Pharmaceutically acceptable lectins derived from plants, fungi and bacteria for the treatment of SARS-CoV-2 infections

The present application relates to pharmaceutically acceptable lectins derived from plants, fungi or bacteria for use in the prevention or treatment of a SARS-CoV-2 infection. Pharmaceutical compositions, combinations with antiviral agents, advantageous formulation techniques and a method of treatment are disclosed.

BACKGROUND OF THE INVENTION

As a result of ecological, climatic and demographic changes, so-called 'emerging' viruses are increasingly being transmitted from their natural animal hosts to humans. Due to accelerated globalization they bear the risk of triggering a pandemic. Emerging viruses may cause acute and often life-threatening diseases. Coronaviridae have become notorious for such transmissions. Examples are Severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), and most recently, the outbreak of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in Wuhan, China. By August 17 ^th 2021 a total of worldwide over 207,9 million SARS-CoV-2 cases with over 4,3 million casualties have been reported by Johns Hopkins University. The incubation period of SARS-CoV-2 ranges between two days and one month. The disease resulting from a SARS-CoV-2 infection is called COVID-19.

Typical symptoms of COVID-19 are fever, cough, and shortness of breath. However, the infection can also cause severe pulmonary injury, leading to rapid onset of progressive malfunction of the lungs, especially with regard to the ability to take up oxygen. This is usually associated with the malfunction of other organs. This acute lung injury (ALI) condition is associated with extensive lung inflammation and accumulation of fluid in the alveoli. It is characterized by diffuse pulmonary microvascular injury resulting in increased permeability and, thus, non-cardiogenic pulmonary edema. In consequence, this leads to pathologically low oxygen levels in the lungs. Other common symptoms associated with COVID-19 patients in ICU care are pulmpnary embolism, thrombosis, venous thromboembolism and brain ischemia.

Coronaviruses are primarily spread through close contact, in particular through respiratory droplets from coughs and sneezes and aerosols. In contrast to the SARS-CoV-1 and MERS- CoV, SARS-CoV-2 can be transmitted from human to human during the incubation period while the infected patient does not show yet any symptoms of disease. Moreover, SARS- CoV-2 can already replicate in the throat. In contrast, the receptors for SARS-CoV and

CONFIRMATION COPY MERS-CoV are located deep in the lungs. Thus, SARS-CoV-2 can be transmitted much easier from human to human in comparison to SARS-CoV-1 and MERS-CoV, which strongly increases the infection rate.

In general, coronaviruses (family Coronaviridae, group Coronaviruses) form a relatively diverse group of large, enveloped, positive strand RNA viruses, which can cause different types of diarrhea and respiratory diseases in humans and animals. They have a very narrow host range and replicate very poorly in cell culture. However, cell culture systems for SARS- CoV-2 could be successfully established.

Sequencing of SARS-CoV-2 revealed an approx. 29.8 kbp genome consisting of 14 open reading frame. Moreover, the virus is phylogenetically closely related to the SARS-CoV-1 (89.1% nucleotide similarity) (cf. Wu et al. (2020) Nature, Epub ahead of print). Like other coronaviruses, SARS-CoV-2 enters the cell by endocytosis and membrane fusion. The viruses are released from the cell by the secretory pathway. The natural reservoir of the virus is unknown.

To date, no specific therapeutic options for the treatment of SARS-CoV-2 infections, respectively COVID-19 are established.

Thus, there is a strong medical need for an effective pharmacological treatment for patients infected with SARS-CoV-2 or similar coronaviruses, respectively to prevent such an infection, and for limiting the epidemic spread of this virus. Ideally, such a pharmacological treatment should also offer at least a treatment option for future coronavirus outbreaks.

Surprisingly, this task is solved by the administration of pharmaceutically acceptable lectins from plants, fungi and bacteria according to the invention.

DESCRIPTION OF THE INVENTION

Lectins are oligomeric proteins or glycoproteins that bind mono- and oligosaccharides reversibly and specifically while displaying no catalytic or immunological activity (Lis and Sharon (2002) Chem Rev 98: 637-674). They can interact with cell membranes and thus can trigger biochemical reactions in the cell (Goldstein and Hayes (1978) in: Advances in Carbohydrate Chemistry and Biochemistry 35: 127-340). However, they do not show a proper enzymatic activity.

Plant lectins are most abundantly localized in the seeds but they are also found in different vegetative tissues such as in roots, leaves, barks, flowers, bulbs and rhizomes (van Damme et al. (2000) EurJ Biochem 267: 2746-2759). Lectins are known to interfere specifically with cell adhesion, cell agglutination, cell division, cell movement, ribosomal protein synthesis, glycoprotein synthesis, protein folding, the immune system, first line-defense against invading microorganisms, self-recognition, regulation of blood protein levels, binding of extracellular and intracellular glycoproteins.

Lectins are ubiquitous in nature. They are mainly found in plants, but also in animals, algae, fungi, bacteria and other microorganisms.

Some lectins are used in medical research e.g. for the identification of several blood groups (cf. Sharon and Lis (2004) Glycobiology 14: 53R-62R). Lectins such as PAH or ConA have been used as a study tool to investigate carbohydrate recognition. ConA is used in affinity chromatography for purifying glycoproteins (e.g. from Dionex Corporation, Sunnyvale, CA, USA).

Animal lectins and their receptors differ from those of plants, fungi and bacteria. It was found that SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2 (Lu et al. (2021) Immunity 54:1304-1319).

Plant lectins are discussed as potential cancer therapeutics and diagnostic tools (cf. Mazalovska and Kouokam (2020) BioMed Res Int: 1631394).

Plant lectins are usually subdivided into five major groups: a) mannose- / mannose glucose-binding lectins b) galactose- 1 N-acetylgalactosamine-binding lectins c) N-acetylglucosamine-binding lectins d) N-acetylneuraminic acid-binding lectins e) fucose-binding lectins.

Several lectins have also a double or multiple affinity to a certain carbohydrate structure, but usually with a different affinity. Therefore, they can’t be assigned exclusively to one of these groups. In the scope of the present disclosure also binding-active subunits of lectins shall be subsumed under these specific lectins.

Pharmaceutically acceptable mannose- / mannose glucose-binding lectins are found in the group comprising, but without being limited to, lentil lectin (LCH), snowdrop lectin (= Galanthus nivalis agglutinin, GNA), Agardhiella subulata lectins (ASL-1, ASL-2), Eucheuma amakusaensis agglutinins (EAA-1 , EAA-2, EAA3), Oscillatoria agardhii agglutinin (OAA), Eucheuma serra agglutinins (ESA-1 , ESA-2), Kapphaphycus alvarezii agglutinin (= Eucheuma cottonii agglutinins; KAA-2, ECA-1 , ECA-2)), Kappaphycus striatum agglutinin (KSA-2), Meristiella echinocarpa lectin (MEL), Meristotheca papulosa agglutinins (MPA-1, MPA-2), Solieria filiformis lectins (SfL-1 , SfL-2), Hydropuntia fisheri agglutinin (HFA), Nannochloropsis gaditana lectin (NgL), Ostreococcus tauri lectin (OtL), Boodlea coacta agglutinin (BCA), Bryopis plumosa lectin (BPL-2), Halimeda renschii lectin (HRL40-1/2), Narcissus pseudonarcissus agglutinin (NPA), Narcissus tazetta lectin (NTL), Narcissus tortifolius agglutinin (NTA), Hippeastrum hybrid agglutinin (HHA), Clivia minata agglutinin (CMA), Allium ursinum agglutinin I (AUAI), Allium ursinum agglutinin II (AUAII), Allium cepa agglutinin (ACA), Allium ascalonicum agglutinin (AAA), Allium porrum agglutinin (APA), Listera ovata agglutinins (LOA, LOMBP, LNL), Polygonatum roseum lectin, Phlebodium aureum lectin (PAL), Gingko biloba lectin (Gnk2), Cycas revoluta lectin (CRLL), Cajanus cajan lectin (CcL), Camptosema pedicellatum lectin (CPL), Canavalia boliviana lectin (ConBo), Canavalia gladiata lectin (CGL), Canavalia grandiflora lectin (ConGF), Centrolobium microchaete lectin (CML), Cladrastis lutea agglutinins (CLAI, CLAII), Cymbosema roseum lectin CRL I, Dioclea guianensis lectin (Dguia), Dioclea lasiocarpa lectin (DLL), Dioclea rostrata lectin (DRL), Dioclea sclerocarpa lectin (DSL), Dioclea virgata lectin (DvirL), Lathyrus aphaca lectin (LaphL), Lathyrus articulatus lectin (LarL), Lathyrus cicera lectin (LcL), Lathyrus hirsutus lectin (LhL), Lathyrus nissolia lectin (LnL), Lathyrus sphaericus lectin (LsphL), Lathyrus tingitanus lectin (LtL), Onobrychis viciifolia lectin (OVA), Pisum arvense lectin (PAL), Pterocarpus angolensis lectin (PAL), Sophora flavescens lectin (SFL), Vicia cracca lectin, Vicia ervilia lectin, Vicia faba agglutinin (VfA), Parkia biglobosa lectin (PBL), Parkia platycephala lectin (PPL), Platymiscium floribundum lectin (PFL), Artocarpus heterophyllus lectin (ArtinM), Artocarpus incisa lectin (Frutapin), Helianthus tuberosus lectin (Heltuba), Arabidopsis thaliana lectin (PP2-A1), Arabidopsis lyrate lectins, Clematis montana lectin (CML), Arisaema lobatum agglutinin (ALA), Arisaema heterophyllum agglutinin (AHA), Dieffenbachia sequina lectin, Remusatia vivipara lectin (RVL), Typhonium divaricatum lectin (TDL), Xanthosoma sagittifolium lectin (XSL), Ophiopogon japonicus lectin (OJL), Polygonatum odoratum lectin (POL), Ipomoea batatas lectin (ipomoelin), Ipomoea trifida lectins, Amaryllis vittata agglutinin (AVA), Crinum asiaticum agglutinin (CAA), Leucojum vernum lectin (LVL), Leucojum aestivm lectin, Zephyranthes Candida agglutinin (ZCA), Zephyranthes grandiflora agglutinin (ZGA), Lycoris aurea agglutinin (LAA), Lycoris radiata agglutinin (LRA), Dioscorea bulbifera lectin (DBF), Dioscorea polystachya lectin, Crocus sativus lectin (CSL), Crocus vernus agglutinin (CVA), Aspidistra elatior lectin (AEL), Smilax glabra lectin (SGM2), Scilla campanulata agglutinin (SCAman), Musa acuminata lectin (BanLec), Pandanus amaryllifolius lectin (pandanin), Cymbidium hybridum agglutinin (CHA), Dendrobium officinale agglutinin (DOA2), Epipactis helleborine lectin (EHMBP), Gastrodia elata lectin (gastrodianine), Liparis noversa lectin (LNL), Bryothamnion seaforthii lectin (BSL), Bryothamnion triquetrum lectin (BTL), Griffithsia sp. lectin (griffithsin), Hypnea cervicornis agglutinin (HCA), Hypnea japonica agglutinin (HJA), Laccaria bicolor lectin (tectonin 2), Penicillium chrysogenum lectin (PeCL), Saccharomyces cerevisiae agglutinin (Flo5A), Saccharomyces pasteurianus lectin (Flolp), Schizosaccharomyces pombe lectin (glucosidase), Hygrophorus russula lectin (HRL), Ceratopteris richardii lectin (cyanovirin), Neurospora crassa lectin (cyanovirin), Tuber borchii lectin (cyanovirin), Brassica napus lectins, Brassica campestris lectins, Brassica insularis lectin, Brassica amplexicaulis lectin, Brassica barrelled lectin, Brassica deflexa lectin, Brassica maurorum lectin, Brassica nigra lectin, Brassica oxyrrhina lectin, Brassica tournefortii lectin, Brassica villosa lectin, Daucus carota lectin, Zea mays lectin, Hyacinthoides hispanica lectins, Hernandia moerenthutiana lectin, Sinapis arvensis lectins, Sinapis alba lectin, Raphanus raphanistrum lectins, Hirschfeldia incana lectins, Ananas comosus lectin (AcmJRL) , Sorghum bicolor lectin, Linum usitasissimum lectin, Erythrina cristagalli lectin, Amorphophallus konjac lectins, Amorphophallus paenifolius lectin, Solanum bulbocastanum lectins, Zantedeschia aethiopica lectin (ZAA), Taxus x media lectin, Lycoris sp JKB-2004 lectins, Arachis hypogaea lectin, Zingiber officinale lectin, Picea abies lectin, Erysimum cheiri lectin, Crambe kalikii lectin, Diplotaxis erucoides lectin, Diplotaxis siifolia lectin, Eruca sativa lectin, Eruca vesicaria lectin, Erucastrum abyssinicum lectin, Erucastrum gallicum lectin, Lunaria annua lectin, Moricandia arvensis lectin, Nicotiana tabacum lectin, Curculigo latifolia lectin (curculin), Ulex europeus lectin, Pseudoalteromonas haloplanktis TAC125 lectins, Alteromonas macleodii lectins, Marinomonas sp MED121 lectin, Burkholderia cenocepacia AU 1054 lectin, Solibacter usitatus Ellin6076 lectin, Arthrobacter sp FB24 lectin, Ralstonia metallidurans CH34 lectin, Rhodopirellula baltica SH 1 lectins, Microcystis viridis lectin, Neoregelia flandria lectin.

