition of virus-induced hemagglutination. Results are shown in Figure 1 and Table 2.

Table 2. Inhibitory effect of compounds tested against different IAV subtype strains. The Ki(HAi) reflects the lowest inhibitor concentration necessary to achieve full inhibition of virus-induced agglutination.

The homomultivalent SA and SL polymers showed some inhibitory activity against certain virus subtypes. The homomultivalent ZA polymers showed little or no HA inhibition. In contrast, the heteromultivalent polymers (LPGZA0.10SA0.40 and LPGZA0.40SL0.40) showed increased hemagglutination inhibition over the homomultivalent counterparts, with LPGZA0.40SL0.40 in particular showing broad HA inhibition against all tested IAV strains.

No HA inhibition was observed with control compounds LPG10OH, Zanamivir, and 6 '-sialyllactose.

Example 4 - Test of inhibition of virus-cell binding

The therapeutic activity against virus propagation was analyzed in a multicyclic infection setup with the A/X31 (H3N2), A/Panama/2007/2009 (H3N2) and A/Bayem/63/2009 (HINlpdm) subtypes.

Madin-Darby Canine Kidney (MDCK II) cells were washed with PBS and subsequently infected with the indicated virus at multiplicity of infection (MOI) 0.01 for 1 h. Input virus was removed, and unbound virus washed off with PBS. Cells were then incubated with infection medium (MEM supplemented with 0.2% BSA, 2 mM L-glutamine, 100 mg/ml streptomycin and 100 units/mL penicillin and 2.5 mg/mL TPCK-treated trypsin) containing the indicated compound at the indicated concentration. After 24 h, virus titers in the supernatants were determined by plaque assay as described before (M. Matrosovich et al. Virol J 2006, 3, 63.)

IC50 values were calculated by fitting the data from the curves obtained by plotting the different concentrations of each compound (for each compound and each concentration data from three independent experiments were determined in duplicates), using a 4^th-order non-linear regression fit in Graphpad Prism. Results are shown in Table 3.

Table 3. Inhibition of propagation of diverse IAV virus strains in cell culture. IC50 values are given as particle concentrations. In addition, the concentrations of the respective ligands are given in brackets.

ND: not detected

The control compound LPG10OH did not show inhibition of vims propagation.

The comparator compounds, including homomultivalent compounds and Zanamivir showed some activity against one or more of the tested strains. In comparison, the heteromulti valent compounds of the present invention showed markedly increased inhibition of vims propagation as indicated by lower IC50 values. LPG10ZA0.10SA0.40 demonstrated broad antiviral activity against all three strains and LPG10ZA0.40SL0.40 showed even lower IC50 values.

Importantly, the heteromultivalent compounds of the present invention were able to overcome decreased zanamivir sensitivity of the strain A/Bayem/63/2009 (HlNlpdm), indicating suitability to treat infections with NA inhibitor-resistant vimses as well.

A comparison of covalently bound heteromultivalent compound LPG10ZA0.10SA0.40 with the physical mixture of LPG10ZA0.10 and LPG10SA0.40 was performed in the multi cyclic infection setup at an inhibitor concentration of 10 nM to demonstrate synergism of having both hemagglutinin and neuraminidase binding moieties on a single polymer backbone. The LPG10ZA0.10SA0.40 at 10 nM corresponds to ZA and SA concentrations of 130 nM and 530 nM, respectively. A physical mixture containing 130 nM (ZA concentration) LPG10ZA0.10 and 530 nM (SA concentration) LPG10SA0.40 was used in the same experimental setting. Results are shown in Figure 4.

The heteromultivalent compound reduced the vims titer by one order of magnitude more than the physical mixture of the analogs at 10 nM concentrations. Example 5 - comparison with heteromultivalent nanoparticles

The compounds of the present invention were also compared with heteromultivalent nanoparticles from the prior art (Chuanxiong Nie et al., Angew. Chem. 2020, 132, 1-6) in a plaque reduction assay. Results are shown in Table 4

Table 4 Inhibition of propagation of diverse IAV virus strains in cell culture. IC50 values are given as particle concentrations. IC50 values are provided here in weight/mL concentrations. The assay conditions are as given above for Example 3 - Test of inhibition of virus-cell binding.

