WO2022160327A1 - Application of gold complex in preparation of drug for treating novel coronavirus pneumonia - Google Patents

Abstract

The present invention provides an application of a gold complex in preparation of a drug for treating novel coronavirus pneumonia, and relates to the technical field of biomedicines. The gold complex can effectively inhibit the catalytic activity of Mpro protein, and inhibit the replication of SARS-CoV-2 live virus in cells in living cells. The gold complex can significantly inhibit activation of an NFkB inflammatory molecular pathway in macrophages and pulmonary bronchial cells, thereby reducing the expression and secretion of inflammatory factors IL-6, IL-1β and TNF-α. The gold complex can inhibit virus replication in lung tissues and inhibit inflammatory injury of animal lung tissues on a COVID-19 model animal. The gold complex can inhibit replication of SARS-CoV-2 in cells and animals, and can also directly inhibit the damage of the immune inflammatory storm induced by the abovementioned virus infection on the lung tissues of a living body.

Description

Application of gold complexes in the preparation of medicines for the treatment of novel coronavirus pneumonia

This application claims the priority of the Chinese patent application with the application number 202110109926.4 and the invention title "Application of Gold Complexes in the Preparation of Medicines for the Treatment of Novel Coronavirus Pneumonia", which was filed with the China Patent Office on January 27, 2021. The entire contents of this application are incorporated by reference.

technical field

The invention relates to the technical field of biomedicine, in particular to the application of gold complexes in the preparation of medicines for the treatment of novel coronavirus pneumonia.

Background technique

Novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19), referred to as "new coronary pneumonia". The main manifestations of COVID-19 are fever, dry cough, and fatigue. A small number of patients are accompanied by upper respiratory and gastrointestinal symptoms such as nasal congestion, runny nose, and diarrhea. Severe cases mostly develop dyspnea after 1 week, and severe cases rapidly progress to acute respiratory distress syndrome, septic shock, metabolic acidosis that is difficult to correct, coagulation dysfunction, and multiple organ failure. There is currently no drug proven to be effective in treating COVID-19.

Current drug design focuses on small-molecule compounds that inhibit viral replication and antibodies/small-molecule compounds that inhibit inflammation. Many traditional medicines have been used to treat COVID-19. For example, remdesivir can effectively inhibit the replication of SARS-COV-2, but it cannot effectively treat patients with lung inflammation caused by infection. Ruxolitinib and acalatinib can directly inhibit inflammatory cytokines, but cannot effectively inhibit SARS-COV-2 replication. At present, there is a lack of a drug that can not only directly inhibit the replication of SARS-COV-2 but also directly inhibit the inflammatory damage of the body's lungs.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide the application of gold complexes in the preparation of medicines for the treatment of novel coronavirus pneumonia, which can not only directly inhibit the replication of SARS-COV-2 but also directly inhibit the inflammatory damage of the body's lungs.

In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:

The invention provides the application of gold complexes in the preparation of medicines for inhibiting the replication of SARS-COV-2 and/or inhibiting the activity of SARS-COV-2.

The invention also provides the application of the gold complex in the preparation of a medicine for inhibiting the inflammatory damage of the body's lungs induced by virus infection.

Preferably, the virus includes SARS-COV-2.

The invention also provides the application of the gold complex in the preparation of a medicine for treating novel coronavirus pneumonia.

Preferably, the gold complex includes auranofin, gold glucosinolate or gold nanoclusters.

Preferably, the chemical composition of the gold nanocluster is _{Aux Peptide y ;} the Peptide represents a peptide and/or protein molecule; the x represents the number of gold atoms, and the value of x ranges from 3 to 200; The y represents the number of peptide and/or protein molecules, and the value of y ranges from 2 to 220.

Preferably, the peptide and/or protein molecule contains free sulfhydryl groups.

Preferably, the gold nanoclusters include one or more of Au ₂₉ GS ₂₇ , Au ₂₈ GS ₁₆ , Au ₂₄ C ₈ , and Au ₂₅ H ₁ ; wherein, GS represents glutathione molecule, and H represents serum Protein molecule, C stands for artificially synthesized small peptide molecule whose amino acid sequence is CCY.

Preferably, the dosage form of the medicament includes injection, respiratory nebulizer or transdermal agent.

Preferably, the content of the gold complex in the medicine is 1-20 mg/ml.

