EP4164670A1 - Bromelain protease, bromelain, jacalin-like lectin, extract from the stem and/or the fruit of a pineapple plant, combination preparation, bromelain protease inhibitor, protein/protease mix, and glycated bromelain protein formed by exogenous non-enzymatic glycation, for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a human or animal - Google Patents

Abstract

The present invention addresses the problem of indicating active-ingredient classes which can treat virus diseases caused by coronaviruses in a human or animal. Said treatment includes the acute treatment of an already existing virus disease and the prophylaxis of same. The present invention relates to a bromelain protease, bromelain, jacalin-like lectin, extract from the stem and/or the fruit of a pineapple plant, combination preparation, bromelain protease inhibitor, protein/protease mix, and glycated bromelain protein formed by exogenous non-enzymatic glycation, for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a human or animal.

Description

Bromelain protease, bromelain, jacalin-like lectin, extract from the stem and / or fruit of a pineapple plant, combination preparation, bromelain protease inhibitor, protein-protease mixture, glycated bromelain protein produced by exogenous non-enzymatic glycation for use in the treatment or prophylaxis of viral infections caused by coronaviruses in a person or animal In view of the ongoing COVID-19 pandemic, there is still an acute need to provide additional active ingredients or active ingredient classes for the treatment of viral diseases. The present invention therefore has the task of showing classes of active substances with which viral diseases caused by coronaviruses in a person or animal can be treated. The treatment includes the acute treatment of an already existing viral disease as well as the prophylaxis of the same. According to a first aspect, the present invention relates to a bromelain protease (synonym “bromelain”) for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a human or animal. The bromelain protease is, in particular, a bromelain protease selected from the group consisting of parent Bromelain (SBM) (EC 3.4.22.32, CAS number: 37189-34-7), fruit bromelain (EC 3.4.22.33, CAS number: 9001-00-7), ananain (EC 3.4.22.31) and mixtures and combinations thereof. The production and isolation of bromelain proteases, in particular stem bromelain (SBM) (EC 3.4.22.32) and fruit bromelain (EC 3.4.22.33) from the stem or fruit of pineapple plants (Ananas comosus) is from the Prior art is known and is described, for example, by Rowan, AD, Buttle, DJ & Barrett, AJ in Arch. Biochem. Biophys. 267, 262-270 (1988) or in ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, Vol. 267, No. 1, Nov. 15, pp. 262-270 (1988). In addition to direct antiviral effects, the bromelaine mentioned also have systemic effects, which are generally helpful in the treatment of viral infections. In particular, anti-inflammatory effects that slow down an excessive immune reaction, anti-edematous effects that counteract edema in the lungs, for example, and anticoagulant effects that counteract inflammatory and / or thrombosis caused by an overactive coagulation system are particularly important. According to a second aspect, the present invention relates to a jacalin-related lectin for use in the treatment or prophylaxis of viral infections caused by coronaviruses in a human or animal. The jacalin-like lectin is selected in particular from the group consisting of mannose-specific and glucose-specific lectins. The jacalin-like lectin is particularly preferably selected from the group consisting of pineapple lectin (Jacalin-related lectin from Ananas comosus (AcmJRL)), jacalin, artocarpine lectin, MPA lectin, Heltuba lectin agglutinin, griffithsin, and mixtures and combinations thereof. The invention further relates in a third aspect to an extract from the stem and / or the fruit of a pineapple plant for use in the Treatment or prophylaxis of viral infections caused by coronaviruses in a human or animal. The pineapple plant can in particular be Ananas comosus and Ananas sativus. Such extracts contain one or more of the aforementioned bromelain proteases and / or ananain. In addition, according to a fourth aspect, the present invention relates to a combination preparation containing at least one bromelain protease and at least one jacalin-like lectin for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a person or animal . In a preferred embodiment, the weight ratio of the total of the at least one bromelain protease to the total of the at least one jacalin-related lectin is from 50:50 to 0.1: 99.9, preferably 40:60 to 1: 99, more preferably 30:70 to 2:98, more preferably 20:80 to 3:97, particularly preferably 10:90 to 5:95. Another advantage of the combination preparation according to the invention is that it contains at least one bromelain protease, preferably the Total concentration of all bromelain proteases in the extract or combination preparation from 0.01 to 50.0% by weight, more preferably 0.1 to 20.0% by weight, particularly preferably from 1.0 to 10.0% by weight amounts to. In addition, with the combination preparation it is advantageous if at least one jacalin-related lectin is contained, preferably the total concentration of the at least one jacalin-like lectin in the extract of 0.01 to 60.0% by weight, more preferred 1.5 to 50.0% by weight, particularly preferably from 2.0 to 30% by weight. In 1973 Perlstein & Kezdy discovered protease inhibitors in bromelain base powder (BBP), which is obtained from the stem of the pineapple plant (Perlstein & Kezdy, Struct., Vol. 1, 249-254). These protease inhibitors were able to inhibit the enzymatic activity of the bromelain proteases from BBP. Originally, seven isoforms of these bromelain protease inhibitors were described in 1973 (Perlstein & Kezdy., Struct., Vol.1, 249-254). In 1975, Reddy et al. the primary structure of isoform VII completely and indicated the microheterogeneity of the seven isolated isoforms (Reddy et al., J. Biol. Chem., Vol.250, 1741-1750). Lenarcic et al. clarified the primary structure of a further bromelain protease inhibitor in 1992 and also showed an inhibitory effect against cathepsin L (Lenarcic et al., Biol. Chem., Vol. 373, 459-464). From Hatano et al. the primary and secondary structure of bromelain protease inhibitor VI was published in 1995 (Hatano et al., Eur. J. Biochem., Vol. 232, 335-343). In the following year, the similarity of bromelain protease inhibitor VI with the Bowman-Birk trypsin inhibitor already described was demonstrated (Hatano et al., Biochemistry, Vol. 35, 5379-5384). The amino acid sequences of all seven isoforms of the bromelain protease inhibitors described so far were finally by Hatano et al. published in 1998 (Hatano et al., J. Biochem., Vol 124, 457-461). All isolation processes of bromelain protease inhibitors described in the literature so far use a two-stage chromatographic process. The basic principle of this method was already published in 1973 by Perlstein & Kezdy (Perlstein & Kezdy, Struct., Vol. 1, 249-254). In the first dimension, i.e. in the first purification step, the chromatographic process of size exclusion chromatography (SEC) is applied. With the SEC, the molecules contained in the BBP can be separated from one another due to their different sizes. In particular, the bromelain proteases (approx. 25 kDa) and the bromelain protease inhibitors (approx. 6 kDa) can be separated from one another. According to the Perlstein & Kezdy method, anion exchange chromatography (e.g. weak anion exchange chromatography = WAX) is generally used in a second chromatographic separation. With this method, Perlstein & Kezdy succeeded in isolating seven bromelain Protease inhibitors (seven different isoforms) from BBP. Using this method, a yield of about 3 mg of the bromelain protease inhibitor isoform VII or 1 mg of the bromelain protease inhibitor isoform VI from 1 g of BBP is reported. (Reddy et al., Biol. Chem., Vol. 250, 1741-1750; Hatano et al., Eur. J. Biochem., Vol. 232, 335-343). The purification process published by Perlstein & Kezdy, which can also be referred to as SEC / WAX, has the disadvantage that the isolation of a bromelain protease inhibitor isoform in high purity or pure form has so far not been successful. There is consensus that all of the so far purified bromelain protease inhibitor isoforms are actually mixtures of different isoforms of bromelain protease inhibitors (Hatano et al., Biol. Chem., Vol. 383, 1151-1156). In addition, scaling up the SEC / WAX method to an industrial scale is not economical. The decisive factor here is the use of the SEC method in the first dimension, i.e. in the first cleaning step. Both the capacity and the separation efficiency of the SEC are lower compared to protein purification methods using adsorption chromatography. This is particularly clear in the specific case that Hatano et al. have repeated the first SEC step three times to isolate 1 mg bromelain protease inhibitor VI, which represents a considerable expenditure of time even on this small scale (1 g BBP) (Hatano et al. 1995, Eur. J. Biochem., Vol.232 , 335-343). Since three chromatographic steps are generally considered to be the economical upper limit, repeated SEC chromatography is uneconomical for industrial use. In order to obtain a yield of around 1 g of bromelain-protease inhibitor mixture with the SEC / WAX method, for example, an SEC column with a volume of around 100 liters would have to be used. As a result, the SEC / WAX process is uneconomical in terms of both material technology and time and is of no interest for commercial use. In the case of the purification of bromelain proteases, various methods are described in the literature (Rowan et al., Arch. Biochem. Biophys., Vol. 267, 262-270; Harrach et al., Protein Chem., Vol. 14, 41 -52). It was therefore also an object of the present invention to provide an improved method for isolating bromelain protease inhibitors and bromelain proteases and, moreover, a bromelain protease inhibitor and a bromelain protease mixture in high purity and enriched biological activity. In a fifth aspect, the