Pharmaceutically acceptable galactose- / N-acetylgalactosamine-lectins are found in the group comprising, but without being limited to, peanut agglutinin (PNA), jacalin (AIL), Erythrina cristagalli lectins (ECL), Arachis hypogea lectin (PNA), Phragmites australis agglutinin (PallGIcNac), Nicotiana tabacum agglutinin (nictaba), Urtica dioica agglutinin (UDA), Bryonia dioica agglutinin (BDA), Glechoma hederacea (gleheda), Rhizoctonia solani agglutinin (RSA), Butea monosperma lectin (BMSL), Griffonia simplicifolia lectins I + II (GSA- I, GSL-I, GSL-II), Medicago sativa lectin, Trifolium repens lectin, Triticum aestivum lectins, Triticum monococcum lectin, Arachis hypogaea lectins, Maackia amurensis lectin, Arabidopsis thaliana lectins, Sorghum bicolor lectin, Sandersonia aurantiaca lectins, Pyrus pyrifolia lectins, Fragaria ananassa lectins, Flavobacterium johnsoniae UW101 lectin, Burkholderia thailandensis E264 lectin, Burkholderia pseudomallei 1710b lectins, Burkholderia mallei ATCC 23344 lectin, Vicia cracca lectin, Galactia tashiroi lectin, Ulex europeus lectins, Momordica charantia lectin.

Pharmaceutically acceptable N-acetylglucosamine-binding lectins (chitin-binding lectins) are found in the group comprising, but without being limited to, wheat germ agglutinins (Triticum aestivum; WGA, sWGA), Triticum durum lectin, Urtica dioica lectins, Griffonia simplicifolia lectins, Maackia amurensis lectin, Erythrina cristagalli lectin, Ulex europeus lectin, Phytolacca americana lectins, Oryza rufipogon lectin, Oryza alta lectin, Oryza minuta lectin, Galega orientalis lectins, Dioscorea japonica lectin, Streptomyces olivaceoviridis lectin (CHB1), Agropyron repens lectins, Brachypodium sylvaticum lectin, Phragmites australis lectins, Eucheuma denticulatum agglutinins (EDA-1 , EDA-2).

Pharmaceutically acceptable N-acetylneuraminic acid-binding lectins (sialic acid-binding lectins) are found in the group comprising, but without being limited to, Maackia amurensis leucoagglutinin (MAL), Maackia amurensis hemoagglutinin (MAH), Triticum aestivum lectins, Polygonatum roseum lectin.

Pharmaceutically acceptable fucose-binding lectins are found in the group comprising, but without being limited to, Ulex europaeus agglutinins (UEA, UEA-I), Griffonia simplicifolia lectin IV (GSL-IV), Ralstonia solanacearum lectin (RSL), Burkholderia cenocepacea lectin (BC2L-C), Streptomyces rapamycinicus lectin (SL2-1), Erythrina cristagalli lectins, Blastopirellula marina lectin.

Many lectins showed to be toxic. Among them are ricin from Ricinus communis (castor bean) such as RCA and RCA120, abrin from Abrus precatorius, soybean agglutinin (SBA), Psophocarpus tetragonolobus lectins, Phaseolus lunatus lectin (LBL), Phaseolus vulgaris lectins such as phytohemagglutinin (PHA), winged bean agglutinin (WBA I), Cucurbita pepo lectin, Dolichos biflorus lectins such as DBL, Pisum sativum agglutinin (PsA), Viscum album lectins, alpha-sarcin from Aspergillus giganteus, concanavalin A (ConA) from Canavalia ensiformis, Canavalia maritima lectin (ConM), Canavalia virosa lectin (ConV), Canavalia bonarensis lectin (CaBo), Canavalia brasiliensis lectin (ConBr), Canavalia lineata lectin, cotin from Croton tiglium, agglutinin from Cratylia argentea (CAA), lectin from Robinia pseudoacacia, Lycopersicon esculentum lectins such as LEL, Solanum tuberosum lectin (STL), Lablab purpureus lectin (FRIL), Lathyrus ochrus lectin (LoL), Lathyrus odoratus lectin (LodL), Lathyrus sylvestris lectin (LsiL), Lathyrus sativus lectin (LsL), Diphtheria toxin from Corynebacterium diphtheriae, Exotoxin A from Pseudomonas aeruginosa such as LecB and PA-IIL, mitogilline and restrictocin from Aspergillus restrictus, phasins from French beans, kidney beans and chickpea such as PHA-E and PH-L, lectin from winter aconite, Shiga toxin from Shigella dysenteriae, Adenia digitata lectin (modeccin), Vicia villosa lectins (WL, WL- A4, WL-B4), Vicia graminea lectin, Vicia sativa lectin, Fusarium graminearum lectin, Vero toxin from enterohemorrhagic Escherichia coli, mistletoe toxic lectins-l, II + III (ML-I, ML-II, ML-III), Glycine max lectin, Asparagus officinalis lectin, Raphanus sativus lectins, Oryza sativa agglutinins (orysata, OSA), Hordeum vulgare lectin, Musa paradisiaca lectin, Prunus americana lectin, Vitus vinifera lectin, Allium sativum agglutinin I (ASAI), Allium sativum agglutinin II (ASAII), Porphyra umbilicalis lectin (BU14), Hypnea musciformis agglutinin (HMA), Adenia volkensii lectin, mannan-binding lectin (MBL, MBL2, MBP), Allium altaicum agglutinin (AALTA), Allium tuberosum agglutinin (ATA), Arum maculatum agglutinin (AMA), Tulipa cv Apeldoorn lectin (TLMIII), Tulipa hybrid lectins (TxLCI, TL-MII), Araucaria brasiliensis lectins I and II, Bowringia mildbraedii agglutinin (BMA), Centrolobium tomentosum lectin (CTL), Cratylia mollis lectin (CRAMOLL), Phoradendron californicum lectin, Pineilia pedatisecta lectin, Pineilia ternata agglutinin (PTA), Lotus tetragonolobus agglutinin (LTA), Aleuria aurantia lectin (AAL), Wistaria floribunda lectin (WFL), Datura stamonium lectin (thorn apple lectin, TAL), Amaranthus caudatus lectin, Bauhinia purpurea alba lectin (BPL), Artocarpus integrifolia lectins (artocarpin, jacalin), Maclura pomifera agglutinin (MPA, MPL), Sophora japonica lectin, Clitocybe nebularis lectin, Agaricus bisporus lectin, Coprino psiscinerea lectin, Laetiporus sulphureus lectin, Marasmus oreades agglutinin (MOA), Polyporus squamosus lectin, Sclerotinia sclerotiorum lectin, Dioscorea batatas lectin (DB1), Colocasia esculenta agglutinin (CEA, tarin), Brassica oleracea lectins, Clostridium phytofermentans ISDg lectin, Aspergillus fumigatus agglutinins (FleA, Afu-FleA, AFL), Lens culinaris agglutinin (LcA), Dioclea violacea lectin (DVL), Dioclea lasiophylla lectin (DlyL), Dioclea grandiflora lectin (DGL), Dioclea wilsonii lectin (DwL), Dioclea reflexa lectin (DrfL), Polygonatum multiflorum agglutinin (PMA), Polygonatum cyrtonema lectin (PCL), Cratylia floribunda lectin (CFL), Sambucus ebulus lectin, Sambucus nigra agglutinins (SNA, SNA-I, SNLRP), Sambucus sieboldiana lectin, Morus nigra lectin (Moniga-M), Calystegia sepium lectin (Calsepa), Vatairea macrocarpa lectin (VML), Hevea brasiliensis agglutinin (hevein), Cymbosema roseum lectin CRL II, Millettia dielsiana lectin (MDL), Trigonella foenumgraecum lectin, Platypodium elegans lectin (nPELa), Castanea mollisima lectin, Castanea crenata agglutinin (CCA), Artocarpus integer lectin (CMB), Artocarpus lakoocha lectin (artocarpin), Aloe arborescens lectin (ALOE), Lysichiton camtchatscensis lectin (LCL), Typhonium giganteum lectin (TGL), Prunus persica lectins, Cichorium intybus lectin, Pseudoalteromonas tunicata D2 lectins, Burkholderia ambifaria AMMD and BamBL lectins, Burkholderia pseudomallei 1710b lectin, Chromobacterium violaceum ATCC 12472 and CV- IIL lectins, Streptomyces coelicolor A3(2) lectin, Cryptosporidium parvum lectin, Erythrina corralodendron lectin (coral tree lectin, ECorL), Salvia sclarea lectin (SSL), Amphicarpaea bracteata lectin, Cytisus scoparius lectin, Cytisus multiflorus lectin, Cytisus sessilifolius lectins, Photorhabdus luminescens subsp laumondii TTO1 lectin, Caragana arborescens lectins such as CAA, Crotalaria juncea lectin, Crotalaria striata lectin, Falcata japonica lectin., Laburnum alpinum lectins, Lotononis bainesii lectins, Macrotyloma axillare lectin (LMA), Ononis spinosa lectin, Chelidonium majus lectin, Cyphomandra betacea lectin, Secale cereale lectin Ulva lactuca lectin.

As these toxic lectins are not suitable for a pharmaceutical use in humans the present invention does expressly not refer to them. Adverse reactions of humans to lectins in diet comprise nausea, bloating, vomiting and diarrhea. In experimental animals fed on diets containing plant lectins the evident adverse symptoms include loss of appetite and decreased body weight (cf. Lajolo and Genovese (2002) J Agric Food Chem 50: 6592-6598). Some plant lectins show subtoxic effects of hemagglutination or binding to other blood cells. Some plant lectins were found to be virtually resistant to proteolysis in vitro (Carbonaro et al. (1997) J Agric Food Chem 47: 3387-3394) and in the gut in vivo (Pusztai (1991) in: Plant lectins. Cambridge University Press, 105-205).