The invention provides the application of the gold complex in the preparation of a medicine for treating novel coronavirus pneumonia. When the gold complex collides with the main hydrolytic protease (Mpro) of the SARS-CoV-2 viral protein in solution or body fluid, the gold complex releases monovalent gold ions, which specifically bind to SARS-CoV-2 The amino acids of Cys145 and Cys156 of the Mpro protein of the virus lock the active pocket of Mpro and effectively inhibit the catalytic activity of the Mpro protein. The functional poly-protein of the COVID-19 virus is mainly released after being hydrolyzed by the main protease (Mpro), which plays an important role in the virus life cycle. The inhibition of the catalytic activity of Mpro can effectively reduce the activity of the COVID-19 virus. In addition, the gold complexes were able to inhibit the replication of live SARS-CoV-2 virus in living cells. Gold complexes can significantly inhibit the activation of NFkB inflammatory molecular pathway in macrophages and lung bronchial cells, thereby reducing the expression and secretion of inflammatory factors IL-6, IL-1β and TNF-α. The results of the examples of the present invention show that the gold complexes can inhibit the virus replication in the lung tissue and inhibit the inflammatory damage of the animal lung tissue in the COVID-19 model animals. Gold complexes can not only inhibit the replication of SARS-CoV-2 in cells and animals, but also directly inhibit the damage to living lung tissue caused by the immune inflammatory storm caused by the above-mentioned viral infections.

Description of drawings

Figure 1 is the Mpro homodimer in the Au-S binding state in Example 1, and chain A and chain B are shown in green and purple, respectively;

Figure 2 shows the structural domains I-III of Mpro monomer in Example 1, and the structural domains I-III are shown in light blue, light pink and light cyan respectively; the Au(I)-S binding site region shows Au( Anomalous Fourier plots of I)2 and Au(I)1 (blue grid with 5 sigma outline); residues His41, Cys145 and Cys156 are represented by sticks, and the two Au(I) ions are represented by spheres;

Figure 3 is the comparison of the Au(I)-S binding state and the original structure of Mpro in Example 1; AF (Auranofin) treatment group (purple), GA (Au ₂₉ GS ₂₇ ) treatment group (yellow) and untreated Superposition of crystal structures of the treated Mpro group (blue); the catalytic pocket presented on the surface of native Mpro and Au(I)-bound Mpro and the surrounding amino acid residues represented by sticks;

Figure 4 is the result of DFT calculation of the interaction between Au1 ions and Mpro's Cys145 in Example 1; A shows the protein binding pocket composed of amino acids and Au1 ions, and B shows the geometry of the binding pocket encapsulating Au1 ions; C, N, O, S and Au atoms are shown in grey, blue, red, pink and yellow, respectively; all

Au-N atomic distance within (with

units) are marked with the corresponding distances obtained from the experimental crystal structures given in parentheses for comparison;

Figure 5 is the result of DFT calculation of the interaction between Au2 ions and Mpro's Cys156 in Example 1; wherein A shows the protein binding pocket composed of amino acids and Au2 ions, and B shows the geometry of the binding pocket encapsulating Au2 ions; C, N, O, S and Au atoms are shown in grey, blue, red, pink and yellow, respectively; all

Au-N atomic distance within (with

units) are marked with the corresponding distances obtained from the experimental crystal structures given in parentheses for comparison;

Figure 6 is the IC50 of the AF treatment group in Example 2, that is, the AF concentration required for the Mpro enzyme activity to be inhibited by 50%;

Figure 7 is the IC50 of the GA treatment group in Example 2, that is, the GA concentration required for 50% inhibition of Mpro enzyme activity;

Figure 8 is the EC50 of the AF treatment group in Example 3, that is, the AF concentration required for the replication of live virus to be inhibited by 50% of the enzymatic activity in living cells;

Figure 9 is the EC50 of the GA treatment group in Example 3, that is, the GA concentration required for the replication of the live virus to be inhibited by 50% of the enzymatic activity in living cells;

Figure 10 shows the inhibition of IL-6, IL-1β, TNF-α inflammatory cytokine expression and NFκB activation in macrophages with different concentrations of AF and GA in Example 4; A in Figure 10 is Visualization observation results, B in Figure 10 is the statistical result of GA at different concentrations, C in Figure 10 is the statistical result of AF at different concentrations; unpaired t-test, ***p<0.005, **p<0.01, *p<0.05 ;