invention thus relates to a bromelain protease inhibitor containing or consisting of at least one peptide with an amino acid sequence which is at least 90%, preferably 95%, particularly preferably 100%, identical to one of the sequences from SEQ ID NO: 1-7 is, the at least one peptide preferably having a purity of at least 80% by weight, particularly preferably at least 95% by weight, for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a human or animal. According to the invention, a method for purifying at least one bromelain protease inhibitor is also provided, which is characterized in that an aqueous solution containing a dissolved extract from the stem of the pineapple plant at a pH in the range from pH 6.5 to 9, 5 is purified by cation exchange chromatography, the cation exchange material binding bromelain proteases at a pH in this range and the run of the chromatography containing at least one bromelain protease inhibitor. The aqueous solution and / or further solutions which can be used in cation exchange chromatography (e.g. an elution buffer) optionally contain a buffer substance which has a buffer effect in a range from pH 6.5 to 9.5. Strong or weak cation exchange chromatography (SCX or WCX) can be used for high capacity and separation efficiency, i.e. a cation exchange chromatography in which a strong or weak cation exchange material is used. The buffer conditions are preferably chosen so that in cation exchange chromatography the bromelain protease inhibitors from the extract from the stem of the pineapple plant do not even bind to the cation exchange material (cation exchange column), but do bind all the bromelain proteases. The bromelain protease inhibitors are therefore in the process of cation exchange chromatography, which can be collected and subjected to a further chromatography step. In a preferred embodiment, the buffer conditions are chosen so that the cation exchange chromatography is carried out at a pH of 5.0-10, preferably 7.0-9.5. For example, the aqueous solution in the method can contain a buffer substance which is selected from the group consisting of TRIS, HEPES, sodium phosphate and / or potassium phosphate. In a preferred embodiment, the aqueous solution has a low conductivity. The buffer substance can be contained in the aqueous solution in a concentration of 5-100 mM, preferably 10-50 mM. The bromelain proteases which are bound to the cation exchange material can be detached from the cation exchange material and isolated in a further step. This can be done by eluting the bromelain proteases with a suitable elution buffer. The buffer conditions in the elution buffer are chosen so that the binding of the bromelain proteases to the cation exchange material is abolished. The buffer can have a concentration of 0.01-1.0 M, preferably 0.10-0.5 M, of salt (e.g. NaCl or KCl). Alternatively, the elution from the cation exchange material can take place via an elution buffer with a pH which is higher than the pH of the aqueous solution or a washing buffer. The elution can take place in a step gradient or a linear gradient. If at least one further purification step of the bromelain proteases is provided, is preferably eluted with a linear gradient. In a particularly preferred embodiment, individual fractions of the eluate are isolated here. The elution in a step gradient leads to a bromelain protease mixture with an enriched biological activity compared to the BBP. The eluate of the cation exchange material contains bromelain proteases, which are essentially free of inhibitors. The bromelain proteases can be less than 5.0% (w / w), preferably less than 2.0% (w / w), more preferably less than 1.0% (w / w), more preferably less than 0 , 5% (w / w), more preferably less than 0.2% (w / w), particularly preferably less than 0.1% (w / w), bromelain protease inhibitors, based on the total peptide mass. The degree of purity of the bromelain proteases can be determined by SEC-HPLC or RP-HPLC. If the bromelain protease inhibitors are to be purified further, the cation exchange material, which contains bromelain protease inhibitors, can be passed through in a subsequent second step via anion exchange chromatography (AX), hydrophobic interaction chromatography (HIC), reversed-phase HPLC (RP-HPLC) or SEC to be cleaned. The buffer conditions can be chosen here so that at least one bromelain protease inhibitor binds to the anion exchange material, the material of the hydrophobic interaction chromatography or the material of the RP-HPLC and is then isolated. Apart from SEC, the isolation is preferably done by washing with buffer and then eluting with another buffer. This step is not necessary for the SEC since the bromelain protease inhibitors do not bind to the SEC chromatography material at all. Suitable buffer conditions (for binding, washing and / or eluting peptides or proteins) for the respective materials are known to the person skilled in the art from the prior art. The term “washing” is known to the person skilled in the art. Contacting the chromatography material with a buffer is preferred under “washing” to understand, which weakens the binding of undesired material to the chromatography column, particularly preferably completely eliminates it, while the binding of the bromelain protease inhibitors to the chromatography material is retained. The elution can take place with a step gradient or a linear gradient, with the eluate optionally being collected in individual fractions. Depending on the required quality of the bromelain protease inhibitors, a third chromatography step can be carried out after the second step. In this third step, a further purification takes place, in which at least one isolated bromelain protease inhibitor is purified via RP-HPLC, AX or SEC, the buffer conditions being chosen so that at least one bromelain protease inhibitor adapts to the material of the RP-HPLC or the anion exchange material binds and is then isolated. Apart from SEC, isolation is preferably carried out by first washing with buffer and then eluting with another buffer. Since the bromelain protease inhibitors do not bind to the SEC material, washing and eluting are not necessary (a running buffer is sufficient). In all processes according to the invention, the cation exchange material can be selected from the group consisting of strong and weak cation exchangers, the anion exchange material can be selected from the group consisting of strong and weak anion exchangers, the material of hydrophobic interaction chromatography can be selected from the group consisting of linear, cyclic , non-aromatic and aromatic ligands with a carbon number of C3 to C20, the material of the RP-HPLC can be selected from the group consisting of linear, cyclic, non-aromatic and aromatic ligands (preferably linear ligands) with a chain length of C4 to C18, the material Gel filtration chromatography can use a Superdex^TM-Material (e.g. Superdex30Prepgrade from GE Healthcare). In a preferred embodiment of the method according to the invention, the extract from the stem of the pineapple plant is BBP. The advantage of the method according to the invention is that a mixture of bromelain protease inhibitor isoforms is obtained which is free from other constituents of the extract from the stem of the pineapple plant. The method makes it possible to obtain a bromelain-protease inhibitor mixture (ie the entirety of all bromelain-protease inhibitor isoforms) in a yield of about 1-50% (w / w), preferably 5-30% (w / w) to provide the starting substance Bromelain Base Powder ("BBP" = commercially available extract from the stem of the pineapple plant). Since the prior art reports yields of individual bromelain protease inhibitor isoforms of 0.1% (w / w) or 0.3% (w / w), this means a great improvement over the prior art for the process according to the invention. Consequently, the method according to the invention for isolating bromelain protease inhibitor isoforms from BBP is significantly more efficient and more economical than methods from the prior art. It is also possible to provide individual, highly pure bromelain protease inhibitor isoforms. This can be achieved by running an AX in the second dimension (= 2nd step) and RP-HPLC chromatography in the third dimension (= 3rd step). This enables individual, highly pure bromelain protease inhibitor isoforms to be isolated from an extract from the stem of the pineapple plant. The present invention comprises a bromelain protease inhibitor containing or consisting of at least one peptide with an amino acid sequence which is at least 90%, preferably 95%, particularly preferably 100%, identical to one of the sequences from SEQ ID NO. 1-7 (sequence of the known bromelain protease inhibitors I-VII). According to the invention, the at least one peptide in the bromelain protease inhibitor (for example at least one isoform of a bromelain protease inhibitor) can have a purity of at least 80% by weight, preferably at least 90% by weight, particularly preferably at least 95% by weight, in relation to to contaminating molecules and other bromelain protease isoforms. Furthermore, according to the invention, a bromelain protease inhibitor can be provided which is a mixture of at least two, preferably at least three, particularly preferably at least four, bromelain protease inhibitor isoforms. The mixture can optionally contain all seven known bromelain protease inhibitor isoforms (see SEQ ID NO. 1-7). The mixture of several bromelain protease inhibitor isoforms has the advantage of an improved effect compared to individual bromelain protease inhibitor isoforms, since a larger range of molecular targets can thus be bound. In a further preferred embodiment, the bromelain protease inhibitor according to the invention contains at least the bromelain protease inhibitor isoform IV (SEQ ID NO.4) and / or the bromelain protease inhibitor isoform V (SEQ ID NO.5). The mixture can have a purity of at least 80% by weight, preferably at least 90% by weight, particularly preferably at least 95% by weight, based on the ratio of bromelain protease inhibitor (s) to contaminated molecules which do not contain bromelain Are protease inhibitors (e.g. bromelain proteases). The at least one