In the scope of the present disclosure the term “antinutritional lectin” shall be used for lectins commonly found in human food sources and beverages that negatively interfere with the absorption of nutrients. Such lectins are not suitable for oral administration.

In the scope of the present disclosure the term “pharmaceutically acceptable lectin” refers to all lectins from plants, fungi and bacteria for which no or at least no serious pharmacological adverse effects have been described for humans, as e.g. a serious toxicity. This term does not exclude those lectins for which mild adverse effects have been described or suggested that can be handled by a pharmacologically tolerable dosage or the choice of a suitable administration form, or that show side effects which in the light of the positive effects on a SARS-CoV-2 infection appear to be tolerable.

Not all of these pharmaceutically acceptable lectins are suitable for every application route. One would not choose a lectin that causes digestive problems for an oral application. Those lectins liable to hemagglutination are not the first choice for a parenteral application route. However, the expert in the art will not have a problem to choose a suitable administration route for each envisaged lectin.

Thus, the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria for use in the prophylaxis or treatment of a SARS-CoV-2 infection.

In one aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria from the mannose- / mannose glucose-binding type for use in the prophylaxis or treatment of a SARS-CoV-2 infection.

In another aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria from the galactose- / N- acetylgalactosamine-binding type for use in the prophylaxis or treatment of a SARS-CoV-2 infection.

In another aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria from the N-acetylglucosamine- / chitin-binding type for use in the prophylaxis or treatment of a SARS-CoV-2 infection. In another aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria from the N-acetylneuraminic acid / sialic acid-binding type for use in the prophylaxis or treatment of a SARS-CoV-2 infection.

In yet another aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria from the fucose-binding type for use in the prophylaxis or treatment of a SARS-CoV-2 infection.

As shown in Examples 1 and 2, wheat germ agglutinin (WGA) inhibits dose-dependently the replication of SARS-CoV-2 virions in a non-cytotoxic dosage range over 3 to 4 log decades.

WGA was shown to be resistant against in vivo breakdown by proteolytic enzymes (cf. Bardocz et al. (1995) in: Lectins. Biomedical Perspectives, Taylor and Francis). It transverses the rat and human small intestine intact (Brady et al. (1978) Gastroenterology 75: 236-239).

In rats, WGA binds to and is endocytosed into epithelial cells of the small intestine (Pusztai et at. (1993) Brit J Nutr 70: 313-321 ). WGA is discussed as a potential therapeutic agent for leukemia (Ryva et al. (2019) Front Oncol 9: 100).

Both oral and intranasal delivery of plant lectins such as WGA stimulated the production of specific serum IgG and IgA antibodies (Lavelle et al. (2000) Immunology 2000 30-37).

WGA protects crops against insect pests, e.g. corn, sugarcane, alfalfa and mustard. WGA was expressed in transgenic plants in order to provide protection to the host plant (e.g. tomatoes) against insect pests (cf. Makkendram Nannan and Ponnusamy (2012) in: Genetic manipulation of tomato plant with WGA gene. Lampert Academic Publishing).

A method for microbial production of WGA is disclosed in JPH 05199881 A. A method for the prurification of WGA using a macroporous or microporous filtration membrane was described in US 617443 B.

WO 2002/059619 reveals a method for diagnosing Alzheimer’s disease, dementia and transmissible spongiform encephalopathies by measuring the concentration of WGA-binding glycoproteins. Covalent surface modification of microparticles containing a gemcitabine derivative with WGA resulted in enhancing of binding duration on urothelial cells which allowed to withstand extensive washout (Neutsch et al. (2013) J Control Release 169: 62- 72). WGA was covalently coupled with nanoparticles for carrying thymopentin (Yin et al. (2006) J Control Release 116: 337-345). WGA nanoparticles are thought to be promising candidates for mucosal drug delivery to treat lactose intolerance (Sheng et al. (2014) Drug Delivery 21: 370-378). In a particularly preferred embodiment, the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria for use in the prophylaxis or treatment of a SARS-CoV-2 infection, wherein the pharmaceutically acceptable lectin is wheat germ agglutinin.

It was recently shown that griffithsin (GRFT), a mannose- / mannose glucose-binding lectin from Griffithsia spec., shows likewise SARS-CoV-2 inhibiting actions. It blocks the entry of SARS-CoV-2 in Vero6 cell lines (Ahan et al. (2021) bioRxiv Preprint Server https://doi.org/10.1101/2021.07.22.453309). Also lentil lectin (LHA), a mannose- 1 mannose glucose-binding lectin from Lens culinaris, exhibits broad antiviral activities against SARS- CoV-2 variants (Wang et al. (2021) Emerging Microbes and Infections 10: 1519-1529). It was demonstrated that the partially toxic FRIL lectin from Lablab purpureus prevents infections form influenza viruses better than from SARS-CoV-2 (Liu et al. (2020) Cell Reports 32: 108016). Mannose-specific lectins from plants, fungi, algae and cyanobacteria are proposed as potential blockers for SARS-CoV, MERS-CoV and SARS-CoV-2 infections (Barre et al. (2021) Cells 10: 1619). Also Gupta and Gupta (2021 ) suggest mannose-binding plant lectins in the treatment of COVID-19 patients (Mol Cell Biochem 476: 2917-2942). On the other hand, the use of lectin inhibitors in prevention and therapy of SARS-CoV-2 infections is discussed also (Lardone et al. (2021) J Biol Chem 296: 100375).

For an effective treatment of a SARS-CoV-2 infection it may be advantageous to provide to a patient in need thereof a combinational therapy by combining the lectin according to the invention with at least one antiviral agent.

For example, from HIV, respectively anti-retroviral therapy the following classes are known:

Reverse transcriptase inhibitors suitable for such a combination therapy are nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI). Examples of NRTI include, but are not limited to, abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine, zalcitabine, entecavir, adefovir, elvucitabine, fosalvudine(-tidoxil), fozivudintidoxil, lagiciclovir, alamifovir, clevudine, pradefovir, telbivudine. Examples of NNRTI include, but are not limited to, efavirenz, etravirine, nevirapine, rilpivirine, delavirdine, emivirine, lersivirine.

Suitable for a combination therapy according to the invention are integrase inhibitors such as raltegravir, elvitegravir, dolutegravir, MK-2048.

Examples of HIV protease inhibitors suitable for a combination therapy according to the invention are saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, darunavir, brecanavir, mozenavir, tipranavir. Examples of entry inhibitors suitable for a combination therapy according to the invention are enfuvirtide and maraviroc.

Further, general virostatic agents suitable for a combination therapy according to the invention can be selected from the group comprising ancriviroc, aplaviroc, cenicriviroc, enfuvirtide, maraviroc, vicriviroc, amantadine, rimantadine, pleconaril, idoxuridine, aciclovir, brivudine, famciclovir, penciclovir, sorivudine, valaciclovir, cidofovir, ganciclovir, valganciclovir, sofosbusvir, foscarnet, ribavirine, taribavirine, filibuvir, nesbuvir, tegobuvir, fosdevirine, favipiravir, merimepodib, asunaprevir, balapiravir, boceprivir, ciluprevir, danoprevir, daclatasvir, narlaprevir, telaprevir, simeprevir, vanipevir, rupintrivir, remdesivir, fomivirsen, amenamevir, alisporivir, bevirimat, letermovir, laninamavir, oseltamivir, peramivir, zanamivir.

General immunostimulatory agents suitable for a combination therapy according to the invention can be selected from the group comprising interferons (alpha-, beta-, gamma-, tau- interferon), interleukins, CSF, PDGF, EGF, IGF, THF, levamisol, dimepranol, inosine.

Furthermore, possible combinations according to the invention include adjuvants such as cobicistat.

The terms “medicine" or “medical" comprise human as well as veterinary medicine.

The term “organism" refers to a living being, especially a human or an animal, possessing a self-regulating immunological system.

The term “host organism" is used in terms of the application for those organisms exploited for replication by viruses, herein especially retroviruses, following an infection with them.

The term "active agent" in this application refers to lectins according to the invention. Moreover, this term can comprise further pharmaceutical agents, known from the state of the art.

The terms “composition” and “pharmaceutical composition" comprise at least one lectin according to the invention in any pharmacologically suitable defined dose and dosage form together with at least one suitable excipient or carrier substance as well as all substances which are directly or indirectly generated as a combination, accumulation, complex formation or crystal of the aforementioned ingredients, or come into being as a result of other reactions or interactions as well as optionally at least one further pharmaceutical agent known in the state of the art.

The term "excipient" is used in this application to describe each component of a pharmaceutical composition in addition to the active agent. The selection of a suitable excipient depends on factors such as dosage form and dose as well as the influence on the solubility and stability of the composition by the excipient itself.

The term “action" describes the inherent specific mode of action of the respective agent in the scope of the present application.

The terms “effect", “therapeutic effect", “action”, “therapeutic action” regarding at least one active agent according to the invention refer to causally occurring beneficial consequences for the organism, to which the at least one active agent has been administered.

In terms of the application, “therapeutically effective dose" means that a sufficient dose of the at least one lectin according to the invention is administered to a living being or to a patient in need of such a treatment.

The terms “joint administration", “combined administration" or "simultaneous administration" of at least one pharmaceutical agent according to the invention and/or of at least one pharmaceutical agent from the state of the art comprise the administration of the mentioned agents at the same time or at time points factually related close to each other, as well as administrations of said agents at different times within a coherent experiment. The chronological order of the administration of said agents is not limited by these terms. Those skilled in the art will have no difficulties to deduce the described administrations in respect to their chronological or local order from his knowledge and experience.

The term “living being" refers to every animal, especially vertebrate, including human. A "patient" in terms of the application is a living being who suffers from a definable and diagnosable disease, and to whom a suitable active agent can be administered.

The terms “prophylaxis", “treatment" and “therapy" comprise the administration of at least one lectin according to the invention, alone or in combination with at least one further pharmaceutical agent known in the art, to a living being, in order to prevent the development of a certain disease, to inhibit, and to alleviate the symptoms, or to initiate a healing process of the respective disease.

The at least one lectin according to the invention can be applied in the prophylaxis and/or treatment of a SARS-CoV-2 infection by any medically acceptable administration route to a patient in need thereof. Such medically acceptable administration routes can be e.g. by inhalation, by intubation, orally, parenterally, intraperitoneally, intravenously, intraarterially, intramuscularly, topically, transdermally, subcutaneously, intradermally, sublingually, conjunctivally, intravaginally, rectally or nasally.

In another aspect of the invention a pharmaceutical composition is disclosed that comprises at least one pharmaceutically acceptable lectin derived from plants, fungi or bacteria according to the invention and at least one pharmaceutically acceptable excipient for use in the prophylaxis or treatment of a SARS-CoV-2 infection.

The term “pharmaceutically acceptable excipient(s)” refers to natural or synthetic compounds that are added to a pharmaceutical formulation alongside the pharmaceutical active agent. They may help to bulk up the formulation, to enhance the desired pharmacokinetic properties or the stability of the formulation, as well as being beneficial in the manufacturing process. Advantageous classes of excipients according to the invention include, carriers, binding agents, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickening agents, pH-regulators, acidity regulators acidifiers, solvents, isotonizing agents, penetration enhancers, disintegrants, glidants, lubricants, emulsifiers, solubilizing agents, stabilizers, diluents, anti-caking agents (antiadherents), sorbents, foaming agents, anti-foaming agents, opacifiers, fatliquors, consistency enhancers, hydrotropes, aromatic and flavoring substances.