The compounds of the present invention show markedly improved efficacy compared with the heteromultivalent nanoparticles from the prior art.

Example 6 - imaging at 24 hpi with A/X31 (H3N2)

Cells were imaged at 24 hpi with A/X31 (H3N2) virus in presence of different compounds. Influenza A/X31 (H3N2) viral nucleoproteins (NP) were labeled with antibodies (antibodies (influenza A NP monoclonal antibody, Invitrogen and Alexa Fluor 488 coupled secondary antibody, Invitrogen) to reveal infected cells and cellular DNA was stained using DAPI using standard protocol as described before (Richard Y Kao et al. Nature Nanotechnology 2010, 28 (6), 600-607) (Representative images are shown in Figure 2). In the infection control (absence of any LPG compound) and LPG10OH treated cells, nearly all the cells were infected within 24 hpi (hours post infection) (MOI (multiplicity of infection) = 0.01). Upon adding polymeric inhibitors to the cell culture medium directly after 45 min of infection, the number of infected cells became substantially reduced.

The heteromultivalent compound LPG10ZA0.40SL0.40 showed the high inhibitory activity, and its activity was significantly higher than the two homomultivalent inhibitors (LPG10ZA0.40 and LPG10SA0.40). These findings rationalize the efficient anti-influenza efficacy of the compounds of the invention and demonstrate additional benefits for inhibiting virus propagation 24 hours post-infection where compounds were added 45 minutes after the infection has started. MDCK II cells were washed with PBS and subsequently infected with the indicated virus at MOI 0.01 for 45 minutes. Input virus was removed, and unbound virus washed off with PBS. Cells were then incubated with infection medium (MEM supplemented with 0.2% BSA, 2 mM L-glutamine, 100 mg/ml streptomycin and 100 units/mL penicillin and 2.5 mg/mL TPCK-treated trypsin) containing the indicated compound at the indicated concentration. After 24 h, virus titers in the supernatants were determined by plaque assay as described before

Example 7 - ex vivo testing in explanted infected human lung tissue

Virus infections were studied in explanted human lung tissue infected ex vivo. Compounds were administered only once at 1.5 hpi with IAV/Panama/2007/1999 (H3N2) virus (0.4 x 10⁶ PFU/mL) and plaque -forming units (PFU) in the supernatants of infected human lung tissue were assessed at 16, 24, and 48 hpi, respectively. Concentrations of compounds were based on the previous in vitro assays and ex vivo optimization.

Tumor-free normal human lung tissue was cut into small pieces (weight -100 mg per piece) and incubated in RPMI 1640 medium overnight to wash off clinically applied antibiotics. The study was approved by the ethics committee at the Charite clinic (projects EA2/050/08 and EA2/023/07), and written informed consent was obtained from all patients. The infection experiments were done in RPMI 1640 infection medium (supplemented with 0.3% BSA and 2 mM l-glutamine) at 37 °C with 5% CO2 as described previously (J. Berg, et al. European Respiratory Journal 2017, 50, 1601953. A. C. Hocke, et al., Am J Respir Crit Care Med 2013, 188, 882. V. K. Weinheimer, Journal of Infectious Diseases 2012, 206, 685). For replication analyses, human lung tissue explants were inoculated with 2 x 10⁵ PFU in RPMI 1640 medium for 1.5 h at room temperature. Excess virus was removed by washing with DPBS, and lung tissue was incubated for 48 hpi (hours post infection) in RPMI infection medium containing different inhibitors. For the experiment, tumor-free tissue specimens from four donors were used. For the replication analysis, at 0, 16, 24 and 48 hpi, supernatants of infected lung tissue were harvested and viral titers were determined by standard plaque titration assay.