peptide in the bromelain protease inhibitor according to the invention can furthermore have a) a post-translational modification characteristic of the pineapple plant, preferably glycosylation, and / or b) no post-translational modification. The bromelain protease inhibitor according to the invention can preferably be produced by the process according to the invention. The bromelain protease inhibitor according to the invention can be used in medicine, preferably in the treatment and / or prevention of a disease which is characterized by increased expression of at least one cellular protease, preferably at least one cysteine protease. In addition, the invention comprises a mixture of bromelain proteases, which is less than 0.5% (w / w), preferably less than 0.2% (w / w), particularly preferably less than 0.1% (w / w) , Bromelain protease inhibitors in terms of total peptide mass. For example, the person skilled in the art can determine the residual content of bromelain protease inhibitors in a mixture of bromelain proteases via analytical SEC- or RP-HPLC. The bromelain protease mixture according to the invention can be produced according to a variant of the method according to the invention. In a sixth aspect, the present invention relates to a bromelain protease mixture which contains less than 5.0% (w / w), preferably less than 2.0% (w / w), more preferably less than 1.0% ( w / w), more preferably less than 0.5% (w / w), more preferably less than 0.2% (w / w), particularly preferably less than 0.1% (w / w), bromelain protease inhibitors , in terms of total peptide mass, for use in the treatment or prophylaxis of viral infections caused by coronaviruses in a human or animal. Furthermore, in a seventh aspect, the present invention relates to a glycated bromelain protein formed by exogenous non-enzymatic glycation, in particular a glycated jacalin-like lectin, a glycated bromelain protease, a glycated bromelain protease inhibitor or mixtures thereof, containing at least one covalent sugar unit bound to the bromelain protein. The glycated bromelain protein is preferably used in the treatment or prophylaxis of viral diseases caused by coronaviruses in a person or animal. Another preferred embodiment of this provides that the at least one sugar unit covalently bound to the bromelain protein is selected from the group consisting of monomeric or oligomeric hexoses, in particular glucose, galactose and / or mixtures and combinations thereof. In particular, 1 to 10, preferably 1 to 5, particularly preferably 1, 2 or 3 sugar units are covalently bound to the bromelain protein, bound by a Maillard reaction. The aforementioned glycated bromelain protein can in particular be produced by mixing at least one bromelain protein with at least one reducing sugar and performing a Maillard reaction. For example, the coronavirus can be selected from the group consisting of orthocoronaviruses, preferably alphacoronavirus, betacoronavirus, gammacoronavirus or deltacoronavirus and letoviruses, preferably alpha-ethovirus, in particular milecovirus, e.g. B. Microhyla letovirus 1 (MLeV-1). The orthocoronaviruses are particularly selected from the group consisting of alphacoronaviruses, selected from the group consisting of colacovirus, such as. B. Bat coronavirus CDPHE15; Decacovirus, such as B. Rhinolophus ferrumequinum alphacoronavirus HuB-2013; Duvinacovirus, such as B. Human coronavirus 229E (Eng. Human coronavirus 229E, HCoV229E); Luchacovirus such as B. Lucheng Rn rat coronavirus; Minacovirus such as B. Ferret coronavirus or Mink coronavirus 1; Minunacovirus such as B. Miniopterus bat coronavirus 1 or Miniopterus bat coronavirus HKU8; Myotacovirus, such as B. Myotis ricketti alphacoronavirus Sax-2011 or Nyctalus velutinus alphacoronavirus SC-2013; Pedacovirus such as B. Porcine epidemic diarrhea virus (PEDV) or Scotophilus bat coronavirus 512; Rhinacovirus such as B. Rhinolophus bat coronavirus HKU2 or Swine Acute Diarrhea Syndrome Coronavirus (SADS-CoV); Setracovirus, such as B. Human coronavirus NL63 (HCov-NL63) or NL63-related bat coronavirus strain BtKYNL63-9b; Tegacovirus such as B. Alphacoronavirus 1, in particular canine coronavirus (canine coronavirus, CCoV), feline coronavirus (feline coronavirus, FCoV), or transmissible gastroenteritis virus (TGEV); Betacoronaviruses selected from the group consisting of Sarbecovirus, such as Severe acute respiratory syndrome-related coronavirus ("SARS-associated Coronavirus "), in particular severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as synonymous or non-synonymous mutants thereof, including the variants B.1.1.7, B.1.351, B.1.617, P.1, P.2, B.1.525, B.1.427, B.1.429, L452R, Fin-796H, B.1.526, S: H66D, S: G142V, S: D215G, S: V483A, S: D614G, S: H655Y, S: G669S, S: Q949R, S: N1187D, ORF6: K23-, ORF6: V24-, ORF6: S25-, ORF6: I26-, ORF6: W27-, ORF6: N28-, ORF6: L29-, ORF6: D30-, ORF6: Y31-, S: Y144-, E484K, VOC 20I / 484Q, B.1, R.1, A.2.5, C.36, B.1.1.318, B.1.621, B.1.623, severe acute respiratory syndrome coronavirus (SARS-CoV, SARS-Coronavirus, also SARS-CoV-1), Embecovirus, e.g. B. Betacoronavirus 1, especially bovine coronavirus (BCoV), equine coronavirus (ECoV-NC99), human coronavirus OC43 (HCoV-OC43), porcine hemagglutinating encephalomyelitis virus (HEV), puffinosis coronavirus (HECoV), coronavirus (PCoV) ); China Rattus coronavirus HKU24; Human coronavirus HKU1 (HCoV-HKU1), murine coronavirus, such as B. Mouse hepatitis virus (Eng. Mouse hepatitis virus, MHV) or rat coronavirus (RtCoV); Hibecovirus such as B. Bat Hp-betacoronavirus Zhejiang 2013; Merbecovirus (formerly MERS-related coronaviruses, MERSr-CoV), such as B. Hedgehog coronavirus 1, MERS coronavirus (Middle East respiratory syndrome-related coronavirus, MERS-CoV), Pipistrellus bat coronavirus HKU5, Tylonycteris bat coronavirus HKU4; Nobecovirus, such as B. Rousettus bat coronavirus GCCDC1 or Rousettus bat coronavirus HKU9; or BatCoV RaTG13, Manis-CoV SRR10168377 and SRR10168378; Gammacoronaviruses selected from the group consisting of cegacovirus, such as. B. Beluga whale coronavirus SW1; or Igacovirus, such as e.g. B. avian coronavirus, in particular turkey coronavirus (TCoV), pheasant coronavirus (PhCoV), infectious bronchitis virus (IBV); and delta coronaviruses selected from the group consisting of andecovirus, such as. B. Wigeon coronavirus HKU20; Buldecovirus such as B. Bulbul coronavirus HKU11 (BuCoV HKU11), Coronavirus HKU15, Bronzemännchen-Coronavirus HKU13 (Eng.Munia coronavirus HKU13, MunCoV HKU13), White-eye coronavirus HKU16 or Thrush-Coronavirus HKU12 (Eng.Thrush coronavirus HKU12, HKCo12); Herdecovirus such as B. Night heron coronavirus HKU19; and Moordecovirus, such as. B Common moorhen coronavirus HKU21. According to the invention, the bromelain protease, the jacalin-like lectin, the extract, the combination preparation, the bromelain protease inhibitor, the bromelain protease mixture or the glycated bromelain protein as described above are suitable for use in the treatment of by an infection with symptoms caused by coronaviruses, in particular fever, cough, pneumonia, lymphopenic community acquired pneumonia (L-CAP), pleurisy, shortness of breath, malaise and / or fatigue, sputum, loss of smell (anosmia) and / or loss of taste (ageusia), shortness of breath, muscle and / or sore throat, joint pain, chest pain, sore throat, headache, back pain, chills, nausea and / or vomiting, runny nose, diarrhea, coughing up blood, decreased white blood cell count (lymphopenia), rash on hands, Feet or in the mouth, bilateral, non-purulent conjunctivitis, hypotension, shock, hype rcytokinemia, dysfunction of the heart muscle, inflammation of the pericardium and / or the heart valve, blood clotting disorders, multisystem inflammatory syndrome in children (Multisystem Inflammatory Syndrome in Children, MIS-C) and swelling of the conjunctiva. In the aforementioned extract or combination preparation, it is advantageous if the weight ratio of the total of the at least one bromelain protease to the total of the at least one jacalin-related lectin is 1:99 to 99.9: 0.1 , preferably 50:50 to 99: 1, more preferably 60:40 to 98: 2, more preferably 70:30 to 97: 3, more preferably 80:20 to 96: 4, particularly preferably 90:10 to 95: 5 . Claims 10-12 specify the weight ratios or amounts of JRL / bromelain as they occur in the natural product (extract) or when they are used in their natural ratio. It preferably contains a bromelain protease, preferably the total concentration of all bromelain proteases in the extract or combination preparation from 0.1 to 80.0% by weight, more preferably from 1.0 to 50.0% by weight, particularly preferably from Is 5.0 to 20.0 weight percent. It is also advantageous with the extract or combination preparation, if at least one jacalin-related lectin is contained, preferably the total concentration of the at least one jacalin-like lectin in the extract of 0.01 to 50.0% by weight, more preferably 0.1 to 10.0% by weight .-%, particularly preferably from 2.0 to 8.0% by weight. In all of the aforementioned embodiments, it is advantageous if these are in the form or as a component of a powder, granules, tablet, in particular a film tablet, a hard capsule, a soft capsule, an effervescent tablet, a solution, in particular an injection solution or an infusion solution , an emulsion, a suspension, an ointment, a cream, a paste, a gel, a tincture, eye drops, an inhalable powder, a nasal spray, a suppository, or a transdermal patch. In all of the aforementioned aspects of the present invention, it is also advantageous if the application of the extract, the bromelain protease, the jacalin-like lectin, the bromelain protease inhibitor, the bromelain protease mixture or the glycated bromelain protein orally or orally, by intravenous, subcutaneous or intramuscular injection, by infusion onto the mucous membranes of the nose, mouth or throat, by inhalation, by application to the surface of the eye, rectally, and / or by means of a transdermal patch. Another exemplary embodiment for all aspects of the present invention provides that administration takes place once a week up to once an hour, preferably once a day up to 10 times a day, particularly preferably 1 to 3 times a day, or continuously. The subject according to the invention is intended to be explained in more detail with the aid of the following figures and the following example, without wishing to restrict it to the specific embodiments shown here. 1 shows the primary structure and molecular mass of previously known isoforms of bromelain protease inhibitors (according to Hatano et al., (2002) Biol. Chem., Vol. 383, 1151-1156). FIG. 2 shows the elution profile of size exclusion chromatography (SEC) with BBP. Figure 3 shows the purification profile of strong cation exchange chromatography (SCX) with BBP. FIG. 4 shows a schematic overview of the HCoV229E test. FIG. 5 shows bromelain and lectin with anti-coronavirus activity from the HCoV229E reporter virus screening. A) to F) The compounds (initial concentrations are given) were preincubated with the HCoV229E virus in a ratio of 1:10 for 30 minutes (Table 2), followed by a serial titration on the target cells Huh-7.5-FLuc and an incubation for 48 h. The activity of RLuc and FLuc was measured as a measure of the residual infectivity and cell viability. The data were normalized to the TBS control. The black arrows mark the 1: 500 dilution or the 1: 2500 dilution, which were plotted normalized in FIG. 6. 