In general, one or more pharmaceutically acceptable carriers are added to a pharmaceutically active agent. Eligible are all carriers known in the art and combinations thereof. In solid dosage forms they can be for example plant and animal fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum, zinc oxide. For liquid dosage forms and emulsions suitable carriers are for example solvents, solubilizing agents, emulsifiers such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyl glycol, cotton seed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethylglycols, fatty acid esters of sorbitan. Suspensions according to the invention may use carriers known in the art such as diluents (e.g. water, ethanol or propylene glycol), ethoxylated isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonites, agar agar, tragacanth.

The term binding agents refers to substances that bind powders or glue them together, rendering them cohesive through granule formation. They serve as a “glue” of the formulation. Binding agents increase the cohesive strength of the provided diluent or filler.

Suitable binding agents are for example starch from wheat, corn, rice or potato, gelatin, naturally occurring sugars such as glucose, sucrose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or ammonium calcium alginate, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, magnesium aluminum silicate, waxes and others. The percentage of the binding agent in the composition can range from 1 - 30 % by weight, preferred 2 - 20 % by weight, more preferred 3 - 10 % by weight and most preferred 3 - 6 % by weight. Colorants are excipients that bestow a colorization to the pharmaceutical formulation. These excipients can be food colorants. They can be adsorbed on a suitable adsorption means such as clay or aluminum oxide. A further advantage of a colorant is that it may visualize spilled aqueous solution on the nebulizer and/or the mouthpiece to facilitate cleaning. The amount of the colorant may vary between 0.01 and 10 % per weight of the pharmaceutical composition, preferred between 0.05 and 6 % per weight, more preferred between 0.1 and 4 % per weight, most preferred between 0.1 and 1 % per weight.

Suitable pharmaceutical colorants are for example curcumin, riboflavin, riboflavin-5’- phosphate, tartrazine, alkannin, quinolione yellow WS, Fast Yellow AB, riboflavin-5’-sodium phosphate, yellow 2G, Sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, Ponceau 4R, Ponceau SX, Ponceau 6R, erythrosine, red 2G, Allura red AC, Indathrene blue RS, Patent blue V, indigo carmine, Brilliant blue FCF, chlorophylls and chlorophyllins, copper complexes of chlorophylls and chlorophyllins, Green S, Fast Green FCF, Plain caramel, Caustic sulphite caramel, ammonia caramel, sulphite ammonia caramel, Black PN, Carbon black, vegetable carbon, Brown FK, Brown HT, alpha-carotene, beta-carotene, gamma-carotene, annatto, bixin, norbixin, paprika oleoresin, capsanthin, capsorubin, lycopene, beta-apo-8’-carotenal, ethyl ester of beta-apo-8’-carotenic acid, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanins, saffron, calcium carbonate, titanium dioxide, iron oxides, iron hydroxides, aluminum, silver, gold, pigment rubine, tannin, orcein, ferrous gluconate, ferrous lactate.

Moreover, buffer solutions are preferred for liquid formulations, in particular for pharmaceutical liquid formulations. The terms buffer, buffer system and buffer solution, in particular of an aqueous solution, refer to the capacity of the system to resist a pH change by the addition of an acid or a base, or by dilution with a solvent. Preferred buffer systems may be selected from the group comprising formate, lactate, benzoic acid, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(N-morpholino) ethanesulfonic acid), maleic acid, cacodylate (dimethyl arsenate), carbonic acid, ADA (N-(2-acetamido)imino diacetic acid, PIPES (4- piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1,3- bis[tris(hydroxymethyl)methylaminol] propane), ethylene diamine, ACES (2-[(amino-2- oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morphino) propanesulfonic acid), diethyl malonic acid, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid), as well as other buffers with a pK _a between 3.8 and 7.7. Preferred are carbonic acid buffers such as acetate buffer and dicarboxylic acid buffers such as fumarate, tartrate and phthalate as well as tricarboxylic acid buffers such as citrate.

A further group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide and phosphate buffers. Another group of preferred buffers are nitrogen-containing puffers such as imidazole, diethylene diamine and piperazine. Furthermore preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1 ,1-bis-(hydroxymethyl)ethyl)amino]-1- propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1 -propanesulfonic acid (EEPS), MOPS and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycyl-glycine, glycyl-glycyl-glycine, N,N-bis-(2- hydroxyethyl)g lycine and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine). Preferred are also amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxy proline, N,N,N- trimethyllysine, 3-methyl histidine, 5-hydroxy-lysine, o-phosphoserine, gammacarboxyglutamate, [epsilon]-N-acetyl lysine, [omega]-N-methyl arginine, citrulline, ornithine and their derivatives.

Preservatives for liquid and/or solid dosage forms can be used on demand. They may be selected from the group comprising, but not limited to, sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methyl paraben, ethyl paraben, methyl ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl p-hydroxybenzoate, sodium methyl para-hydroxy benzoate, sodium ethyl parahydroxybenzoate, sodium propyl para-hydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohols, cresols, cetylpyridinium chloride, chlorbutanol, thiomersal (sodium 2-(ethylmercurithio) benzoic acid), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium hydrogen sulfite, potassium hydrogen sulfite, biphenyl, orthophenyl phenol, sodium orthophenyl phenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper- (ll)-sulfate, chlorine, chlorine dioxide and other suitable substances or compositions known to the person skilled in the art. The addition of a sufficient amount of antioxidants is particularly preferable for liquid and topical dosage forms. Suitable examples for antioxidants include sodium metabisulfite, alphatocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisol, butylated hydroxytoluene, fumaric acid or propyl gallate. Preferred is the use of sodium metabisulfite, alpha-tocopherol and ascorbyl palmitate.

Tablets or pills are usually coated, i.e. the coating constitutes the outer layer. This can be a film coating, a sugar coating with saccharides and a compression coating. Pharmaceutically acceptable varnishes or waxes, HPMC (hydroxypropylmethylcellulose), MC (methylcellulose) or HPC (hydroxypropylcellulose) can be used. Such a coating may help to disguise the taste, to ease the swallowing or the identification. Often plasticizers and pigments are included in the coating. Capsules normally have a gelatinous envelope that encloses the active substance. The specific composition and thickness of this gelatinous layer determines how fast absorption takes place after ingestion of the capsule. Of special interest are sustained release formulations, as known in the art.

Suitable sweeteners can be selected from the group comprising mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidine dihydrochalcone, steviol glycosides, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, erythritol.

Suitable thickening agents can be selected from the group comprising, but not limited to, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, dextrins, polydextrose, modified starch, alkaline modified starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, distarch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphate distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerin, hydroxypropyl starch, hydroxy propyl distarch glycerin, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, starch sodium octenyl succinate, acetylated oxidized starch, hydroxyethyl cellulose.

Suitable pH-regulators for liquid dosage forms are e.g. sodium hydroxide, hydrochloric acid, buffer substances such as sodium dihydrogen phosphate or disodium hydrogenphosphate.

Suitable acidity regulators can be selected from the group comprising acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, carbon dioxide, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, ammonium lactate, magnesium lactate, citric acid, mono-, di-, trisodium citrate, mono-, di-, tripotassium citrate, mono-, di-, tricalcium citrate, tartaric acid, mono-, disodium tartrate, mono-, dipotassium tartrate, sodium potassium tartrate, ortho-phosphoric acid, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate, adipic acid, sodium adipate, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1 ,4-heptonolactone, triammonium citrate, ammonium ferric citrate, calcium glycerophosphate, isopropyl citrate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, magnesium carbonate, magnesium bicarbonate, ferrous carbonate, ammonium sulfate, aluminum potassium sulfate, aluminum ammonium sulfate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium hydroxide, gluconic acid.

Acidifiers use to be inorganic chemicals that either produce or become acid. Suitable examples are: Ammonium chloride, calcium chloride.

Suitable solvents may be selected from the group comprising, but not limited to, water, carbonated water, water for injection, water with isotonizing agents, saline, isotonic saline, alcohols, particularly ethyl and n-butyl alcohol, and mixtures thereof.

Suitable isotonizing agents are for example pharmaceutically acceptable salts, in particular sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrate, phosphate, borate and mixtures thereof.

Penetration enhancers (permeation or permeability enhancers) are substances that temporarily diminish the barrier of the skin and promote or accelerate the absorption of cosmetic agents. Suitable penetration enhancers can be selected from the group comprising, but not limited to, dimethyl isosorbide (Arlasolve®), dimethyl sulfoxide (DMSO) and its analogues, dimethyl formamide (DMF), azone (1-dodecylazacycloheptan-2-one), pyrrolidones such as 2-pyrrolidone, fatty acids such as oleic acid, lauric acid, myristic acid and capric acid, nonic surfactants such as polyoxyethylene-2-oleyl ether and polyoxyethylene-2-stearyl ether, terpenes, terpenoids and sesquiterpenes such as those from essential oils of eucalyptus, chenopodium and ylang-ylang, oxazolidinones such as 4- decyloxazolidin-2-one, turpentine oil, pine oil, menthol.

Suitable disintegrants can be selected from the group comprising starch, cold water-soluble starches such as carboxymethyl starch, cellulose derivatives such as methyl cellulose and sodium carboxymethyl cellulose, microcrystalline cellulose and cross-linked microcrystalline celluloses such as croscarmellose sodium, natural and synthetic gums such as guar, agar, karaya (Indian tragacanth), locust bean gum, tragacanth, clays such as bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, foaming compositions a.o. Moisture expansion is supported by for example starch, cellulose derivatives, alginates, polysaccharides, dextrans, cross-linked polyvinyl pyrrolidone. The amount of the disintegrant in the composition may vary between 1 and 40% per weight, preferred between 3 and 20% per weight, most preferred between 5 and 10% per weight.

Glidants are materials that prevent a baking of the respective supplements and improve the flow characteristics of granulations so that the flow is smooth and constant. Suitable glidants comprise silicon dioxide, magnesium stearate, sodium stearate, starch and talcum. The amount of the glidant in the composition may vary between 0.01 and 10% per weight, preferred between 0.1 and 7% per weight, more preferred between 0.2 and 5% per weight, most preferred between 0.5 and 2% per weight.

The term “lubricants” refers to substances that are added to the dosage form in order to facilitate tablets, granulates etc. to be released from the press mold or the outlet nozzle. They diminish friction or abrasion. Lubricants are usually added shortly before pressing, as they should be present on the surface of the granules and between them and the parts of the press mold. The amount of the lubricant in the composition may vary between 0.05 and 15% per weight, preferred between 0.2 and 5% per weight, more preferred between 0.3 and 3% per weight, most preferred between 0.3 and 1.5% per weight. Suitable lubricants are a.o. sodium oleate, metal stearates such as sodium stearate, calcium stearate, potassium stearate and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, waxes having a high melting point, polyethylene glycol.