The results are shown in Figure 3A-C. The heteromultivalent compounds of the invention significantly reduced the virus titer, compared to all other tested compounds. The heteromultivalent compounds of the present invention outperformed homomultivalent compounds and physical mixtures thereof. This indicates a synergistic effect.

The data presented herein demonstrate that the heteromultivalent compounds of the invention were able to overcome this decreased zanamivir sensitivity, indicating efficacy against NA inhibitor-resistant strains.

Importantly, none of the compounds of the present invention showed any toxicity against MDCK-II cells in an MTS assay (Riss TL et al. et al. Cell Viability Assays. 2013 May 1 [Updated 2016 Jul 1]. In: Markossian S, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004.) up to 10 pM concentration (data not shown herein).

Materials and Methods

Cytotoxicity assessment

Cytotoxicity was measured using the CellTiter 96® AQueous One Solution Cell Proliferation Assay (Promega) according to the manufacturer’s instructions, which assesses cell viability based on mitochondrial activity. 15,0000 MDCK II cells were seeded per well of a 96 well plate. On the next day, a dilution series of the compounds was prepared in cell culture medium (MEM supplemented with 10% fetal calf serum, 2 mM L-glutamine, 100 mg/mL streptomycin and 100 units/mL penicillin). The cells were washed once with PBS and afterwards the compound-containing medium was added. After 24 h at 37 °C and 5% CO2, 20 pL MTS solution was added to each well and incubated at 37 °C and 5% CO2 for 1 h. Absorbance was read at 490 nm. Blank-subtracted data was normalized to untreated cells.

Hemagglutination inhibition assay (HAI)

Inhibitors were fourfold serially diluted in PBS. Then, 4 HAU from A/X31 (H3N2), A/Panama/2007/2009 (H3N2), A/Califomia/7/2009 (H1N1) or A/Bayem/63/2009 (H1N1) virus containing approximately 4 xlO⁷ virus particles were added and gently mixed. After 15 min inculabtion at rt, 50 pl of a 1% chicken erythrocyte solution (preclinics GmbH) was added, gently mixed, and incubated for 30 min at rt. The inhibitor constant KiHAI, reflects the lowest inhibitor concentration, which is necessary to achieve full inhibition of virus induced hemagglutination. To check for full hemagglutination inhibition, the microtiter plate was tilted by 60° to cause droplet formation from red blood cell pellet. NA inhibition test

MUNANA assay was used to determine the NA activity of A/X31 H3N2 being treated with the inhibitors.¹²¹ Briefly speaking, the inhibitors were firstly diluted 10-fold in 25 pL reaction buffer (150 mM sodium acetate buffer, pH 7 and 1 mM calcium chloride) and then incubated with 25 pL of A/X31 H3N2 viral particles for 45 min at 37 °C. Afterwards, 50 pL of 160 pM substrate solution [4- MUNANA; 2’-(4-methylumbelliferyl)-a-D-N-acetylneuraminic acid sodium] was added and the mixture was incubated at rt for 2h. Finally, fluorescence density was measured by fluorescence plate reader (Tecan infinite 200Pro) at an excitation wavelength of 360 nm and an emission wavelength of 465 nm. The NA inhibition ratio was calculated by comparing the intensity with non-treated control. The dose-dependent inhibition curves were fitted by Prism 7.0, from which the IC50 values were also estimated.

Information on different Influenza A strains

Influenza A viruses A/X31 (H3N2) (reassortant with HA and NA segment of influenza strain A/Aichi/2/68 (H3N2) in the background of A/PuertoRico/8/1934 (H1N1)), A/Panama/2007/1999 (H3N2), A/PR/8/34 (H1N1) and A/Bayem/63/2009 pdm (H1N1) were grown in embryonated chicken eggs. Virus was harvested from the allantoic fluid, cleared by centrifugation (300 g, 10 min) and stored at -80 °C until use. Titers of virus stocks were determined by plaque titration. Influenza A Virus A/Bremen/5/2017 (H3N2) was grown on MDCK II cells. Virus was harvested from the cell culture supernatant, cleared by centrifugation (300 g, 10 min) and stored at -80°C until use.