6 shows lectin with anti-coronavirus activity from the HCoV229E reporter virus screening. The compounds were preincubated with HCoV229E virus in a ratio of 1:10 for 30 minutes (Table 2), followed by titration along the target cells. A) The values of the HCoV229E virus replication and the cell viability were shown normalized for the 1: 500 dilution (black arrows in FIG. 5) against the TBS control. B) Normalized representation of the 1: 2,500 dilution. 7 shows lectin with anti-coronavirus activity from the HCoV229E reporter virus screening. The compounds were preincubated with HCoV229E virus in a ratio of 1: 2 for 30 minutes (Table 2), followed by titration along the target cells. Remdesivir was used as a positive control, DMSO as a negative control. A) Dose-response titration of lectin starting with a 1: 500 dilution. The HCoV229E virus infectivity (absolute values) are shown on the left-hand side and the corresponding cell viability (logarithmic values) of the Huh-7.5-FLuc cells on the right-hand side. B) The values of the HCoV229E virus replication and the cell viability were shown normalized against the BSA control for the 1: 500 dilution and the 1: 2,500 dilution (red rectangles in A). FIG. 8 shows exemplary UV / VIS spectra of various Anlec batches produced. 9 shows a detailed evaluation of an exemplary Anlec UV / VIS spectrum by forming the second derivative. The maximum of the UV / VIS spectrum is at 280.0 nm, significant sub-bands are indicated in red, these correspond to the typical absorption positions of the aromatic amino acids Phe, Tyr and Trp. FIG. 10 shows an SDS-PAGE analysis of representative lectin batches . Here show: Lane 1-3: (5.6 / 11.1 / 22.2) μg HZI 2-09. Lane 4: 4.5 µl SERVAChrom Protein Standard III. Lane 5-7: (8.9 / 17.8 / 35.6) μg HZI 2-10. (T = 14%, C = 5%; samples were reduced with DTT before application and heat-denatured for 3 min at 95 ° C with addition of SDS.) Figure 11 shows an RP-HPLC UV chromatogram of the Anlec batch HZI 2-09. Detection of the absorption at λ = 214 nm (blue) and λ = 280 nm (red). 12 shows a surface plasmon resonance spectroscopy (SPR) - binding kinetics and affinity test for SARS-CoV-2 spike protein and various lectin batches isolated from bromelain A) HZI 2-05, (B) HZI 2-06, C) HZI 2 -09, D) HZI 2-10 and E) Acm-JRL 2). Increasing concentrations of the ligand (highest concentration: A) 100 µM, B) 80 µM, C + D) 50 µM, E) 20 µM, assuming 51: 1 dilutions) were injected for single cycle measurements. The sensorgram shows a faster binding than dissociation of the lectins to the spike Protein (on-off rate). Between the individual batches, the surface containing the spike protein was regenerated with 80% ethylene glycol. 13 shows a surface plasmon resonance spectroscopy (SPR) - binding kinetics and affinity test for ACE-2 receptor and lectin HZI 2-09. Increasing concentrations of the ligand (highest concentration: 50 μM, assuming 51: 1 dilutions) were injected for single cycle measurements. FIG. 14 shows deconvoluted mass spectrograms of recombinant SARS-CoV-2 spike (shown above) and recombinant SARS-CoV-2 spike digested with PNGase F (shown below) to detect glycosylation. FIG. 15 shows an SDS-PAGE for the detection of the proteolytic degradation of the recombinant SARS-CoV-2 spike and the inhibitory function of the HZI 2-07. SARS-CoV-2 spike with bromelain protease (HZI 2-08) and bromelain inhibitor (HZI 2-07) in a molar ratio of 1: 1: 1. 1) PageRulerPrestained. The rectangle marks the intact spike protein at around 150 kDa, the dashed rectangle the spike degradation product at around 24 kDa. 16 shows an SDS-PAGE for the detection of the proteolytic degradation of the recombinant SARS-CoV-2 spike and the inhibitory function of the HZI 2-07 for the bromelain protease fraction HZI 2-08. SARS-CoV-2 spike with bromelain protease fraction HZI 2-08 and bromelain inhibitor HZI 2-07 in a molar ratio of 1: 1: 1 and 1: 1: 10 1) PageRulerPrestained. The rectangle marks the intact spike protein at around 150 kDa. 17 shows an SDS-PAGE for the detection of the proteolytic degradation of the recombinant SARS-CoV-2 spike and the inhibitory function of the HZI 2-07 for the bromelain protease fraction HZI 2-08. SARS-CoV-2 Spike with Bromelain Protease HZI 2-08 in a molar ratio of 10: 1 and 100: 1 as well as SARS-CoV-2 Spike with Bromelain Protease HZI 2-08 and Bromelain Inhibitor HZI 2-07 in a molar ratio of 1: 1: 0.5.1) PageRulerPrestained. The rectangle marks the intact spike protein at around 150 kDa, the dashed rectangle the spike degradation product at around 24 kDa. 18 shows a total ion chromatogram and deconvoluted mass spectrogram of recombinant SARS-CoV-2 spikes incubated with bromelain protease fraction HZI 2-08 in a molar ratio of 100: 1, 10 min, 37 ° C. The arrow marks the intact spike protein at around 150 kDa. 19 shows a total ion chromatogram and deconvoluted mass spectrogram of recombinant SARS-CoV-2 spikes incubated with bromelain protease fraction HZI 2-08 in a molar ratio of 100: 1, 2 h, 37 ° C. The right arrow marks the intact spike protein at approx. 150 kDa, the left arrow the spike breakdown product of 24 kDa. FIG. 20 shows a total ion chromatogram and deconvoluted mass spectrogram of recombinant SARS-CoV-2 spikes incubated with bromelain protease fraction HZI 2-08 in a molar ratio of 1: 1, 2 h, 37 ° C. The right arrow marks the intact spike protein at approx. 150 kDa, the left arrow the spike breakdown product of 24 kDa. Fig. 21 shows a total ion chromatogram and deconvoluted mass spectrogram of recombinant SARS-CoV-2 spikes incubated with bromelain protease fraction HZI 2-08 and bromelain inhibitor HZI 2-07 in a molar ratio of 1: 1: 1, 2 h, 37 ° C. The arrow marks the intact spike protein at around 150 kDa. 22 shows an SDS-PAGE gel in which recombinant SARS-CoV-2 spike protein incubated with bromelain (crude fraction) was applied; SARS-CoV-2 spike protein not incubated with bromelain is also shown for comparison. Details SDS-PAGE analysis: Lane 1: 2 µg lectin batch HZI 2-09. Lane 2: 2 µg of lectin lot HZI 2-10. Lane 4: 40 µg Bromelain (Ursapharm). Lane 5-6: 1 µg recombinant SARS-CoV-2 Spike and 0.4 µg bromelain after 1 h incubation at 37 ° C (molar ratio protein: protease ~ 1: 1). Lane 7/8: 1 / 1.5 µg recombinant SARS-CoV-2 spike. Lane 9: 2 µg horseradish peroxidase. Lane 3/10: 3.5 µl SERVA Triple Color Protein Standard III. (T = 14%, C = 5%; samples were reduced with DTT before application, heat-denatured for 3 min at 95 ° C with the addition of SDS and centrifuged.) FIG. 1 shows in tabular form the primary structure (amino acid sequence) of the seven known bromelain Protease inhibitors I, II, III, IV, V, VI and VII. In addition, the average and monoisotopic molecular mass in daltons is given for each isoform. FIG. 2 shows the elution profile of BBP which was applied to a preparative SEC. The y-axis stands for the absorption strength at 214 nm, while the x-axis reflects the elution volume. The first signal of the elution profile (1) is a component of BBP with a molecular mass of approx. 24 kDa, which has been identified as bromelain proteases. The second signal of the elution profile (2) is a component of BBP with a molecular mass of about 6 kDa, which was identified as a mixture of bromelain protease inhibitors. The two signals at (3) are the result of a first and second rechromatography of the pooled fraction of the second signal (2). Figure 3 (a) shows the profile of a purification of BBP over a strong cation exchange column (SCX). The y-axis represents the absorption signal at 280 nm, while the x-axis denotes the volume of elution buffer. (a) There is a strong signal in the passage of the SCX column (signal I.) i.e. molecules, obviously do not bind to the SCX column. These molecules could be identified as bromelain protease inhibitors by SDS-PAGE and mass spectrometry. With a higher volume of elution buffer and a higher ion concentration (linear gradient), another signal occurs (signal II.). SDS-PAGE and mass spectrometry confirmed the assumption that these are bromelain proteases. (b) Rechromatography of the pooled fractions of the first signal (signal I.), ie of the run of the first chromatography, with the same SCX column under the same conditions as in the first run, demonstrates that the second signal (peak II.) no longer occurs. The bromelain proteases, which are responsible for the second signal, could thus be separated from the bromelain protease inhibitors. Example 1 Investigation of the effectiveness of bromelain against the alpha coronavirus HCoV229E 1. Sample preparation Bromelain was dissolved in TRIS-buffered saline solution (TBS) with a pH of 7.3 (10 mg / ml). Dry substances (HZI 2-01 to -03) were dissolved in TBS buffer. The suspensions were briefly centrifuged to pellet the insolubles. Samples HZI 2-01 and HZI 2-02 were not soluble and were not used for further testing. HZI 2-07 was suspended in 200 mM NaCl 20 mM TRIS pH 8.0.

en Table 1 summarizes all samples used.