Emulsifiers can be selected for example from the following anionic and non-ionic emulsifiers: Anionic emulsifier waxes, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 to 60 mol ethylene oxide to castor oil and/or hardened castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethene sorbitan monolaurate, polyoxyethene sorbitan monooleate, polyoxyethene sorbitan monopalmitate, polyoxyethene sorbitan monostearate, polyoxyethene sorbitan tristearate, polyoxyethene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1, 2-diol alginate, carrageenan, processed eucheuma seaweed, locust bean gum, tragacanth, acacia gum, karaya gum, gellan gum, gum ghatti, glucomannane, pectin, amidated pectin, ammonium phosphatides, brominated vegetable oil, sucrose acetate isobutyrate, glycerol esters of wood rosins, disodium phosphate, trisodium diphosphate, tetrasodium diphosphate, dicalcium diphosphate, calcium dihydrogen diphosphate, sodium triphosphate, pentapotassium triphosphate, sodium polyphosphates, sodium calcium polyphosphate, calcium polyphosphates, ammonium polyphosphate, beta-cyclodextrin, powdered cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl hydroxyethyl cellulose, croscarmellose, enzymically hydrolyzed carboxymethyl cellulose, mono- and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, acetic acid esters of mono- and diglycerides of fatty acids, lactic acid esters of mono- and diglycerides of fatty acids, citric acid esters of mono- and diglycerides of fatty acids, tartaric acid esters of mono- and diglycerides of fatty acids, mono- and diacetyl tartaric acid esters of mono- and diglycerides of fatty acids, mixed acetic and tartaric acid esters of mono- and diglycerides of fatty acids, succinylated monoglycerides, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propane-1, 2-diol esters of fatty acids, propylene glycol esters of fatty acids, lactylated fatty acid esters of glycerol and propane-1 , thermally oxidized soy bean oil interacted with mono- and diglycerides of fatty acids, dioctyl sodium sulphosuccinate, sodium stearoyl-2-lactylate, calcium stearoyl-2- lactylate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, sodium laurylsulfate, ethoxylated mono- and diglycerides, methyl glucoside-coconut oil ester, sorbitan monostearate, sorbitan tristrearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, calcium sodium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salts, distarch glycerol, starch sodium octenyl succinate, acetylated oxidized starch. Preferred are glycerin monooleate, stearic acid, phospholipids such as lecithin.

Suitable as surface-active solubilizing agents (solubilizers) are for example diethylene glycol monoethyl ester, polyethyl propylene glycol co-polymers, cyclodextrins such as a- and P- cyclodextrin, glyceryl monostearates such as Solutol HS 15 (Macrogol-15-hydroxystearate from BASF, PEG 660-15 hydroxystearates), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitanic acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleates.

Stabilizers are substances that can be added to prevent unwanted changes. Though stabilizers are not real emulsifiers they may also contribute to the stability of emulsions. Suitable examples for stabilizers are oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethene stearate, aspartame-acesulfame salt, amylase, proteases, papain, bromelain, ficin, invertase, polydextrose, polyvinyl pyrrolidone, polyvinyl polypyrrolidone, triethyl citrate, maltitol, maltitol syrup. Diluents or fillers are inactive substances added to drugs in order to handle minimal amounts of active agents. Examples for suitable diluents are water, mannitol, pre-gelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, xanthum gum, gum arabic or any combination thereof.

Anti-caking agents (antiadherents) can be added to a supplement or a composition of supplements in order to prevent the formation of lumps and for easing packaging, transport, release from the at least one chamber of the dispensing cap and consumption. Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethyl siloxane.

Sorbents are materials that soak up oil from the water. Suitable examples include natural sorbents such as peat moss, sawdust, feathers, and anything else natural that contains carbon and synthetic sorbents such as polyethylene and nylon. Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by adsorption or by adsorption) in a dry state.

In some galenic formulations it may be desirable that a liquid oral dosage form generates some foam on being dissolved. Such an effect can be supported through the addition of a foaming agent that reduces the surface tension of the liquid, thus facilitating the formation of bubbles, or it increases its colloidal stability by inhibiting coalescence of bubbles.

Alternatively, it may stabilize foam. Suitable examples include mineral oil, quillaia extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, ammonium lauryl sulfate.

Alternatively, some liquid oral dosage forms may appear slightly foamy upon preparation. Though this does not interfere with the desired application it may affect patient compliance in case of a medication or the commercial success in case of dietary supplements. Therefore, it may be desirable to add a pharmaceutically acceptable anti-foaming agent (defoamer). Examples are polydimethylsiloxane or silicone oil in dietary supplements or simethicone in pharmaceuticals.

Opacifiers are substances that render the liquid dosage for, opaque, if desired. They must have a refractive index substantially different from the solvent, in most cases here water. At the same time, they should be inert to the other components of the composition. Suitable examples include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.

Suitable fatliquors are e.g. oleic acid decyl ester, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium laurylsulfate.

Consistency enhancers are e.g. cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline waxes, non-ionic emulsifier waxes, beeswax, paraffin or stearyl alcohol.

Suitable hydrotropes are alcohols such as ethanol, isopropyl alcohol or polyols such as glycerin.

Suitable aromatic and flavoring substances comprise above all essential oils that can be used for this purpose. In general, this term refers to volatile extracts from plants or parts of plants with the respective characteristic smell. They can be extracted from plants or parts of plants by steam distillation.

Suitable examples are: Essential oils, respectively aromatic substances from achillea, sage, cedar, clove, chamomile, anise, aniseed, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineol, borneol, zingerol, eucalyptus, mango, figs, lavender oil, chamomile blossoms, pine needle, cypress, orange, rose, rosewood, plum, currant, cherry, birch leaves, cinnamon, lime, grapefruit, tangerine, juniper, valerian, lemon, lemon balm, lemon grass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leave extract, blueberry, kaki, melon, alpha- or beta-pinene, alpha-pinene oxide, alpha- campholenic aldehyde, alpha-citronellol, alpha-isoamyl-cinnamic, alpha-cinnamic terpinene, alpha-terpineol, alpha-terpinene, aldehyde C16, alpha-phellandrene, amyl cinnamic aldehyde, amyl salicylate, anisic aldehyde, basil, anethole, bay, benzyl acetate, benzyl alcohol, bergamont, bitter orange peel, black pepper, calamus, camphor, cananga oil, cardamom, carnation, carvacrol, carveol, cassia, castor, cedarwood, cinnamaldehyde, cinnamic alcohol, cis-pinane, citral, citronella, citronellal, citronellol dextro, citronellol, citronellyl acetate; citronellyl nitrile, citrus unshiu, clary sage, clove bud, coriander, corn, cotton seed, d- dihydrocarvone, decyl aldehyde, diethyl phthalate, dihydroanethole, dihydrocarveol, dihydrolinalool, dihydromyrcene, dihydromyrcenol, dihydromyrcenyl acetate; dihydroterpineol, dimethyl salicylate, dimethyloctanal, dimethyloctanol, dimethyloctanyl acetate, diphenyl oxide, dipropylene glycol, d-limonen, d-pulegone, estragole, ethyl vanillin, eucalyptol; eucalyptus citriodora, eucalyptus globulus, eugenol, evening primrose, fenchol, fennel, ferniol, fish, florazon, galaxolide, geraniol, geranium, geranyl acetate, geranyl nitrile, guaiacol, guaiacwood, gurjun balsam, heliotropin, herbanate, hiba, hydroxycitronellal, i- carvone, i-methyl acetate, ionone, isobutyl quinoleine, isobornyl acetate, isobornyl methylether, isoeugenol, isolongifolene, jasmine, lavender, limonen, linallol oxide, linallol, linalool, linalyl acetate, linseed, litsea cubeba, l-methyl acetate, longifolene, mandarin, mentha, menthane hydroperoxide, menthol crystals, menthol laevo, menthone laevo, methyl anthranilate, methyl cedryl ketone, methyl chavicol, methyl hexyl ether, methyl ionone, methyl salicylate, mineral, mint, musk ambrette, musk ketone, musk xylol, myrcene, nerol, neryl acetate, nonyl aldehyde, nutmeg, orris root, para-cymene, parahydroxy phenyl butanone crystals, patchouli, p-cymene, pennyroyal oil, pepper, perillaldehyde, petitgrain, phenyl ethyl alcohol, phenyl ethyl propionate, phenyl ethyl-2methylbutyrate, pimento berry, pimento leaf, pinane hydroperoxide, pinanol, pine ester, pine, pinene, piperonal, piperonyl acetate, piperonyl alcohol, plinol, plinyl acetate, pseudo ionone, rhodinol, rhodinyl acetate, rosalin, ryu, sandalwood, sandenol, sassafras, sesame, soybean, spearmint, spice, spike lavender, spirantol, starflower, tea seed, terpenoid, terpineol, terpinolene, terpinyl acetate, tert-butylcyclohexyl acetate, tetrahydrolinalool, tetrahydrolinalyl acetate, tetrahydromyrcenol, thulasi, thymol, tomato, trans-2-hexenol, trans-anethole, turmeric, turpentine, vanillin, vetiver, vitalizair, white cedar, white grapefruit, Wintergreen etc. or mixtures thereof, as well as mixtures of menthol, peppermint and star anise oil or menthol and cherry flavor.

These aromatic or flavoring substances can be included in the range of 0.0001 to 10 % per weight (particularly in a composition), preferred 0.001 to 6% per weight, more preferred 0.001 to 4% per weight, most preferred 0.01 to 1% per weight, with regard to the total composition. Application- or single case-related it may be advantageous to use differing quantities.

According to the invention all of the aforementioned excipients and classes of excipients can be used without limitation alone or in any conceivable combination thereof, as long as the inventive use is not thwarted, toxic actions may occur, or respective national legislations are infracted.

The at least one lectin according to the invention or one of its pharmaceutically acceptable salts and the further active ingredient can be used simultaneously, separately or sequentially in order to treat or prevent disease symptoms. The two active agents may be provided in a single dosage form or as separate formulation, each formulation containing at least one of the two active agents. One or both of the two active agents may be formulated as a bolus.

Pharmaceutical formulations suitable for oral dosage forms of the at least one lectin according to the invention, a composition according to the invention or a combination according to the invention may be administered as separate units such as capsules, tablets, sugar-coated tablets or pills; powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water or water-in-oil in emulsions. In oral dosage forms such as a tablets or capsules the active agent can thus be combined with a non-toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerol or water. Powders are produced by grinding the compound to a suitably tiny particle size and mixing them with a pharmaceutical carrier in a similar manner, e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant or colorant can also be present.

Tablets are formulated by producing, granulating or dry-pressing a powder mixture, adding a lubricant and a disintegrants and pressing the mixture to a tablet. A powder mixture is produced by mixing a suitably ground compound with a diluent or a base as described before, and if applicable, with a binding agent such as carboxymethyl cellulose, an alginate, gelatin or polyvinyl pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbent, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acacia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting mold. The lubricated mixture is then pressed to give tablets. The compounds according to the invention can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or drypressing steps.

In another aspect of the invention a lectin according to the invention, a composition according to the invention or a combination according to the invention is provided in hard gelatin capsules. They are fabricated by producing a powder mixture as described before and filling it into shaped gelatin covers. Glidants and lubricants such as highly dispersed silica, talcum, magnesium stearate, calcium stearate or polyethylene glycol can be added to the powder mixture as solids. A disintegrant or solubilizer such as agar agar, calcium carbonate or sodium carbonate can be added likewise in order to improve the availability of the medication after intake of the capsule. Additionally, suitable binding agents and/or colorants can be added to the mixture, if desirable or necessary.

In another aspect of the invention a lectin according to the invention, a composition according to the invention or a combination according to the invention is included in soft gelatin capsules (SGC). SGCs are dissolved on their passage through the gastrointestinal tract. They consist mainly of gelatin enriched with variable amounts of plasticizers such as glycerol or sorbitan. The release rate depends on the specific formulation of the SGC carrier material. They are also suitable for a sustained release of the active agent. SGCs are particularly useful for the administration of poorly water-soluble active agents.

Thus, in another aspect of the invention the present application relates to at least one lectin according to the invention for use in the prophylaxis or treatment of a SARS-CoV-2 infection in a formulation for oral administration.

In yet another aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria according to the invention for use in the prophylaxis or treatment of a SARS-CoV-2 infection in a formulation for inhalatory administration.