Infection assay

MDCK II cells were washed with PBS and subsequently infected with the indicated virus at MOI 0.01 for 45 minutes. Input virus was removed, and unbound virus washed off with PBS. Cells were then incubated with infection medium (MEM supplemented with 0.2% BSA, 2 mM L-glutamine, 100 mg/ml streptomycin and 100 units/mL penicillin and 2.5 mg/mL TPCK-treated trypsin) containing the indicated compound at the indicated concentration. After 24 h, virus titers in the supernatants were determined by plaque assay as described before.¹³¹ The cells were fixed by 2.5% formalin, permeabilized by 0. 1% Triton X-100 and then labeled by antibodies (influenza A NP monoclonal antibody, Invitrogen and Alexa Fluor 488 coupled secondary antibody, Invitrogen). After staining the cell nucleus with DAPI, the images were acquired by Zeiss Axio Observer. For growth curves, infectious particles in the supernatants were titrated after incubation for the indicated time. IC50 values were calculated from data of 24 h incubation with serially diluted compounds by fitting normalized and transformed data with nonlinear regression using GraphPad Prism 8.4.0. Ex-vivo HuLu post infection inhibition

Tumor-free normal human lung tissue was cut into small pieces (weight -100 mg per piece) and incubated in RPMI 1640 medium overnight to wash off clinically applied antibiotics. The study was approved by the ethics committee at the Charite clinic (projects EA2/050/08 and EA2/023/07), and written informed consent was obtained from all patients. The infection experiments were done in RPMI 1640 infection medium (supplemented with 0.3% BSA and 2 mM 1-glutamine) at 37 °C with 5% CO2 as described previously. ^[4-61 For replication analyses, human lung tissue explants were inoculated with 2 x 10⁵ PFU in RPMI 1640 medium for 1.5 h at room temperature. Excess virus was removed bywashing with DPBS, and lung tissue was incubated for 48 hpi (hours post infection) in RPMI infection medium containing different inhibitors. For the experiment, tumour-free tissue specimens from four donors were used. For the replication analysis, at 0, 16, 24 and 48 hpi, supernatants of infected lung tissue were harvested and viral titres were determined by standard plaque titration assay.

References cited in the preceding sections

[1] Papp, I. et al.. ChemBioChem 2011, 12, 887-895

[2] Sunder, A.et al. Macromolecules 1999, 32, 4240-4246;

[3] Haag, R.; Sunder, A; Stumbe, J. F. J. Am. Chem.Soc. 2000, 122, 2954-2955.

[4] Sunder, A.; Mtilhaupt, R.; Haag, R.; Frey, H. Adv. Mater. 2000, 12, 235-239.

[5] Ul-haq, M. I.; Shenoi, R. A.; Brooks, D. E.; Kizhakkedathu, J. N. J. Polym. Sc. Part A: Polym. Chem. 2013, 51, 2614-262.

[6] Wilms, D. (Wurm, F.; Nieberle, J.; Bohm, P.; Kemmer-Jonas, U.; Frey, H. Macromolecules 2009, 42, 3230-3236.

[7] Gan, Z.; Roy, R. Can. J. Chem. 2002, 80, 908-916.

[8] Ogura, H.; Furuhata, K.; Itoh, M.; Shitori, Y. Carhohydr. Res. 1986, 158, 37-51

[9] Vonneman et al, "Size Dependence of Steric Shielding and Multivalency Effects for Globular Binding Inhibitors", JACS 2015, 137.

[10] Kitov, P.I. and Bundle, D.R. "On the Nature of the Multivalency Effect: A Thermodynamic Model", JACS 2003, 125.

[11] Cross, G. Semin. Avian Exot. Pet Med 2002, 11, 15-18.