Figure 11 shows the inhibitory effects of different concentrations of AF and GA on the expression of IL-6, IL-1β, TNF-α inflammatory cytokines and the inhibition of NFκB activation in airway epithelial cells in Example 4; A in Figure 11 In order to develop the observation results, B in Figure 11 is the statistical result of GA at different concentrations, and C in Figure 11 is the statistical result of AF at different concentrations; unpaired t-test, ***p<0.005, **p<0.01, *p< 0.05;

Figure 12 shows the administration time of the Mock (normal mice) group, the GA (gold cluster-treated virus-infected mice) group and the NS (physiological saline-treated virus-infected mice) group in Example 5;

Figure 13 is a body weight graph of GA or saline-treated infected mice in Example 5;

Figure 14 shows the number of replicating viral RNA copies in the lungs of mice on day 4 (24h after the last GA injection, unpaired t-test, ***p<0.001) in Example 5;

Figure 15 is the pathological score of hematoxylin-eosin (HE) staining of dissected mouse lungs in Example 5;

16 is a pathological picture of lung inflammation in SARS-CoV-2 infected mice in Example 5.

Detailed ways

The invention provides the application of gold complexes in the preparation of medicines for inhibiting the replication of SARS-COV-2 and/or inhibiting the activity of SARS-COV-2.

The invention provides the application of the gold complex in the preparation of a medicine for inhibiting the inflammatory damage of the body's lungs induced by virus infection. In the present invention, the virus preferably includes SARS-COV-2.

The invention provides the application of the gold complex in the preparation of a medicine for treating novel coronavirus pneumonia.

In the present invention, the gold complex preferably includes auranofin, gold glucosinolate or gold nanoclusters.

In the present invention, the chemical formula of auranofin is C ₂₀ H ₃₆ AuO ₉ PS; the auranofin comes from conventional commercial sources.

In the present invention, the chemical formula of the gold glucosinolate is C ₆ H ₁₁ AuO ₅ S; the gold glucosinolate is from conventional commercial sources.

In the present invention, the chemical composition of the gold nanocluster is _{Aux Peptide y ;} the Peptide represents a peptide and/or protein molecule, and the peptide and/or protein molecule preferably contains a free thiol group; the x represents gold The number of atoms; the y represents the number of peptides and/or protein molecules; the value of x ranges from 3 to 200; the value of y ranges from 2 to 220; the molecular formula represents a plurality of peptides and/or The gold cluster molecules complexed by protein molecules, each gold nano-cluster contains 3-200 gold atoms and 2-220 peptide and/or protein molecules. In the present invention, the gold nanoclusters preferably include one or more of Au ₂₉ GS ₂₇ , Au ₂₈ GS ₁₆ , Au ₂₄ C ₈ and Au ₂₅ H ₁ ; wherein, GS represents glutathione molecule , H stands for serum protein molecule, C stands for artificially synthesized small peptide molecule with amino acid sequence CCY. In the present invention, the Au ₂₉ GS ₂₇ , Au ₂₈ GS ₁₆ , Au ₂₄ C ₈ and Au ₂₅ H ₁ are derived from artificial synthesis, and the Au ₂₉ GS ₂₇ , Au ₂₈ GS ₁₆ , Au ₂₄ C ₈ and Au ₂₅ For the synthesis method of H1, see [ _F.Gao , Q.Yuan, P.Cai, L.Gao, L.Zhao, M.Liu, Y.Yao, Z.Chai, X.Gao, Au clusters treat rheumatoid arthritis with uniquely reversing cartilage/bone destruction, Adv. Sci. 6, 1801671 (2019)]. In the present invention, the dosage form of the medicament preferably includes injection, respiratory tract aerosol or transdermal agent; the content of the gold complex in the medicament is preferably 1-20 mg/ml, more preferably 5-10 mg/ml .

The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Auranofin (AF) in the examples of the present invention is derived from conventional commercial sources, and gold nanoclusters Au ₂₉ GS ₂₇ (GA) are derived from artificial synthesis. L. Gao, L. Zhao, M. Liu, Y. Yao, Z. Chai, X. Gao, Au clusters treat rheumatoid arthritis with uniquely reversing cartilage/bone destruction, Adv. Sci.6, 1801671 (2019)]. For the method of obtaining purified Mpro protein, see [Z. Jin, X. Du, Y. Xu, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors, Nature 582, 289–293 (2020).].