For an effective prophylactic or therapeutic treatment of a SARS-CoV-2 infection that may cause pneumonia, pulmonary edema and/or acute lung injury with at least one lectin according to the invention it is advantageous to reach the patient’s alveoli. Therefore, the particle size must be sufficiently small to reach the lowest parts of the airways of the pulmonary tissue. The best inhalatory device class for inhalatory application of a pharmaceutically active agent are the so-called mesh nebulizers described before. In the scope of the present application practically all mesh nebulizers known in the art can be used, from rather simple single-use mesh nebulizers for cough and cold or for fancy purposes to sophisticated high-end mesh nebulizers for clinical or domestic treatment of serious diseases or conditions of the lower airways.

Suitable commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers and (pressurized) metered-dose inhalers comprise, without being limiting, PARI eFlow®rapid, PARI LC STAR®, PARI Velox and PARI Velox Junior (PARI GmbH, Starnberg, Germany), Philips Respironics l-neb and Philips InnoSpire Go (Koninklijke Philips N.V., Eindhoven, Netherlands), VENTA-NEB®-ir, OPTI-NEB®, M-neb® dose ⁺ mesh nebulizer inhalation MN-300/8, M-Neb Flow+ and M-neb® mesh nebulizer MN-300/X (NEBU-TEC, Elsenfeld, Germany), Hcmed Deepro HCM-86C and HCM860 (HCmed Innovations Co., Ltd, Taipei, Taiwan), OMRON MicroAir U22 and U100 (OMRON, Kyoto, Japan), Aerogen® Solo, Aerogen® Ultra and Aerogen® PRO (Aerogen, Galway, Ireland), KTMED NePlus NE-SM1 (KTMED Inc., Seoul, South Korea), Vectura Bayer Breelib™ (Bayer AG, Leverkusen, Germany), Vectura Fox, MPV Truma and MicroDrop® Smarty (MPV MEDICAL GmbH, Kirchheim, Germany), MOBI MESH (APEX Medical, New Taipei City, Taiwan), B.Well WN- 114, TH-134 and TH-135 (B.Well Swiss AG, Widnau, Switzerland), Babybelle Asia BBU01 (Babybelle Asia Ltd., Hongkong), CA-MI Kiwi and others (CA-MI sri, Langhirano, Italy), Diagnosis PRO MESH (Diagnosis S.A., Bialystok, Poland), DIGI O2 (DigiO2 International Co., Ltd., New Taipei City, Taiwan), feellife AIR PLUS, AEROCENTRE+, AIR 360+, AIR GARDEN, AIRICU, AIR MASK, AIRGEL BOY, AIR ANGEL, AIRGEL GIRL and AIR PRO 4 (Feellife Health Inc., Shenzhen, China), Hannox MA-02 (Hannox International Corp., Taipei, Taiwan), Health and Life HL100 and HL100A (HEALTH & LIFE Co., Ltd., New Taipei City, Taiwan), Honsun NB-810B (Honsun Co., Ltd., Nantong, China), K-jump® KN-9100 (K-jump Health Co., Ltd., New Taipei City, Taiwan), microlife NEB-800 (Microlife AG, Widnau, Switzerland), OK Biotech Docspray (OK Biotech Co., Ltd., Hsinchu City, Taiwan), Prodigy Mini-Mist® (Prodigy Diabetes Care, LLC, Charlotte, USA), Quatek NM211 , NE203, NE320 and NE403 (Big Eagle Holding Ltd., Taipei, Taiwan), Simzo NBM-1 and NBM-2 (Simzo Electronic Technology Ltd., Dongguan, China), Mexus® BBU01 and BBU02 (Tai Yu International Manufactory Ltd., Dongguan, China), TaiDoc TD-7001 (TaiDoc Technology Co., New Taipei City, Taiwan), Vibralung® and HIFLO Miniheart Circulaire II (Westmed Medical Group, Purchase, USA), KEJIAN (Xuzhou Kejian Hi-Tech Co., Ltd., Xuzhou, China), YM- 252, P&S-T45 and P&S-360 (TEKCELEO, Valbonne, France), Maxwell YS-31 (Maxwell India, Jaipur, India), Kernmed® JLN-MB001 (Kernmed, Durmersheim, Germany).

Preferred are mesh nebulizers with a piezoelectric activation of the nebulization process, respectively vibrating mesh nebulizers.

Thus, in another aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria according to the invention for use in a formulation in the prophylaxis or treatment of a SARS-CoV-2 infection for inhalatory administration, wherein the inhalatory administration is carried out by means of a vibrating mesh nebulizer.

Mesh nebulizers can be classified into two groups according to patient interaction: Continuous mode devices and trigger-activated devices. In continuous mode mesh nebulizers the nebulized aerosol is continuously released into the mouth piece and the patient has to inhale the provided aerosol. In trigger-activated devices a defined amount of aerosol is released only upon an active and deep inspiratory breath. This way a far larger amount of active agent-containing aerosol is inhaled and reaches the lowest airways than with continuous mode devices. The latter lose a large amount of active agent-containing aerosol either to the surrounding or on the passage of the upper airways, as the aerosol release is not coupled to the respiratory cycle.

Therefore, trigger-activated mesh nebulizers are preferred, in particular vibrating mesh nebulizers.

Particularly preferred are trigger-activated mesh nebulizers with a piezoelectric activation of the nebulization process. Preferred are the mesh nebulizer models PARI eFlow®rapid, Philips Respironics l-neb, Philips InnoSpire Go, M-neb® dose ⁺ mesh nebulizer inhalation MN-300/8, Homed Deepro HCM-86C and HCM860, OMRON MicroAir U100, Aerogen® Solo, KTMED NePlus NE-SM1, Vectura Bayer Breelib™.

The most preferred vibrating mesh nebulizer models are high-end models such as PARI eFlow®rapid, PARI Velox, Philips Respironics l-neb, M-neb® dose ⁺ mesh nebulizer inhalation MN-300/8, Vectura Bayer Breelib™.

The mean droplet size is usually characterized as MMAD (median mass aerodynamic diameter). The individual droplet size is referred to as MAD (mass aerodynamic diameter). This value indicates the diameter of the nebulized particles (droplets) at which 50% are smaller or larger, respectively. Particles with a MMAD > 10 pm normally don’t reach the lower airways, they often get stuck in the throat. Particles with a MMAD > 5 pm and < 10 pm usually reach the bronchi but not the alveoli. Particles between 100 nm and 1 pm MMAD don’t deposit in the alveoli and are exhaled immediately. Therefore, the optimal range is between 1 pm and 5 pm MMAD. Recent publications even favor a narrower range between 3.0 pm and 4.0 pm (cf. Amirav et al. (2010) J Allergy Clin Immunol 25: 1206-1211 ; Haidl et al. (2012) Pneumologie 66: 356-360).

A further commonly accepted quality parameter is the percentage of the particles in the generated aerosol with a diameter in the range of 1 pm to 5 pm (FPM; fine particle mass). FPM is a measure for the particle distribution. It is calculated by subtracting the percentage of the particles in the generated aerosol with a diameter in the range < 1 pm from the overall percentage of the particles in the generated aerosol with a diameter in the range < 5 pm (FPF; fine particle fraction).

In another aspect of the invention the present application refers also to a method for producing an aerosol according to the invention, comprising the following steps: a) filling 0.1 ml to 5 ml of an aqueous solution containing the at least one lectin according to the invention and optionally at least one pharmaceutically acceptable excipient into the nebulization chamber of a mesh nebulizer, b) starting vibration of the mesh of the mesh nebulizer at a frequency of 80 kHz to 200 kHz, and c) discharging the generated aerosol at the side of the mesh of the mesh nebulizer opposite to the nebulization chamber.

The vibration frequency of vibrating mesh nebulizers is normally in the range of 80 kHz to

200 kHz, preferred 90 kHz to 180 kHz, more preferred 100 kHz to 160 kHz, most preferred 105 kHz to 130 kHz (cf. Chen, The Aerosol Society. DDL2019; Gardenshire et al. (2017) A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th ed.).

Thus, the aforementioned method is also disclosed with said vibration frequency ranges.

The method according to the invention is thus characterized in that at least 80 % in weight, preferred at least 85 % in weight, most preferred at least 90 % in weight of the at least one lectin according to the invention contained in said aqueous solution are nebulized in the generated aerosol.

The method of the invention is particularly effective in nebulizing a high percentage of the pharmaceutically active agent(s) from the provided aqueous solution during a short time.

This is an important feature for patient compliance. A considerable percentage of the patient population finds the inhalatory process to be uncomfortable, weary and physically demanding. On the other hand, the patient’s active cooperation is essential for an effective and targeted inhalatory application. Therefore, it is desirable that a therapeutically sufficient amount is applied during a period of time as short as possible. During a three minutes time span 95 % of the substance provided in the aqueous solution can be nebulized. This is an ideal time span for a high patient compliance.

Therefore, the method according to the invention is thus characterized in that at least 80 % of the generated aerosol are produced during three minutes after starting nebulization in the mesh nebulizer, preferred at least 85 % and most preferred at least 90 %.

While the pharmaceutically active agent is usually provided in a single dosage container for every nebulization procedure the nebulizer and/or the mouthpiece can be used over a certain period of time and have to be replaced at certain intervals. A cleaning of the nebulizer and the mouthpiece is recommended by default after each nebulization. But herein patient compliance cannot be reasonably taken for granted. But even after a meticulous cleaning there are always some deposits of the aerosol in the nebulization chamber, the outlet and/or the mouthpiece. As the aerosol is produced from an aqueous solution these depositions bear the risk of producing a bioburden of bacteria that might contaminate the inhaled aerosol. Deposits may also plug holes in the mesh membrane of the mesh nebulizer. In general, the nebulizer and/or the mouthpiece should be exchanged every one or two weeks. Therefore, it is convenient to offer the medication and the nebulizer as a combined product.

Thus, in another aspect of the invention the present application refers also to a kit comprising a mesh nebulizer and a pharmaceutically acceptable container with an aqueous solution containing the at least one lectin according to the invention and optionally at least one pharmaceutically acceptable excipient. In an alternative kit the at least one lectin according to the invention is not provided in form of an aqueous solution but in two separated containers, one for a solid form for the active agent and the other for an aqueous solution. The final aqueous solution is freshly prepared by solving the active agent in the final solution. Thereupon the final aqueous solution is filled into the nebulization chamber of the mesh nebulizer. These two containers can be completely separated containers, e.g. two vials, or e.g. a dual-chamber vial. For solving the active agent e.g. a membrane between the two chambers is perforated to allow for mixing of the content of both chambers.

Thus, the present application discloses also a kit, comprising a mesh nebulizer, a first pharmaceutically acceptable container with water for injection or physiological saline solution and a second pharmaceutically acceptable container with a solid form of the at least one lectin according to the invention, wherein optionally at least one pharmaceutically acceptable excipient is contained in the first pharmaceutically acceptable container and/or the second pharmaceutically acceptable container.

The aerosol generated by the method according to the invention is administered, respectively self-administered by means of a mouthpiece. Optionally, such a mouthpiece can be additionally included in the beforementioned kits.

A common way to transfer the provided aqueous solution or final aqueous solution into the nebulization chamber of the mesh nebulizer by means of a syringe equipped with an injection needle. First, the aqueous solution is drawn up into the syringe and then injected into the nebulization chamber. Optionally, such a syringe and/or injection needle can be additionally included in the beforementioned kits. Without being limiting, typical syringes made of polyethylene, polypropylene or cyclic olefin co-polymers can be used, and a typical gauge for a stainless steel injection needle would be in the range of 14 to 27.