Table 1

MMTS: methyl methanethiosulfonate; RP-HPLC: reversed-phase high performance liquid chromatography; TBS: TRIS-buffered saline solution (pH 7.3) 2. Carrying out the tests for the antiviral in vitro activity of bromelain, fractions and lectin against HCoV229E Bromelain and lectin were dissolved in TBS. The suspensions were briefly centrifuged to pellet the insolubles. Firefly luciferase-expressing Huh-7.5-FLuc cells were grown in DMEM medium (Gibco # 41965-039) + 10% fetal calf serum (FCS) + 1% penicillin / streptomycin + 1% L-glutamine + 1% non-essential Amino acids (= DMEM complete) + 5 mg / ml blasticidin cultured. ^{24 hours before the experiment, 2x10 4} cells / well (96-well plate) were sown in 100 µl DMEM complete. The alphacoronavirus HCoV229E, which contains a Renilla luciferase (RLuc) reporter gene, was preincubated with the compounds for 30 min at room temperature in a ratio of 10: 1 (90 μl virus + 10 μl compound). The titer of the virus stock solution for all experiments was 3.41x10 ⁶ TCID50 / ml (virus concentration at which 50% of the cells per ml are infected. This corresponds to the number of infectious particles per ml.). After the preincubation, the Mixture diluted 1:10 in media and titrated in 1: 5 steps on target cells. FIG. 4 shows a schematic representation of the test procedure for the alpha coronavirus HCoV229E. For further experiments, the preincubation was carried out in a ratio of 1: 2 (10 μl virus + 10 μl compound). Firefly luciferase-expressing Huh-7.5-FLuc cells were infected with HCoV229E [serial titration (1: 5) of the cells] one day after sowing in the presence of the indicated concentrations of the compound. The initial viral dilution was 1: 500, based on the initial concentration in the original sample and are shown in Table 2. The information for the bromelain sample with a stock concentration of 10 mg / ml is analogous to sample HZI 2-03 and is not listed separately.

48 h after the inoculation and incubation of the cells at 33 ° C. and 5% CO ₂ , the virus inoculum was removed, the cells were washed twice in phosphate-buffered saline (PBS) and lysed in 50 μl PBS / 0.5% Triton X-100. The lysis of the cells was further enhanced by freezing the plates at -20 ° C. 20 μl of the lysate were used to measure the cell viability via the firefly luciferase signal and 20 μl of the lysate in each case were used to analyze the virus replication / infection efficiency via the Renilla luciferase signal. 3. Results of the tests for the antiviral in vitro activity of bromelain, fractions and lectin against HCoV229E First, bromelain and batches of lectin were tested with a HCoV229E Renilla luciferase reporter virus, an alphacoronavirus, using Huh 7.5 FLuc cells, which are highly permissive to HCoV229E infection. These cells are engineered to express a firefly luciferase reporter gene, allowing cell viability to be assessed in a dual luciferase reporter assay. All lectin samples consisted of various isolates of the lectin from bromelain. Because of their insolubility, samples HZI 2-01 and 2-02 were not used. Bromelain was used as a control at concentrations of 2 mg / ml and 10 mg / ml, respectively. It could be shown that bromelain and lectin showed promising antiviral activity against the HCoV229E reporter virus (FIG. 5). High concentrations of bromelain (FIGS. 5E and 5F) resulted in low cell viability. At 100% cell viability (indicated by the dashed line), an approx. 50% reduction (round dots) in virus replication of the alphacoronavirus HCoV229E could be observed for bromelain. The black arrows mark the 1: 500 dilution and the 1: 2,500 dilution, which were plotted normalized in FIG. 6. The 1: 2,500 dilution shows a lower cytotoxicity per se due to the reduced compound concentration, whereby occurring antiviral effects - and thus also improved cell viability - can be better demonstrated be able. Even if the results are normalized, the 1: 500 dilution shows a virus replication reduced by approx. 25% with almost 100% cell viability in the samples Acm-JRL 1 and HZI 2-05. HZI 2-03 shows an approximately 20% reduction, whereas HZI 2-04 is inactive. At both concentrations (2 and 10 mg / ml), bromelain is associated with a strong reduction in cell viability, so that no valid conclusions can be drawn about a reduction in virus replication. The reduction in cell viability is mainly due to the protease activity of the bromelain, which causes the cells to detach from the bottom of the well. The subsequent luciferase assay only includes the adherent cells and does not provide for a differentiation between dead and vital cells floating in the culture medium, which can lead to a falsified result of the cell viability. At the 1: 2,500 dilution, a reduction in virus replication of approx. 20-25% can be seen in all lectins with almost 100% cell viability. Bromelain at a stick concentration of 2 mg / ml even shows an approx. 45-50% reduction with a cell viability> 100%. Only the highly concentrated bromelain with a stick concentration of 10 mg / ml shows reduced cell viability, so that no valid conclusions can be drawn about a reduction in virus replication. However, a decrease in virus replication can also be demonstrated here. In a further experiment, the results were to be confirmed with the lectins. In addition, the antiviral effect should be increased with a higher substance-to-virus ratio in the pre-incubation (1: 2 instead of 1:10). Furthermore, the initial concentrations of the titration 1: 500 were set in order to correspond to the first pilot tests. Samples Acm-JRL 1, HZI 2-03 and HZI 2-05 were used for the experiment. Remdesivir (1 μM in TBS), DMSO (1:40 in TBS) and BSA (5 mg / ml in TBS) were used as controls (FIG. 7A). The positive control remdesivir brings about a complete reduction in virus replication. At the 1: 500 dilution, the lectins Acm- JRL 1 and HZI 2-05 moderate antiviral effects on the HCoV229E reporter virus (FIG. 7B), while HZI 2-03 had no antiviral effects. The samples Acm-JRL 1 and HZI 2-05 showed an approximately 25% reduction in HCoV229E virus replication with> 100% cell viability. Looking at the 1: 2,500 dilution, the sample HZI 2-05 showed a 50-60% reduction in virus replication, with> 100% cell viability. The results of the previous experiment could be confirmed with this experiment. A further reduction in virus replication was achieved through a higher concentration of lectins [ratio 1: 2 = about 50-60% reduction vs 1:10 = about 20% reduction in HCoV229E replication (shown in FIG. 6B)] in the sample HZI 2-05 can be achieved. It could be shown that an infection by the HCoV229E can be prevented in an in vitro test. Example 2 Isolation of the sample HZI 2-09 and HZI 2-05 1200 mg of bromelain (Merck, order no. 1.01651, batch no. K38171251719) are added to 40 ml of buffer A (50 mM TRIS, 500 mM NaCl, pH 7.2) mg / ml and centrifuged at 9000 g for 15 min. A 5 ml aliquot of this solution is loaded at a flow rate of about 2 ml / min onto a covalently linked D-mannose agarose chromatography column measuring 10 × 50 mm (packing volume 4 ml), which has previously been equilibrated with buffer A. The column is flushed with at least 25 CV ("Column Volumes") until the original baseline is reached again or a constant baseline is obtained. The Anlec is now eluted by switching to buffer B (50 mM TRIS, 500 mM NaCl, 1 M D-mannose, pH 7.2), and the fraction is collected. This application in 5 ml aliquots is repeated several times, for example five times. The eluted and collected fractions are pooled and filled into a dialysis tube with MWCO 3.5 kDa. The fraction size of an elution is about 7 ml. Dialysis is carried out against 2 l of buffer C (50 mM TRIS, 150 mM NaCl, pH 7.2) with constant stirring at room temperature or 4 ° C. with multiple changes of buffer until the mannose concentration is reached by dialysis is ≤ 1 mM. After dialysis, the flocculants are separated off by centrifugation or filtration. The supernatant is concentrated to a smaller volume using an ultrafiltration membrane with MWCO 5 kDa or smaller, so that the original protein concentration after dialysis is increased many times over. The protein concentration can be calculated as a first approximation by means of the UV absorption at 280 nm, for example by means of a theoretically calculated molar extinction coefficient for Anlec according to www.uniprot.org, as done here. Typical UV / VIS spectra for exemplary batches are shown in FIG. 8, a detailed evaluation by forming the second derivative is shown in FIG. 9. FIG. 10 shows the results of an electrophoretic analysis by means of SDS-PAGE of exemplary Anlec batches. The two batches show a main band at around 15 kDa and several sub-bands, especially in lanes 3 and 7, these sub-bands are recognizable due to the strong gel overload. 11 shows an RP-HPLC analysis of a representative batch, the main mass 1 was determined by LC-MS coupling and calculation via deconvolution to be 15,388 Da (approx. 