Example 1

The purified Mpro protein molecules were crystallized at 20-22 °C to form small crystal particles. These Mpro crystal particles were added with auranofin (AF) molecules or gold nanocluster (GA) molecules, respectively, at 20-22 °C. Incubate for 48h. These gold complexes release monovalent gold ions in solution to bind to protein molecules in Mpro crystals. The crystallographic synchrotron radiation combined with monovalent gold ions is subjected to crystal diffraction.

Three crystal states of SARS-COV-2 Mpro were determined: Mpro incubated with GA, Mpro incubated with AF, and Mpro incubated without gold complexes. The measurement results are shown in Figures 1 to 3.

The determination results showed that the molecular structures of Mpro incubated with AF and GA presented a highly similar structure, which was consistent with the reported crystal structure of Mpro. For details, see ([Z.Jin, X.Du, Y.Xu, et al. from SARS-CoV-2 and discovery of its inhibitors, Nature 582, 289–293 (2020)]).

Densities of two monovalent gold ions on the two cysteines Cys145 and Cys156. The positions of these two monovalent gold ions were confirmed by contrast Fourier mapping (see Figure 2). The two monovalent gold ions are defined as Au1 and Au2, respectively. It can be seen from Figure 2 that AF and GA provide monovalent gold ions, which are added to Cys145 and Cys156 of Mrpo through Michael addition reaction.

The overall Mpro-Au complex presented a dimer state (Fig. 1), and each monomer included 3 domains (Fig. 2). These structures are identical to the previously reported structures of SARS-COV-2 Mpro, see ([Z. Jin, X. Du, Y. Xu, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors, Nature 582, 289–293 (2020).]). Domains 1 and 2 of Mpro are composed of a β-barrel structure similar to that of chymotrypsin, both of which form an enzymatic center of a slit, while domain 3 is mainly composed of an alpha helix. Au1 interacts with the sulfhydryl group of Cys145 in the active center of the enzyme, and this genetically conserved cysteine residue is the core of Mpro catalysis (see Figure 2 and Figure 3). The binding site of Au2 is on Cys156 (see Figure 2), which is more superficial to Mpro.

By comparing the structures of blank Mpro and Au-bound Mpro, it was found that the binding of Au did not cause a change in protein conformation (Fig. 3). Au1 ions specifically bound to Cys145 and embedded in the active pocket, indicating that Au1 ions blocked the active pocket and inhibited its catalytic function (Fig. 3). The structural distance between S and Au1 ions of Cys145 is 2.3A, and from the distance, S and Au1 ions are covalently linked. The Au1 ion not only binds to Cys145, but this binding also changes the distance between Cys145 and His41 in the catalytic center from 3.7A to 3.9A (Fig. 3). Although each Mpro protein monomer contains 12 cysteine residues (Cys16, Cys22, Cys38, Cys44, Cys85, Cys117, Cys128, Cys145, Cys156, Cys160, Cys265, Cys300), only Cys145 and Cys156 are specific Incorporates monovalent gold ions.

The energy relationship between Au and Mpro was calculated by density functional theory model (DFT). Calculations show that the binding energy (EBD's) of Au1 ions to Cys145 is 46 kcal/mol (Fig. 4). The binding energies (EBD's) of Au2 ions to Cys156 were 26 kcal/mol (Fig. 5). It can be seen that the binding energy of Au1 ion and Cys145 and Au2 ion and Cys156 are higher in energy value, and the interaction is stronger, indicating that the monovalent gold ion locks the active pocket of Mpro, thereby effectively inhibiting Mpro's binding energy. catalytic activity.

Example 2

IC50, an indicator for detecting AF and GA inhibiting Mpro activity, see (【V.Grum-Tokars,K.Ratia,A.Begaye,S.C.Baker,A.D.Mesecar,Evaluating the 3C-like protease activity of SARS-Coronavirus:Recommendations for standardized assays for drug discovery, Virus Research 133, 63–73 (2008).]), the activity of Mpro was determined by fluorescence energy resonance brain transfer method, and artificially synthesized fluorescently labeled peptides (( EDNAS-Glu)-Ser-Ala-Thr-Leu-Gln-Ser-Gly-Leu-Ala-(Lys-DABCYL)-Ser) was used as a substrate for viral protein digestion.

The measurement results are as follows:

As shown in Figure 6, the IC50 of AF is approximately equal to 0.46 μM, and the IC50 of the existing drug Ebselen is 0.67 μM (see [Z. Jin, X. Du, Y. Xu, et al. H. Yang, Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors, Nature 582, 289–293 (2020)]), the IC50 value of AF is lower than that of Ebselen, which shows that AF can effectively inhibit the enzymatic activity of Mpro at the test-tube experimental level.