[12] The preparation and chemical characteristics of hemoglobin-free ghosts of human erythrocytes. J.T. Dodge 1962, Archives of biochemistry and biophysics.

[13] Demedde, J et al. Journal of Carbohydrate Chemistry 2011, 30, 347-360.

[14] Papp, I; Demedde, J; Enders, S; Haag, R. Chem. Comm. 2008, 44, 5851-5853. [15] Demedde, J et al, Proc. Nat. Aca. Set. USA 2010, 107, 19679-19684.

[16] Bernardi, A et al. Chem. Soc. Rev. 2013, 42, 4709-4727.

[17] Erberich, M.; Keul, H.; Moller, M. Macromolecules 2007, 40, 3070-3079.

Claims

2. Heteromultivalent polymer according to claim 1, wherein the linear polymer backbone is comprised of a biocompatible hydrophilic polymer.

3. Heteromultivalent polymer according to claim 1 or 2, wherein the linear polymer backbone is selected from the group comprising polyglycerol, PEG, PAMAM, polyoxazoline, chitosan, cellulose, and callose, particularly poly glycerol.

4. Heteromultivalent polymer according to any of the preceding claims, wherein the linear polymer backbone is a linear polyglycerol, particularly consisting of 1,2-linked or 1,3 -linked glycerol units, more particularly 1,3-linked glycerol units.

5. Heteromultivalent polymer according to any of the preceding claims, wherein the linear polymer backbone has a molecular weight from 1.000 to 100.000 Da, particularly from 2.000 to 20.000 Da, particularly from 4.000 to 15.000 Da, particularly from 7.500 to 12.500 Da, particularly about 10.000 Da.

6. Heteromultivalent polymer according to any of the preceding claims, said backbone is substituted with a multitude of hemagglutinin binding moieties and a multitude of neuraminidase binding moieties.

7. Heteromultivalent polymer according to any of the preceding claims, wherein the degree of substitution of said backbone with hemagglutinin binding moieties is from 5% to 70%, particularly from 10% to 65%, particularly from 15% to 65%, particularly from 25% to 65%, particularly from 30% to 60%, particularly from 35% to 50%, particularly from 40% to 50%, particularly about 40%.

8. Heteromultivalent polymer according to any of the preceding claims, wherein the degree of substitution of said backbone with neuraminidase binding moieties is from 5% to 70%, particularly from 10% to 65%, particularly from 15% to 65%, particularly from 25% to 65%, particularly from 30% to 60%, particularly from 40% to 60%, particularly from 35% to 50%, particularly about 40%, or particularly from 10% to 60%, particularly from 20% to 60%.

9. Heteromultivalent polymer according to any of the preceding claims, wherein the degree of substitution of said backbone with neuraminidase binding moieties and hemagglutinin binding moieties (i.e. the degree of substitution with the total of neuraminidase binding moieties and hemagglutinin binding moieties) is from 10% to 100%, particularly from 15% to 90%, particularly from 20% to 95%, particularly from 30% to 90%, particularly from 40% to 85%, particularly from 40% to 80%, particularly from 50% to 80%, particularly from 70% to 90%, particularly from 75% to 85%, particularly about 80%.

10. Heteromultivalent polymer according to any of the preceding claims, wherein the ratio of neuraminidase binding moieties and hemagglutinin binding moieties are from 5: 1 to 1:5, particularly from 4: 1 to 1:4, particularly from 3: 1 to 1:3, particularly from 2: 1 to 1:2, and particularly about even (meaning 1: 1).

11. Heteromultivalent polymer according to any of the preceding claims, wherein the total number of neuraminidase binding moieties is from 1 to 65, particularly 5 to 60, particularly 10 to 55, particularly 13 to 54, particularly about 13 or about 54.

12. Heteromultivalent polymer according to any of the preceding claims, wherein the total number of hemagglutinin binding moieties is from 1 to 65, particularly 5 to 60, particularly 10 to 55, particularly 25 to 55, particularly 40 to 55, particularly 45 to 55, particularly about 54.