15.38 kDa). It was also possible to measure +162 Da species that indicate glycated proteins, see Gross et al. (2020) J. Pharm. Biomed. Anal.181, 113075. Example 3 Investigation of the binding of bromelain to the spike protein of the SARS-CoV-2 virus 1. Sample preparation 1.1 Cloning, expression and purification of the SARS-CoV-2 spike protein The nucleotide sequence of the extracellular domain of the SARS-CoV-2 spike protein (1-1213) was purchased as a synthetic gene from Eurofins MWG. The gene was amplified by means of PCR and provided with the restriction cleavage sites 5'-BamHI / XhoI-3 '. The gene was then ligated into the eukaryotic expression vector pCAGGS (BamHI religated) by sticky end cloning using T4 DNA ligase. The expression of the spike protein was in HEK293 cells. For this purpose, HEK293 cells were cultivated in a hyperflask (growth area 1720 cm ² ) to a confluence of 80-90% in DMEM complete (37 ° C, 5% CO2). The transfection was then carried out with a 1: 2 ratio of pCAGGS spike protein: polyethyleneimine (linear, average molecular weight 25,000 Da). After 5 hours, the DNA-PEI solution was removed and replaced with DMEM complete. The cells were cultured for a further 48 h at 37 ° C. and 5% CO 2 before the culture supernatant was harvested. To purify the SARS-CoV-2 spike protein, the culture supernatant was applied to a 5 ml HisTrap HP column. After thorough washing with lysis buffer (200 mM NaCl, 20 mM TRIS pH 8.0, 20 mM imidazole), the protein was eluted with elution buffer (200 mM NaCl, 20 mM TRIS pH 8.0, 500 mM imidazole). The protein obtained was then further separated using a HiLoad 16/600 Superdex 200 PG and the peak was collected with an elution volume of 60-70 ml. 1.2 SPR binding and affinity test The binding kinetics and affinity tests of lectins were carried out on a Biacore X100 system (GE Healthcare). The purified, extracellular domain of the spike protein (1-1213) as well as the ACE-2 receptor (Sigma Aldrich, No. SAE0064) was covalently attached to a CM5 sensor chip via amine coupling in 10 mM sodium acetate buffer (pH 4.5) for a final 9600 for Spike and 4000 for ACE-2 receptor immobilized. Surface plasmon resonance spectroscopy (SPR) assays were carried out at a flow rate of 30 μl / min in 1x HBS-EP (150 mM NaCl, 10 mM HEPES pH 7.4, 3 mM EDTA, 0.005% Tween-20). Increasing concentrations of lectin (1.25 to 20 μM) for spike were injected for single cycle measurements (120 s contact time, 180 s dissociation time). 1.3 SARS-CoV-2 SDS-PAGE and LC-MS analysis The glycosylation of the recombinantly obtained spike was detected enzymatically: 20 µg SARS-CoV-2 spike in 200 mM NaCl solution and 20 mM TRIS pH 8.0. It was buffered with 2 μl (1000 IU) PNGase F and the associated buffers according to the manufacturer's protocol from New England Biolabs® Inc. and incubated at 37 ° C. for 6 h. The lyophilisate of the bromelain inhibitor (HZI 2- 07) was buffered and suspended in 200 mM NaCl solution with 20 mM TRIS pH 8.0. To pellet the insoluble constituents, the Eppendorf vessel with the suspension was centrifuged and the content of the solution was determined photometrically. To demonstrate the proteolytic degradation of the recombinant SARS-CoV-2 spike and the resulting peptide product fragment sizes as well as the inhibitory function of the HZI 2- 07, recombinantly produced SARS-CoV-2 spike with bromelain protease HZI 2-08 with and without inhibitor HZI was used 2-07 mixed in stoichiometric proportions and incubated at 37 ° C. Sampling for SDS-PAGE or LC-MS analysis was carried out as follows: The sample was washed with SDS dye (1.2 g SDS, 6 mg bromophenol blue, 4 ml glycerol, 0.6 ml 1 M TRIS pH 8.0, 5.4 ml H2O, heated to dissolve all components, then 930 mg dithiothreitol (DTT) added to obtain a 6-fold SDS dye buffer) and immediately boiled for 2-3 min at 100 ° C. Sampling for LC-MS analysis: The sample was immediately frozen in liquid nitrogen, stored at -80 ° C and thawed on ice a few minutes before the LC-MS measurement. The SDS-PAGE with 12% v / v polyacrylamide content was loaded with 10 μl of the prepared samples. 6 µl "PageRuler Prestained Protein Ladder" (Thermo Fisher Scientific) was loaded in order to monitor the progress of the SDS-PAGE and to estimate the approximate size of the separated proteins after staining the gel. The electrophoresis was carried out in a “Mini-PROTEAN® Tetra System” (BIO RAD) with SDS Laemmli buffer with a voltage of 140 V for 90 minutes. After completion of the electrophoresis, the SDS-PAGE was heated in a microwave with staining solution (Coomassie blue 0.05% m / v, methanol 50% v / v, glacial acetic acid 7% v / v, water 43% v / v) and 24 h stored in water before the photo documentation took place. Direct intact protein UPLC-ESI-MS analysis was performed using an UltiMate 3000 UPLC system, coupled with a maXis4G Q-ToF mass spectrometer with an Apollo II ESI source. It was measured in positive mode. The samples were passed through an Aeris Widepore XB-C8 column (3.6 µm, 150 x 2.1 mm; Phenomenex). The separation took place at a flow rate of 0.3 ml / min (eluent A: deionized water with 0.1% v / v acetic acid, eluent B: distilled acetonitrile with 0.1% v / v acetic acid) at 45 ° C. with a Gradients of 2% B for 30 s, followed by a linear gradient to 75% B in 10 min and a constant of 75% B for a further 3 min. The flow rate was reduced to 75 μl / min before entering the ion source. Mass spectra were generated in Centroid mode from 150-2500 m / z at 2 Hz. The mass spectrometry ion source parameters were: 500 V end plate offset, 4000 V capillary voltage, 1.1 bar nebulizer gas pressure, 6 l / min dry gas flow and 180 ° C drying temperature. Protein masses were determined using the total ion chromatogram from the retention time span 6.5 min to 9 min for the bromelain protease fraction (HZI 2-08) assays with and without bromelain inhibitor (HZI 2-07), for the total ion chromatograms for the detection of the glycosylation of 7, 0-7.6 min summed up and deconvoluted to neutral masses with an instrument resolving power of 8000 on the maximum entropy decomposition algorithm in high resolution with Compass DataAnalysis. 2. Results 2.1. SARS-CoV-2 spike protein binding assay For the lectins isolated differently from the bromelain, SARS-CoV-2 spike protein binding assays were carried out using SPR in vitro. For this purpose, purified SARS-CoV-2 spike protein was immobilized on a Cm5 chip by amine coupling. Then the Jacalin-like lectins were tested for their binding; their dissociation constant and their binding kinetics were determined. Various binding characteristics and on-off rates could be observed, which is shown in more detail below. Within the binding assay using SPR, different batches of the lectin isolated from bromelain (HZI 2-05, HZI 2-06, HZI 2-09, HZI 2-10 and Acm-JRL 2) were examined for their characteristics. Slight differences between the batches could be determined, with the association and dissociation rates changing in particular. It could be observed here that the bound lectin in HZI 2-09 and Acm-JRL 2 dissociated from the spike protein more slowly than an association was measured could be, whereby the measured values on the chip increased constantly. In Fig. 12, the measured values of the different injections of the respective lectin batches are shown as a function of time. Between the different measurements, the surface containing the bound spike protein was regenerated with 80% ethylene glycol. 12 shows the sensorgram of the SPR analysis of the binding kinetics and the affinity test for SARS-CoV-2 spike protein and various lectin batches isolated from bromelain (HZI 2-05, HZI 2-06, HZI 2-09, HZI 2-10, Acm-JRL 2) shown in increasing concentrations. The KD values as well as association constants and Rmax values were calculated using the Biacore X100 software (Table 3). We were able to show that the lectin batches HZI 2-09, HZI 2-10 and Acm-JRL 2 have a high affinity for the SARS-CoV-2 spike protein in the micromolar range. In addition, especially for Acm-JRL 2, fast binding (Ka value 10311 / Ms) and slow dissociation (Kd value 0.0031 / s) from the spike protein could be observed. Table 3 Surface plasmon resonance spectroscopy (SPR) - binding kinetics and affinity test for SARS-CoV-2 spike protein and various batches of lectin isolated from bromelain. The values calculated with the Biacore X100 software are shown. In a further experiment, the SPR assay was investigated to analyze the binding kinetics and the affinity test of the lectin to the ACE-2 receptor (FIG. 13). For this purpose, lectin concentrations between 3.125 and 50 µM used. 13 shows the sensorgram of the SPR analysis of the binding kinetics and of the affinity test for the ACE-2 receptor and the lectin batch HZI 2-09 in increasing concentrations. Based on the sensorgram, it can be concluded that there is a dissociation constant of 100 µM or higher. In addition, there are other binding characteristics with regard to the on-off rate. The KD cannot be calculated from the measurement because it lies outside the measured concentrations. 2.2 SARS-CoV-2 Spike SDS-PAGE and LC-MS analysis The glycosylation of the spike protein was detected by means of LC-MS analysis. The deconvoluted mass spectrograms are shown in FIG. PNGase F removes N-linked oligosaccharides from glycoproteins. Oligosaccharides are split off between the innermost GlcNAc and asparagine residues. After digestion of the recombinant SARS-CoV-2 spike protein with PNGase F, a mass shift can be seen in the mass spectrogram, triggered by the loss of oligosaccharides from the spike protein. For the analytical detection of the proteolysis activity of the bromelain protease fraction HZI 2-08 and the inhibitory function of the peptide HZI 2-07 obtained from bromelain, SDS-PAGE and liquid chromatography coupled with mass spectrometry were used. The fragmentation of the recombinant SARS-CoV2 spike and the inhibitory function of HZI 2-07 could be detected via SDS-PAGE (FIGS. 15-17). The mass spectra and the neutral masses deconvoluted from them can also demonstrate the fragmentation (Fig. 18-21). In FIG. 15, in lanes 2 to 7, the proteolytic degradation of the SARS-CoV-2 spike protein by the protease (HZI 2-08) can be seen. The main mass of about 150 kDa of the intact spike cannot be detected. However, one recognizes a main degradation product at approx. 