In yet another aspect of the invention the present application discloses a lectin according to the invention, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of acute lung injury, wherein said substance, composition or combination is provided as an additive to the ventilation air of a cardiopulmonary bypass device, a form of assisted ventilation. When the patient’s condition in intensive care unit worsens they often need to be ventilated in such a device for an indefinite period of time until their own respiration would allow for a sufficient oxygen supply. Good results have been achieved when with an aerosol in a metered-dose inhaler combined with an inhalation chamber at the Y-piece. This can increase the applied dosage of bronchodilators by the factor 1.5 to 4 (Fuller et al. (1994) Chest 105: 214-218). 38% of the pharmaceutically active agent could be delivered (Marik et al. (1999) Chest 115: 1653-1657). Alternatively, a constant output mesh nebulizer yielded rates of 10 - 15%, as assessed in a scintigraphic study (Dugernier et al. (2016) Ann Intensive Care 6: 73). Vibrating mesh nebulizers delivered better results than ultrasonic or jet nebulizers for administration of antibiotics. When a constant output vibrating-mesh nebulizer is placed on the inspiratory limb at 10 cm of the Y-piece and specific ventilation parameters (tidal volume of 8 ml/kg, respiratory rate of 12 c/min, duty cycle of 50%, constant and low inspiratory flow rate inferior to 30 l/min and end inspiratory pause of 20%) are set, 63% of the administered drug (ceftazidime, amikacin) reach the inlet of the endotracheal tube, versus 37% extrapulmonary deposition (Lu et al. (2011 ) Am J Respir Crit Care Med 184: 106-115). Mostly, the administered drug is evenly distributed between both lungs. In pigs, the use of helium (He/02) instead of nitrogen (N2/O2) in inhaled gas was found to increase ceftazidime concentrations in subpleural lung specimens (Tonnelier et al. (2005) Anesthesiology 102: 995-1000).

In these cases a lectin according to the invention can be added to the intubated ventilation air in solid form (dry powder) or in liquid form (in an aqueous solution or as a nebulized aerosol, as described before).

The present application discloses thus also a lectin according to the invention, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of acute lung injury, wherein said substance, composition or combination is added to the ventilation air of a cardiopulmonary bypass device.

In yet another aspect of the invention the present application relates to a lectin according to the invention for use in the prophylaxis or treatment of a SARS-CoV-2 infection in a formulation for sublingual tablets.

In yet another aspect of the invention the present application relates to a lectin according to the invention for use in the prophylaxis or treatment of a SARS-CoV-2 infection in a formulation as a liquid dosage form.

In general, an aqueous solution or a physiological saline solution is preferred. In case of a poorly soluble pharmaceutical agent according to the invention also ethanol or ethanol/water mixtures can be used.

Suitable liquid dosage forms include drops, eyedrops, eardrops, throat sprays, nasal sprays or injection solutions.

The present application discloses also the parenteral administration of lectin according to the invention in the prophylaxis or treatment of a SARS-CoV-2 infection in the form of intravenous injection, intraarterial injection or intraperitoneal injection. These liquid dosage forms comprise solutions, suspensions and emulsions. Examples are water and water/propylene glycol solutions for parenteral injections, or the addition of a sweetener or opacifier for oral solutions, suspensions and emulsions.

These liquid dosage forms can be stored in vials, IV bags, ampoules, cartridges, and prefilled syringes. Suitable excipients include solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers/reducers, surfactants, chelating agents, and adjuvants.

While SARS-CoV-1 and MERS-CoV infect above all the lower airways SARS-CoV-2 infects first the pharynx/throat area. Only a minor percentage of these patients develops later a pulmonary infection and a pneumonia. While these pharyngeal infections cause usually only mild symptoms as in a cold or no symptoms at all these patients are highly infectious for their environment. In most cases they are unaware that they have become spreaders of the infection. Therefore, there is a medical need to treat SARS-CoV-2 infections already when they are still in the pharyngeal stage, not only for treating such a patient but also for epidemiologic reasons to prevent the spreading of the epidemic. For patients with a pharyngeal infection only a systemic route of administration, e.g. intravenously or perorally, with a highly effective drug or drug combination that may also cause adverse side effects is not ideal. Thus, it is desirable to provide routes of administration that treat the infected pharyngeal tissue locally.

Therefore, in yet another aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria according to the invention for use in the prophylaxis or treatment of a SARS-CoV-2 infection in a formulation for pharyngeal administration.

Administration of a medication to the pharynx can be effected by topical administrations, such as brushing of the throat/pharynx area with a suitable liquid dosage form as drops, a lotion or a tincture, or with a viscous dosage form such as a gel or hydrogel, gurgling with a mouthwash, a sublingual tablet, a lozenge, a throat spray or a posterior pharyngeal wall injection.

A lotion is a low-viscosity topical preparation intended for application to the skin or the mucosa. Lotions are applied to the skin or mucosa with bare hands, a brush, a clean cloth, or cotton wool.

An advantage of a lotion is that it may be spread thinly and may cover a large area of skin or mucosa. Typical drugs that can be administered in form of a lotion include antibiotics, antiseptics, antifungals, corticosteroids, anti-acne agents, soothing, smoothing, moisturizing or protective agents, or anti-allergens. Most lotions are oil-in-water emulsions using a substance such as cetearyl alcohol to keep the emulsion together, but water-in-oil lotions are also formulated. The key components are the aqueous and oily phases, an emulgent to prevent separation of these two phases and the drug substance(s). A wide variety of excipients such as fragrances, glycerol, petroleum jelly, dyes, preservatives, proteins and stabilizing agents are commonly added to lotions.

Thickness, consistency and viscosity of the lotion can be adjusted during manufacturing. Manufacturing lotions can be carried out in two cycles: a) Emollients and lubricants are dispersed in oil with blending and thickening agents, b) Perfume, color and preservatives are dispersed in the water phase. Pharmaceutically active principles are broken up in both cycles depending on the raw materials involved and the desired properties of the lotion.

A tincture is typically an alcoholic extract or formulation. Solvent concentrations of 25-60% (or even 90%) are common. Other solvents for producing tinctures include vinegar, glycerin, diethyl ether and propylene glycol. Ethanol has the advantage of being an excellent solvent for both acidic and alkaline constituents. A tincture using glycerin is called a glycerite. Glycerin is generally a poorer solvent than ethanol. Vinegar, being acidic, is a better solvent for obtaining alkaloids but a poorer solvent for acidic components.

A gel is a colloid in which the solid disperse phase forms a network in combination with that of the fluid continuous phase, resulting in a viscous semirigid sol. Gel properties range from soft and weak to hard and tough. They are defined as a substantially dilute crosslinked system, which exhibits no flow in the steady-state. By weight, gels are mostly liquid, yet they behave like solids due to a three-dimensional cross-linked network within the liquid. It is the crosslinking within the fluid that gives a gel its consistency and contributes to the adhesive stick. Gels are a dispersion of molecules of a liquid within a solid medium.

A hydrogel is a network of polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the dispersion medium. A three-dimensional solid results from the hydrophilic polymer chains being held together by cross-links. Because of the inherent cross-links, the structural integrity of the hydrogel network does not dissolve from the high concentration of water. Hydrogels are highly absorbent (they can contain over 90% water) natural or synthetic polymeric networks. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. In medicine, hydrogels can encapsulate chemical systems which upon stimulation by external factors such as a change of pH may cause specific pharmaceutically active agent(s) to be liberated to the environment, in most cases by a gel-sol transition to the liquid state. Suitable gel formers can be selected from the group comprising, but not limited to, agar, algin, alginic acid, bentonite, carbomer, carrageenan, hectorite, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carbomer.

A mouthwash is a liquid which is held in the mouth passively or swilled around the mouth by contraction of the perioral muscles and/or movement of the head, and may be gargled, where the head is tilted back and the liquid bubbled at the back of the mouth. An aqueous or alcoholic solution of a lectin according to the invention can thus be formulated and administered to the pharynx.

Sublingual drug delivery can be an alternative when compared to oral drug delivery as sublingually administered dosage forms bypass hepatic metabolism. A rapid onset of pharmacological effect is often desired for some drugs, especially those used in the treatment of acute disorders. Sublingual tablets disintegrate rapidly, and the small amount of saliva present is usually sufficient for achieving disintegration of the dosage form coupled with better dissolution and increased bioavailability.

The drug must be lipophilic enough to be able to partition through the lipid bilayer, but not so lipophilic such that once it is in the lipid bilayer, it will not partition out again. According to the diffusive model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Therefore, lower salivary solubility results in lower absorption rates and vice versa. In general, a drug which has been formulated for sublingual should ideally have a molecular weight of less than 500 to facilitate its diffusion. The oral cavity has a narrow pH range which lies between 5.0 to 7.0. The inclusion of a suitable buffer during the formulation of an ionizable drug makes it possible to control the pH of aqueous saliva.

In order to avoid a possibly unpleasant taste or smell of the drug taste masking is needed. Sweeteners, flavors, and other taste-masking agents are essential components. Sugarbased excipients quickly dissolve in saliva and produce endothermic heat of dissolution. They create a pleasant feeling in the mouth and are most suitable for sublingual tablets along with other flavors.

Typical techniques for manufacturing sublingual tablets include direct compression, compression molding, freeze drying and hot melt extrusion (Khan et al. (2017) J Pharmaceut Res 16: 257-267).

When swallowing is avoided, an administration of a pharmaceutically active agent by means of a sublingual tablet can also reach the pharynx/throat topically. Absorption of the pharmaceutically active agent occurs to a good part via the pharyngeal mucosa. A lozenge (troche) is a small, disc-shaped or rhombic body composed of solidifying paste containing an astringent, antiseptic, or demulcent drug, used for local treatment of the mouth or throat, the lozenge being held in the mouth until dissolved. The vehicle or base of the loze nge is usually sugar, made adhesive by admixture with acacia or tragacanth, fruit paste, made from black or red currants, confection of rose, or balsam of tolu.

In particular, the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria according to the invention for use in a formulation in the prophylaxis or treatment of a SARS-CoV-2 infection for pharyngeal administration, wherein the pharyngeal administration is carried out by means of a throat spray.

A throat spray is a medicated liquid administered to the throat as a spray, typically for the treatment of a sore throat or cough.

A throat spray may typically contain a local anesthetic (e.g. lidocaine, benzocaine), an antiseptic (e.g. chlorhexidine, cetylpyridinium chloride), herbal extracts or a combination thereof. Whatever the formulation, it should not contain too much sugar or ethanol, which further irritates the mucosa. And finally, the user should not experience any unpleasant aftertaste.

The standard for throat sprays is currently a metering pump attached to a bottle containing between 10 to 30 ml of a liquid formulation. The formulation is filled into a glass or plastic bottle with the pump fixed by a screw closure, crimped on or simply snapped onto the bottle neck. Irrespective of the fixing option selected, the system should be tight, with no leakage observed during carrying or handling by the user. Usually, the container is made from glass or plastic,

Typically, a throat spray pump will deliver a dose in the range of 50 to 200 pl per actuation. For a targeted administration, the pump will be equipped with an actuator with a prolonged nozzle. The nozzle length may range from 30 to 70 mm. It is easier to target the affected area with such a long-fixed nozzle, but this can be too bulky for users to carry, which is why actuators with foldable or swivel-mounted nozzles are preferred.

Alternatively, devices utilize continuous valves. A continuous valve delivers a targeted treatment but not precise dosing, as the formulation will be aerosolized while the actuator is pressed down. One technical solution is a tin or aluminum can with pressurized head space. When actuating the valve, the elevated internal pressure will force the formulation out of the can as long as the valve stem is pressed down.