13. Heteromultivalent polymer according to any of the preceding claims, wherein the neuraminidase binding moieties are selected from the group comprising small molecules, peptides, proteins, nucleic acids, and glycans, particularly neuraminic acid or derivatives thereof.

14. Heteromultivalent polymer according to any of the preceding claims, wherein the neuraminidase binding moieties are a neuraminidase inhibitor with a molecular weight of less than 2.000 g/mol, particularly from 200 to 1.500 g/mol, particularly from 250 to 1.000 g/mol, particularly from 275 to 750 g/mol, particularly from 300 to 500 g/mol, particularly from 300 to 400 g/mol, particularly from 300 to 350 g/mol.

15. Heteromultivalent polymer according to any of the preceding claims, wherein the neuraminidase binding moieties are selected from the group comprising zanamivir, laninamivir, oseltamivir, peramivir, Neuraminidase-IN-5, Neuraminidase-IN-8, Neuraminidase-IN-1, Neuraminidase- IN-6, Neuraminidase-IN-4, Neuraminidase-IN-10, Neuraminidase-IN-7, Ganoderic acid TR, Theaflavin, Massarilactone H, Yadanziolide B, Neuraminidase-IN-9, Neuraminidase-IN-11, Neuraminidase-IN-3, Glyasperin C, 2,3-Dehydro-2-deoxy-N-acetylneuraminic acid, Neu5Ac2en, Emodin- 1-0-P-D-glucopyranoside, Aurintricarboxylic acid, Ganoderic acid T-N, BCX-1898, 4-O-Methylepisappanol and derivatives thereof, particularly, zanamivir, laninamivir, oseltamivir, peramivir, particularly zanamivir.

16. Heteromultivalent polymer according to any of the preceding claims, wherein the hemagglutinin binding moieties are selected from the group comprising small molecules, peptides, proteins, nucleic acids, and glycans, particularly small molecules, peptides and glycans, more particularly Oleanolic acid, Aureonitol, Neoechinulin B, N-cyclohexyltaurine, sialic acid, sialyllactose and derivatives thereof or a peptide having from 8 to 40 amino acids, comprising a sequence XI- X2-X3-Tyr-Asp-X5-X6-X7 (SEQ ID No. 3), wherein XI is selected from the group consisting of Leu, His, He, Trp, Asp, Glu, Gly, Lys, Asn, Pro and Arg, X2 is selected from the group consisting of Leu, Pro, Gin, Arg, Cys, Asp, Glu, lie, Lys, Met and Ser, X3 is selected from the group consisting of Tyr, Gly, Phe, Gly, Gin, Thr, Trp and Leu, X4 is selected from the group consisting of He, Ala, Cys, Asp, Glu, Leu, Met, Pro, Vai and Thr, X5 is selected from the group consisting of Pro, Gin, Asp, Glu, Arg, X6 is selected from the group consisting of Ala, Asp, Pro, Cys, Glu, Lys, Gin, Gly and Thr, and X7 is selected from the group consisting of Phe, Asn, Cys, Asp, Glu, Met, Pro, Leu, Thr, Trp and Ser, more particularly sialic acid and 6 '-sialyllactose, particularly 6 -sialyllactose.

17. Heteromultivalent polymer according to any of the preceding claims, wherein the neuraminidase binding moieties are selected from the group comprising zanamivir, laninamivir, oseltamivir, peramivir and derivatives thereof, particularly zanamivir, laninamivir, particularly zanamivir and wherein the hemagglutinin binding moieties are selected from the group comprising sialic acid, sialyllactose and derivatives thereof, particularly sialic acid and 6 '-sialyllactose, particularly 6 -sialyllactose.

18. Heteromultivalent polymer according to any of the preceding claims, wherein the neuraminidase binding moieties and/or hemagglutinin binding moieties are bound to the linear polymer backbone directly or via a linker group.