24 kDa (dashed rectangle in FIG. 15). After adding HZI 2-07 (= inhibitor), the inhibitory function becomes visible - degradation of the spike protein is inhibited. This results in bands at around 150 kDa in lanes 8-10 (rectangle in Fig. 15). The inhibitory effect of the inhibitor on the protease (HZI 2-08) persists over a longer test period, the test was carried out up to 120 min. This can be seen from the intact spike protein in FIG. 16, which has been marked by a rectangle. The kinetics of the proteolytic degradation of the spike protein is shown in FIG. With a spike: protease ratio of 10: 1, a clear band at around 150 kDa (row 2) can be seen after 10 minutes of incubation, which indicates an intact spike protein. After a longer incubation of 120 min (lane 5) it can be seen that the band has already clearly disappeared and the fragmentation increases. This is not the case with a ratio of 100: 1 (lanes 3 and 6). Here you can see the intact spike protein even after incubation for 120 minutes, which indicates that the protease HZI 2-08 has an insufficient effect. With the results shown in FIG. 15 and FIG. 16, I thus give an optimal spike: protease ratio of 1: 1. In addition, it can be concluded that the ratio of 1: 1: 0.5 (spike: protease: inhibitor) is unfavorable, since the degradation of the spike could not be inhibited. Here the ratio of 1: 1: 1 appears optimal (Fig. 16). FIG. 18 shows the total ion chromatogram (TIC) and the mass spectrum of the SARS-CoV-2 spike protein. After adding the protease (HZI 2- 08; ratio spike: protease: 100: 1), no mass peak at 150 kDa could be detected after just 10 minutes (arrow). The fragments that appear indicate an effective degradation of the spike protein after the addition of protease. This confirms the results which have already been presented by means of SDS-PAGE (FIG. 15). Even after incubation with the protease for 120 min (HZI 2-08; ratio spike: protease: 100: 1), no mass peak at 150 kDa could be detected (right arrow, FIG. 19). This indicates that the proteolytic effect of the protease persists for a period of at least 120 min. In addition, a mass peak is now visible at m / z 24,392, which is the main breakdown product of the spike protein. This confirms the results which have already been presented by means of SDS-PAGE (FIG. 15). The proteolytic effect of the protease (HZI 2-08) is once again clear in FIG. Here there are spikes with protease in a ratio of 1: 1. After incubation for 120 min, the peak of the degradation product (left arrow) is very pronounced. After the addition of the inhibitor HZI 2-07, the intact spike protein becomes visible at m / z 145.196 (FIG. 21). The degradation product at 24 kDa cannot be detected. This confirms the result from FIG. 15, where it has already been shown that the inhibitor inhibits the protease (HZI 2-08). The spike protein can therefore not be broken down. FIG. 22 shows an SDS-PAGE analysis of recombinant SARS-CoV-2 spike protein after digestion with bromelain base powder for 1 hour at 37 ° C. (molar ratio protein: protease approximately 1: 1, lanes 5 and 6). For comparison, SARS-CoV-2 spike protein not incubated with bromelain is also shown. (Lane 7 and 8). The results show that bromelain base powder is also able to digest the spike protein. It could thus be shown that bromelain can bind to the spike protein of coronaviruses and that the lectin contained in bromelain (5% of total bromelain) can bind to both the spike protein and mannose, but not with a comparable KD to the ACE-2 receptor of the host cell.

Claims

Claims 1. Bromelain protease for use in the treatment or prophylaxis of viral infections caused by coronaviruses in a human or animal. 2. bromelain protease according to the preceding claim, characterized in that the bromelain protease is selected from the group consisting of stem bromelain (SBM) (EC 3.4.22.32), fruit bromelain (EC 3.4.22.33), ananain (EC 3.4.22.31) as well as mixtures and combinations thereof. 3. Jacalin-related lectin for use in the treatment or prophylaxis of viral infections caused by coronaviruses in a human or animal. 4. Jacalin-like lectin according to the preceding claim, characterized in that the jacalin-like lectin is selected from the group consisting of mannose-specific and glucose-specific lectins. 5. Jacalin-like lectin according to one of the two preceding claims, characterized in that the jacalin-like lectin is selected from the group consisting of pineapple lectin (jacalin-related lectin from Ananas comosus (AcmJRL)) , Jacalin, Artocarpine Lectin, MPA Lectin, Heltuba Lectin, Agglutinin, Griffithsin, and mixtures and combinations thereof. 6. Extract from the stem and / or the fruit of a pineapple plant for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a person or animal. 7. Extract according to the preceding claim, characterized in that the pineapple plant is selected from the group consisting of Ananas comosus and Ananas sativus. 8. Extract according to one of the two preceding claims, characterized in that at least one bromelain protease, in particular a bromelain protease selected from the group consisting of parent bromelain (SBM) (EC 3.4.22.32), fruit bromelain ( EC 3.4.22.33) and ananain (EC 3.4.22.31) as well as mixtures and combinations thereof. 9. Combination preparation containing at least one bromelain protease and at least one jacalin-related lectin for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a person or animal. 10. Combination preparation according to the preceding claim, characterized in that the weight ratio of the total of the at least one bromelain protease to the total of the at least one jacalin-like lectin is from 50:50 to 0.1 : 99.9, preferably 40:60 to 1:99, more preferably 30:70 to 2:98, more preferably 20:80 to 3:97, particularly preferably 10:90 to 5:95. 11. Combination preparation according to one of the two preceding claims, characterized in that it contains at least one bromelain protease, preferably the total concentration of all bromelain proteases in the extract or combination preparation of 0.01 to 50.0% by weight, more preferably 0.1 to 20.0% by weight, particularly preferably from 1.0 to 10.0% by weight. 12. Combination preparation according to one of claims 9 to 11, characterized in that it contains at least one jacalin-like lectin (Jacalin-related lectin), preferably the total concentration of the at least one jacalin-like lectin in the extract of 0.01 to 60.0 % By weight, more preferably 1.5 to 50.0% by weight, particularly preferably from 2.0 to 30% by weight. 13. Bromelain protease inhibitor containing or consisting of at least one peptide with an amino acid sequence which at least 90%, preferably 95%, particularly preferably 100%, is identical to one of the sequences from SEQ ID NO: 1-7, the at least one peptide preferably having a purity of at least 80% by weight, particularly preferably at least 95% by weight, for use in the treatment or prophylaxis of viral infections caused by coronaviruses in a person or animal. 14. Bromelain protease inhibitor according to the preceding claim, characterized in that the bromelain protease inhibitor contains at least two, preferably at least three, particularly preferably at least four, peptides which have an amino acid sequence that is at least 90%, preferably 95%, particularly preferably 100% , is identical to one of the sequences from SEQ ID NO: 1-7. 15. Bromelain protease inhibitor according to one of the two preceding claims, characterized in that at least one peptide of the bromelain protease inhibitor has a post-translational modification, preferably glycosylation, and / or no post-translational modification, which is characteristic of the pineapple plant . 16. Bromelain protease mixture which is less than 5.0% (w / w), preferably less than 2.0% (w / w), more preferably less than 1.0% (w / w), more preferably less than 0.5% (w / w), more preferably less than 0.2% (w / w), particularly preferably less than 0.1% (w / w), bromelain protease inhibitors, in relation to the Total peptide mass, contains, for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a human or animal. 17. Glycated bromelain protein produced by exogenous non-enzymatic glycation, in particular a glycated jacalin-like lecin, a glycated bromelain protease, a glycated bromelain protease inhibitor or mixtures thereof containing at least one covalent to the bromelain protein bound sugar unit. 18. Glycated bromelain protein according to the preceding claim for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a person or animal. 19. Glycated bromelain protein according to one of the two preceding claims, characterized in that the at least one sugar unit covalently bound to the bromelain protein is selected from the group consisting of monomeric or oligomeric hexoses, in particular glucose, galactose and / or mixtures and combinations thereof. 20. Glycated bromelain protein according to one of the two preceding claims, characterized in that 1 to 10, preferably 1 to 5, particularly preferably 1, 2 or 3 sugar units are covalently bound to the bromelain protein, for example bound by a Maillard reaction . 21. Glycated bromelain protein, in particular according to one of claims 18 to 20, producible by mixing at least one bromelain protein with at least one reducing sugar and performing a Maillard reaction. 22. Bromelain protease, jacalin-like lectin, extract, combination preparation, bromelain protease inhibitor, bromelain protease mixture or glycated bromelain protein according to one of the preceding claims, characterized in that the coronavirus is selected from the group consisting of betacoronaviruses, orthocoronaviruses, preferably alphacoronaviruses, gammacoronaviruses or deltacoronaviruses and letoviruses, preferably alphaletovirus, in particular milecovirus, eg Microhyla letovirus 1 (MLeV-1). 