A related but more sophisticated system is the bag-on-valve (BOV) system. The product is placed inside a bag while a propellant (in most cases compressed air) is filled in the space between the bag and the outer can. The product is squeezed out of the bag by the compressed air when the continuous valve is actuated. A BOV system will work with any 360° orientation.

Care should be taken, as throat spray formulations may contain ingredients that are very aggressive and can lower the surface tension. A simple test for spray performance will ensure that the formulation can be aerosolized by the system and that the delivered spray pattern and particle size is appropriate for the intended use.

Spray pattern and droplet size distribution are the most important parameters for a throat spray. Spray pattern is a term used to describe the spray angle and the shape of the plume for a fully developed spray. The droplet size is characterized once the spray is fully developed using a laser diffraction method. Fine particles (droplets with less than 10 pm mean dynamic diameter) should be as low as possible to avoid droplet deposition in the lower airways.

Recently, some carragelose-based throat sprays emerged, claiming protection to virus born upper respiratory infections. The first polymer of this platform is Carragelose®, a broadly active anti-viral compound for treating respiratory diseases. The compound prevents the binding of viruses on the mucosal cells, in addition to its moistening effect.

Alternatively, a portable nebulizer with a high output rate and a tuned droplet size for deposition in the upper airways can be used. Breathing through a face mask can deposit droplets on the mucosa of the whole upper airways (cf. Marx and Nadler (2018) Drug Development & Delivery).

In particular, the present application relates a lectin derived from plants, fungi or bacteria according to the invention for use in the prophylaxis or treatment of a SARS-CoV-2 infection in a formulation for pharyngeal administration, wherein the pharyngeal administration is carried out by means of a posterior pharyngeal wall injection.

This technique is used for pharyngoplasty by injection of calcium hydroxylapatite and other methods in plastic surgery. However, also a local injection can be made into the pharyngeal tissue in order to administer a pharmaceutically active agent. The injection solution can be roughly the same as for intravenous or intramuscular injections. Preferred are aqueous solutions, physiological saline solutions or, in case of a rather lipophilic pharmaceutically active agent, an ethanol/water mixture.

In a further aspect of the invention the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria according to the invention for use in the prophylaxis or treatment of a SARS-CoV-2 infection in a formulation for nasal administration.

In particular, the nasal administration is carried out by means of a nasal spray or nose drops.

The common formulation types used for nasal spray products are solutions, suspensions, and emulsions. Nasal spray formulations may be aqueous, hydroalcoholic, or nonaqueousbased. Depending on the type of system, the formulation will include a range of functional excipients, including solvents and cosolvents; mucoadhesive agents; pH buffers; antioxidants; preservatives; osmolality and tonicity agents; penetration enhancers; suspending agents; and surfactants. The choice of formulation type and the excipients selected will be driven by the solubility and stability of the respective lectin, as well as the concentration needed to deliver an efficacious dose in a typical 100 pl spray (cf. Kulkarni and Shaw (2016) in: Essential Chemistry for Formulators of Semisolid and Liquid Dosages, Elsevier). The aforementioned Carragelose® technique is used also for nasal sprays.

Nose drops are administered in a similar formulation but dropwise instead of a push on the dispenser.

In particular, the present application relates to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria according to the invention for use in a formulation in the prophylaxis or treatment of a SARS-CoV-2 infection for nasal administration, wherein the nasal administration is carried out by means of a nasal spray or nose drops.

It is known that the eye mucosae are another entry point of SARS-CoV-2 to the organism, e.g. a person carries the viruses on his hands while rubbing his eyes.

Therefore, the present application relates also to a pharmaceutically acceptable lectin derived from plants, fungi or bacteria for use according to the invention, wherein the pharmaceutically acceptable lectin derived from plants, fungi or bacteria is provided in a formulation of eye drops.

Eye drops are mostly aqueous solutions containing a pharmaceutically active agent. The pH is usually adjusted to 7.1 to 7.5. Common buffers for eye drops are boric acid and monobasic sodium phosphate. The tonicity should be adjusted by 0.9 % saline (or another isotonizing agent such as potassium nitrate, boric acid, sodium acetate, sodium acetate phosphate buffer or mannitol) to an osmotic pressure isotonic to the cornea epithelium (225 - 430 mosm/kg). Suitable preservatives include thiomersal, organic mercury compounds such as phenylmercury, benzalkonium chloride, chlorhexidine and benzylic alcohol. For prolonging the contact time viscosity-increasing substances (thickening agents) such as cellulose derivatives (hypromellose, methylcellulose, hydroxypropyl methylcellulose), hyaluronic acid, cellulose acetate phthalate, polyethylene glycol, polyvinyl alcohols or poloxamers can be added. Wetting agents or surfactants such as benzalkonium chloride, polysorbate 20, polysorbate 80, dioctyl sodium sulphosuccinate can be included. Some amino acids, alone or in combination with sodium hyaluronate may be helpful in promoting tissue reconstitution, if needed. Suitable amino acids are glycine, leucine, lysine and proline (cf. EP 1940381 B1).

In a further aspect of the invention a method of treatment for a SARS-CoV-2 infection is disclosed, in which an effective dose of at least one pharmaceutically acceptable lectin derived from plants, fungi or bacteria according to the invention is administered to a patient in need thereof or to a healthy person in risk of being infected with SARS-CoV-2.

For some applications it may be desirable that isotopically enriched forms of the compounds of the invention are used, e.g. for diagnostic purposes. Thus, the present patent application refers also to such isotopically enriched forms of the compounds of the invention.

EXAMPLES

Example 1 : Wheat germ agglutinin (WGA) inhibits the replication of SARS-CoV-2 in infected Vero-B4 cells in a dose-dependent manner in Western Blots

In order to investigate whether WGA has an effect on the spread of viral infection, Western Blot (WB) analyses were carried out. Vero-B4 cells (Meyer et al. (2015) Emerg Infect Dis 21: 181-182) were infected with SARS-CoV-2 for two hours. Cells were then washed with PBS (phosphate buffer saline), provided with fresh medium containing WGA in several non- cytotoxic concentration range (100 pg/ml, 1 pg/ml, 100 ng/ml, 10 ng/ml and 1 ng/ml). The treatment with WGA was carried out over the entire experimental procedure. 3 days post infection (dpi) cells and the virus-containing supernatants were harvested. Then, virions were purified from the cell culture supernatants via a 20% sucrose cushion. The virions were denaturized in SDS (sodium dodecyl sulfate) sample buffer, separated by SDS gel electrophoresis and transferred to a nitrocellulose membrane. SARS-CoV-2 were visualized using a convalescent serum and a horseradish peroxidase-coupled secondary reagent by means of an electrochemiluminescence reaction. Herein, a dose-dependent inhibition of SARS-Cov-2 replication was shown. At a concentration of 10 pg/ml WGA showed a complete block of virus replication (Fig.lA). The half maximal effective concentration EC50 was ca. 5 ng/ml. Densitometric evaluations of SARS-CoV-2 total protein in the virus fraction were carried out with the analysis program AIDA®. The densitometric evaluation allows for the quantification of signal intensities in Western Blot and thus for conclusions on the quantity of a certain protein in the sample. The evaluation showed clearly that after the addition of WGA the generation of SARS-CoV-2 proteins is inhibited in a dose-dependent manner (Fig. 1B).

Example 2: In effective doses WGA is not cytotoxic in Vero-B4 and Caco cell cultures

For addressing the question whether WGA shows a cytotoxic effect in the abovementioned systems non-infected Vero-B4 cells were treated in parallel to the Western blot studies with increasing concentrations of WGA (100 pg/ml, 1 ng/ml, 10 ng/ml, 100 ng/ml, 1 pg/ml, 10 pg/ml, 100 pg/ml). Toxicity was assessed with a Neutral Red Uptake Assay. Herein viable cells are exposed to the supravital dye Neutral Red that is going to be incorporated and bound in the cells. This weakly cationic dye penetrates cell membranes by nonionic passive diffusion and concentrates in the lysosomes, where it binds by electrostatic hydrophobic bonds to anionic and/ or phosphate groups of the lysosomal matrix. The uptake of Neutral Red depends on the cell’s capacity to maintain pH gradients, through the production of ATP. At physiological pH, the dye presents a net charge close to zero, enabling it to penetrate the membranes of the cell. Inside the lysosomes, there is a proton gradient to maintain a pH lower than that of the cytoplasm. Thus, the dye becomes charged and is retained inSide the lysosomes.

96-well tissue culture plates are incubated for 2 h with a medium containing Neutral Red. The cells are subsequently washed, the dye is extracted in each well using an acidified ethanol solution and the absorbance is measured photometrically in a spectrophotometer. Thus, the Neutral Red Uptake Assay is a very sensitive method for measuring the toxicity of substances on the cell metabolism (cf. Repetto et al. (2008) Nat Protoc 3: 1125-1131 ).

In Fig. 2 the percentage of viable cells is depicted in comparison to untreated cells. The value for untreated cells was set to 100% (Fig. 2A: Vero-B4 cells; Fig. 2B: CaCo cells). 1 pM staurosporine (StS; an indolocarbazole compound from Streptomyces staurosporeus, an apoptosis inducer) was used as positive control.

It could be shown that WGA did not display any significant toxic effect in antivirally effective concentrations neither in Vero-B4 cells nor in CaCo cells during an observation period of 3 days. Only at concentrations over 10 pg/ml WGA a clear toxic effect was detectable.

Thus, it can be stated that the antiviral effect of WGA is not due to unspecific cytotoxic effects. The median toxic dose TD50 was ca. 50 pg/ml. In the light of the aforementioned dosedependent efficacy this allows for a broad therapeutic window of WGA of three to four log stages.

Example 3: Composition of a throat spray containing a pharmaceutically acceptable lectin

A throat spray composition containing a pharmaceutically acceptable lectin according to the invention is prepared as follows:

Example 4: Composition of a nasal spray containing a pharmaceutically acceptable lectin

A nasal spray composition containing a pharmaceutically acceptable lectin according to the invention is prepared as follows:

Example 5: Composition of eye drops containing a pharmaceutically acceptable lectin

An eye drops composition containing a pharmaceutically acceptable lectin according to the invention is prepared as follows:

The pH of the resulting solution is adjusted to 7.3 by dropwise adding HCI or NaOH. FIGURES

Fig. 1 A: Western Blot bands of total viral protein from SARS-CoV-2 after 3 d treatment with 1 ng/ml, 10 ng/ml, 100 ng/ml, 1 pg/ml and 10 pg/ml WGA, respectively, vs. untreated cells

Fig.lB: Densitometric evaluation of total viral protein from SARS-CoV-2 detected in

Western Blot bands after 3d treatment with 1 ng/ml, 10 ng/ml, 100 ng/ml, 1 pg/ml and 10 pg/ml WGA, respectively. The percentage of the detected viral protein is indicated. Untreated fraction was set to 100%.

Fig. 2A: Viability of Vero-B4 cells in the Neutral Red Uptake Assay after 3 days after application of 100 pg/ml, 1 ng/ml, 10 ng/ml, 100 ng/ml, 1 pg/m, 10 pg/ml and 100 pg/ml WGA, respectively. The percentage of viable cells is indicated. Untreated cells were taken as 100%. Staurosporine was used as positive control, (mean ± SEM; n = 3)

Fig. 2B: Viability of CaCo cells in the Neutral Red Uptake Assay after 3 days after application of 100 pg/ml, 1 ng/ml, 10 ng/ml, 100 ng/ml, 1 pg/m, 10 pg/ml and 100 pg/ml WGA, respectively. The percentage of viable cells is indicated. Untreated cells were taken as 100%. Staurosporine was used as positive control, (mean ± SEM; n = 3)