19. Heteromultivalent polymer according to any of the preceding claims, wherein the neuraminidase binding moieties and/or hemagglutinin binding moieties are bound to the linear polymer backbone via a linker group selected from the group comprising Ci-ioAlkyl, particularly Ci- 6 Alkyl, wherein one or more methylene groups are optionally replaced by a unit independently selected from the group comprising O, S, NH, NH-0, C(O)NH, NHC(O) and CH2(CCHNNN), or by a group -X-Y-, wherein X = S and Y = CH2, (CH2)3O, or CH2(CCHNNN), or X = O and Y = NHCH₂ or X = NH and Y = COCH₂, preferably X = S and Y = (CH₂)₃OCH₂ or X = S and

Y = (CH₂)₃O .

20. Heteromultivalent polymer according to any of the preceding claims, wherein said heteromultivalent polymer has efficacy against at least one, particularly at least two, particularly at least three hemagglutinin serotypes, particularly in influenza, selected from the group comprising Hl, H3, H5 and H7 and/or, particularly and, at least two neuraminidase serotypes selected from the group comprising Nl, N3 and N9.

21. Heteromultivalent polymer according to any of the preceding claims, wherein said heteromultivalent polymer has efficacy against one or more virus strains selected from the group comprising A/Aichi/2/68 (H3N2), A/NewYork/55/2004 (H3N2), A/Victoria/210/2009 (H3N2), A/Puerto Rico/8/1934 (H1N1), A/Vietnam/1203/2004 (H5N1), A/Mute swan/Germany/R901/06 K3141 (H7N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm) A/Bremen/5/2017 (H3N2), A/Asian/2013 (H7N9), and A/Califomia/7/2009 (HINlpdm), particularly A/Bremen/5/2017 (H3N2), A/PR/8/34 (H1N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm), and A/Califomia/7/2009 (HINlpdm).

22. Heteromultivalent polymer according to any of the preceding claims, for use as a medicament.

23. Heteromultivalent polymer according to any of claims 1 to 21 for use in the treatment of a subject infected with a vims having hemagglutinin and neuraminidase, particularly with an ortho- or paramyxovirus, particularly with an orthomyxovirus, particularly with a vims selected from the group comprising influenza, parainfluenza and mumps, particularly with an influenza vims, more particularly with a vims selected from the group comprising influenza type A and type B, more particularly with influenza type A.

24. Heteromultivalent polymer for use in the treatment of a subject infected with a vims according to claim 23, wherein the infection is with a neuraminidase inhibitor-resistant vims.

25. Heteromultivalent polymer for use in the treatment of a subject infected with a vims according to claim 24, wherein the infection is with a vims selected from the group comprising influenza strains selected from the group comprising hemagglutinin serotypes Hl, H3, H5 and H7, particularly selected from the group comprising A/Aichi/2/68 (H3N2), A/NewYork/55/2004 (H3N2), A/Victoria/210/2009 (H3N2), A/Puerto Rico/8/1934 (H1N1), A/Vietnam/1203/2004 (H5N1), A/Mute swan/Germany/R901/06 K3141 (H7N1), A/X31 (H3N2),

A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm) A/Bremen/5/2017 (H3N2), and A/Califomia/7/2009 (HINlpdm), particularly A/Bremen/5/2017 (H3N2), A/PR/8/34 (H1N1), A/X31 (H3N2), A/Panama/2007/1999 (H3N2), A/Bayem/63/2009 (HINlpdm), and A/Califomia/7/2009 (HINlpdm).

26. Heteromultivalent polymer according to any of claims 1 to 21 for use in preventing vims transmission from one subject to another, particularly transmission of a vims as defined in any of claims 23 to 25.

27. Pharmaceutical composition comprising the heteromultivalent polymer according to any of claims 1 to 21.

28. Pharmaceutical composition according to claim 27, furthermore comprising at least one excipient.

29. Pharmaceutical composition according to any of claims 27 to 28, which is in an aerosol form, particularly formulated for nasal and/or pulmonal administration.