23. Bromelain protease, jacalin-like lectin, extract, combination preparation, bromelain protease inhibitor, bromelain protease mixture or glycated bromelain protein according to the preceding claim, characterized in that the Alphacoronaviruses selected from the group consisting of Colaco virus, such as, for example, Bat coronavirus CDPHE15; Decacovirus, such as, for example, Rhinolophus ferrumequinum alphacoronavirus HuB-2013; Duvinacovirus, such as, for example, human coronavirus 229E (eng. Human coronavirus 229E, HCoV-229E); Luchacovirus, such as, for example, Lucheng Rn rat coronavirus; Minacovirus, such as Ferret coronavirus or Mink coronavirus 1; Minunacovirus, such as, for example, Miniopterus bat coronavirus 1 or Miniopterus bat coronavirus HKU8; Myotacovirus, such as, for example, Myotis ricketti alphacoronavirus Sax-2011 or Nyctalus velutinus alphacoronavirus SC-2013; Pedacovirus, such as, for example, Porcine epidemic diarrhea virus (PEDV) or Scotophilus bat coronavirus 512; Rhinacovirus, such as, for example, Rhinolophus bat coronavirus HKU2 or Swine Acute Diarrhea Syndrome Coronavirus (SADS-CoV); Setracovirus, such as, for example, human coronavirus NL63 (HCov-NL63) or NL63-related bat coronavirus strain BtKYNL63-9b; Tegacovirus, such as alphacoronavirus 1, in particular canine coronavirus (canine coronavirus, CCoV), feline coronavirus (feline coronavirus, FCoV), or transmissible gastroenteritis virus (TGEV); Betacoronaviruses are selected from the group consisting of Sarbecovirus, such as, for example, Severe acute respiratory syndrome-related coronavirus (“SARS-associated coronavirus”), in particular severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and synonyms or non-synonymous mutants thereof, including the variants B.1.1.7, B.1.351, B.1.617, P.1, B.1.525, P.2, B.1.427, B.1.429, L452R, Fin-796H, B.1.526 , S: H66D, S: G142V, S: D215G, S: V483A, S: D614G, S: H655Y, S: G669S, S: Q949R, S: N1187D, ORF6: K23-, ORF6: V24-, ORF6: S25 -, ORF6: I26-, ORF6: W27-, ORF6: N28-, ORF6: L29-, ORF6: D30-, ORF6: Y31-, S: Y144-, E484K, VOC 20I / 484Q, B.1, R. 1, A.2.5, C.36, B.1.1.318, B.1.621, B.1.623, severe acute respiratory syndrome coronavirus (SARS-CoV, SARS-Coronavirus, also SARS-CoV-1), Embecovirus, such as betacoronavirus 1, in particular bovine coronavirus (BCoV), equine coronavirus (ECoV-NC99), human coronavirus OC43 (HCoV-OC43), porcine hemagglutinating encephalomyelitis virus (HEV), puffinosis coron avirus (PCoV), Human Enteric Coronavirus (HECoV); China Rattus coronavirus HKU24; Human coronavirus HKU1 (HCoV-HKU1), murine coronavirus, such as, for example, murine hepatitis virus (mouse hepatitis virus, MHV) or rat coronavirus (RtCoV); Hibecovirus such as Bat Hp-betacoronavirus Zhejiang2013; Merbe covirus (formerly MERS-related coronaviruses, MERSr-CoV), such as Hedgehog coronavirus 1, MERS-Coronavirus (Middle East respiratory syndrome-related coronavirus, MERS-CoV), Pipistrellus bat coronavirus HKU5, Tylonycteris bat coronavirus HKU4; Nobecovirus, such as, for example, Rousettus bat coronavirus GCCDC1 or Rousettus bat coronavirus HKU9; Sarbecovirus, such as, for example, Severe acute respiratory syndrome-related coronavirus (“SARS-associated coronavirus”, in particular severe acute respiratory syndrome coronavirus (SARS-CoV, SARS-Corona virus, also SARS-CoV-1), acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or BatCoV RaTG13, Manis-CoV SRR10168377 and SRR10168378; gammacoronaviruses selected from the group consisting of cegacovirus, such as Beluga whale coronavirus SW1; or Igacovirus, such as Vogel- Coronavirus (Avian coronavirus), in particular turkey coronavirus (TCoV), pheasant coronavirus (PhCoV), infectious bronchitis virus (IBV); and delta coronaviruses, selected from the group consisting of andecovirus, such as Wigeon coronavirus HKU20; Buldecovirus, such as Bulbul coronavirus HKU11 (BuCoV HKU11), Coronavirus HKU15, Bronzemännchen-Coronavirus HKU13 (Eng.Munia coronavirus HKU13, MunCoV HKU13), White-eye coronavirus HKU12, ThCoV H KU12); Herd covirus, such as, for example, Night heron coronavirus HKU19; as well as Moordecovirus, such as, for example, Common moorhen coronavirus HKU21. 24. Bromelain protease, jacalin-like lectin, extract, combination preparation, bromelain protease inhibitor, bromelain protease mixture or glycated bromelain protein according to one of the preceding claims, for use in the treatment of infection with betacoronaviruses caused symptoms, especially fever, cough, pneumonia, lymphopenic community acquired pneumonia "(lymphopenic community acquired pneumonia, L- CAP), pleurisy, shortness of breath, malaise and / or fatigue, sputum, loss of smell (anosmia) and / or loss of taste (ageusia), shortness of breath, muscle and / or sore throat, joint pain, chest pain, sore throat, headache, back pain, Chills, nausea and / or vomiting, runny nose, diarrhea, coughing up blood, reduced leukocyte count (lymphopenia), rash on hands, feet or in the mouth, bilateral, non-purulent conjunctivitis, hypotension, shock, hypercytokinemia, dysfunction of the Heart muscle, inflammation of the pericardium and / or heart valve, blood clotting disorders, multisystem inflammatory syndrome in children (Multisystem Inflammatory Syndrome in Children, MIS-C) and swelling of the conjunctiva. 25. Extract or combination preparation according to one of claims 6 to 12 and 22 to 24, characterized in that the weight ratio of the total of the at least one bromelain protease to the total of the at least one jacalin-like lectin (Jacalin-related lectin) of 1 : 99 to 99.9: 0.1, preferably 50: 50 to 99: 1, more preferably 60:40 to 98: 2, more preferably 70:30 to 97: 3, more preferably 80:20 to 96: 4, particularly preferably 90:10 to 95: 5. 26. Extract or combination preparation according to one of claims 6 to 12 and 22 to 24, characterized in that it contains at least one bromelain protease, preferably the total concentration of all bromelain proteases in the extract or combination preparation of 0.1 to 80.0 wt. -%, more preferably 1.0 to 50.0% by weight, particularly preferably from 5.0 to 20.0% by weight. 27. Extract or combination preparation according to one of claims 6 to 12 and 22 to 26, characterized in that it contains at least one jacalin-like lectin, preferably the total concentration of the at least one jacalin-like lectin in the extract from 0.01 to 50.0% by weight, more preferably from 0.1 to 10.0% by weight, particularly preferably from 2.0 to 8.0% by weight. 28. Bromelain protease, jacalin-like lectin, extract, combination preparation, bromelain protease inhibitor, bromelain protease mixture or glycated bromelain protein according to one of the preceding claims, in the form or as a component of a powder or granulate, a tablet, in particular a film tablet, a hard capsule, a soft capsule, an effervescent tablet, a solution, in particular an injection solution or an infusion solution, an emulsion, a suspension, an ointment, a cream, a paste, a gel, a drink , eye drops, an inhalable powder, a nasal spray, a suppository, or a transdermal patch. 29. Bromelain protease, jacalin-like lectin, extract, combination preparation, bromelain protease inhibitor, bromelain protease mixture or glycated bromelain protein according to one of the preceding claims, characterized in that the application of the extract, the bromelain Protease, the jacalin-like lectin, the bromelain protease inhibitor, the bromelain protease mixture or the glycated bromelain protein orally or orally, by intravenous, subcutaneous or intramuscular injection, by infusion onto the mucous membranes of the nose and mouth or the throat, by inhalation, by application to the surface of the eye, rectally, and / or by means of a transdermal patch. 30. Bromelain protease, jacalin-like lectin, extract, combination preparation, bromelain protease inhibitor, bromelain protease mixture or glycated bromelain protein according to one of the preceding claims, characterized in that the administration once a week up to once an hour, preferably once a day up to 10 times takes place per day, particularly preferably 1 to 3 times per day or continuously. 31. A method for purifying at least one bromelain protease inhibitor from an extract from the stem of the pineapple plant, in which an aqueous solution of the extract from the stem of the pineapple plant at a pH in the range from pH 6.5 to pH 9.5 is purified by means of cation exchange chromatography, the cation exchange material binding bromelain proteases at a pH value in this range and the run of the chromatography containing at least one bromelain protease inhibitor. 32. The method according to the preceding claim, characterized in that in a subsequent second step the run is purified via anion exchange chromatography, hydrophobic interaction chromatography, RP-HPLC or gel filtration chromatography, the buffer conditions being selected so that at least one bromelain Protease inhibitor binds to the anion exchange material, the material of the hydrophobic interaction chromatography or the material of the RP-HPLC and is then isolated. 33. The method according to the preceding claim, characterized in that a further purification takes place in a third step in which at least one isolated bromelain protease inhibitor is purified via RP-HPLC, anion exchange chromatography or gel filtration chromatography, the buffer conditions as follows be chosen so that at least one bromelain protease inhibitor binds to the material of the RP-HPLC or the anion exchange material and is then isolated. 34. The method according to any one of claims 31 to 33, characterized in that at least one bromelain protease inhibitor in a purity of at least 80% by weight, preferably at least 90% by weight, particularly preferably at least 95% by weight. %, is isolated. 35. The method according to claim 31, characterized in that the bromelain proteases bound to the cation exchange material are eluted in a further step. 36. The method according to the preceding claim, characterized in that the bromelain proteases are less than 5.0% (w / w), preferably less than 2.0% (w / w), more preferably less than 1.0% (w / w), more preferably less than 0.5% (w / w), more preferably less than 0.2% (w / w), particularly preferably less than 0.1% (w / w), bromelain Protease inhibitor, in relation to the total peptide mass. 37. Method according to one of the two preceding claims, characterized in that the bromelain proteases have at least 80%, preferably at least 90%, particularly preferably at least 95%, of the uninhibited protease activity. 38. The method according to any one of claims 31 to 37, characterized in that the extract from the stem of the pineapple plant is bromelain base powder (BBP). 39. Bromelain protease inhibitor according to one of claims 13 to 15, producible by a method of claims 31 to 38. 40. Bromelain protease mixture according to the preceding claim, producible by a method according to one of claims 35 to 38.