As shown in Figure 7, the IC50 of GA is about 3.3 μM, and GA can effectively inhibit the enzymatic activity of Mpro at the test tube level. Next, we tested whether GA could effectively inhibit the enzymatic activity of Mpro in cells.

The SARS-COV-2 Mpro plasmid with strep-tag was transiently transfected into HEK293 cells. After 24 h of Mpro gene expression, GA was added to the cell culture medium at a concentration of 500 μM, and the culture was continued for 24 h. Mpro protein was extracted and purified from cultured cells, and Mpro protease activity was measured. The assay results showed that the activity of SARS-Cov-2 Mpro in cells before GA treatment was 100%, and the activity of SARS-Cov-2 Mpro in cells treated with GA was suppressed, retaining about 60% of the activity .

Example 3

EC50, an indicator for detecting the ability of AF and GA to inhibit the replication of SARS-COV-2 virus on Vero cell model, see ([Z.Jin, X.Du, Y.Xu, Y.Deng, M.Liu, Y. Zhao,B.Zhang,X.Li,L.Zhang,C.Peng,Y.Duan,J.Yu,L.Wang,K.Yang,F.Liu,R.Jiang,X.Yang,T.You, X.Liu,X.Yang,F.Bai,H.Liu,X.Liu,L.W.Guddat,W.Xu,G.Xiao,C.Qin,Z.Shi,H.Jiang,Z.Rao,H.Yang , Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors, Nature 582, 289–293 (2020)]).

The measurement results are as follows:

As shown in Figure 8, the EC50 of AF was close to 0.83 μM, and as shown in Figure 9, the EC50 of GA was close to 7.32 μM. Both gold complexes can well inhibit virus replication in mammalian cells.

Example 4

RAW264.7 cells were cultured and incubated with different concentrations of GA and AF for 24 h, where the concentrations of GA were 0 μM, 0.3 μM, 0.6 μM, 1.2 μM, 10 μM, 20 μM, and 40 μM, respectively; the concentrations of AF were 0 μM, 0.3 μM, and 0.6 μM, respectively. μM and 1.2 μM. Then the cells were lysed, run on a gel (western blot), and the following protein contents were observed by antibody labeling and development, and the level of protein expression was analyzed by the gray value of the development (see [F.Gao, Q.Yuan, P.Cai, L. Gao, L. Zhao, M. Liu, Y. Yao, Z. Chai, X. Gao, Au clusters treat rheumatoid arthritis with uniquely reversing cartilage/bone destruction, Adv. Sci.6, 1801671 (2019)]).

As shown in Figure 10, AF at a low concentration of 0.6 μM could significantly inhibit the expression levels of IL-6, IL-1β, and TNF-α in macrophages. At a concentration of 20 μM, GA inhibited the expression levels of IL-6, IL-1β, and TNF-α in macrophages. The data in Figure 10 also show that AF and GA can effectively inhibit the phosphorylation level of IKK, thereby inhibiting the downstream phosphorylation of IkB and p65, thereby inhibiting the activation of NFkB. The COVID-19 virus-infected cell population is bronchial epithelial cells, which ultimately activate the expression of inflammatory factor genes through the NFkB pathway. These cytokines in turn activate macrophages, creating an inflammatory environment. We evaluated whether GA and AF could inhibit the NFkB pathway and thereby inhibit the expression of inflammatory factors in human bronchial epithelial cells. As shown in Figure 11, the phosphorylation of IKK, IkB, and p65 can be significantly inhibited at the concentration of 0.08 μM AF and 10 μM GA, thereby significantly inhibiting the expression of inflammatory factors IL-6, IL-1beta, and TNF-alpha. . Both AF and GA can suppress the NFκB pathway and thereby inhibit the expression of inflammatory cytokines in human bronchial epithelial cells.

Example 5

The 12 BALB/c mice were divided into three groups, namely the Mock group (normal mice), the GA group (based on BALB/c mice, and GA-treated mice with COVID-19 after constructing a COVID-19 model) and NS group (based on BALB/c mice, the mice were treated with saline after the COVID-19 model was constructed), the reference for the construction of the COVID-19 model (【J.Sun, Z.Zhuang, J.Zheng, K.Li ,RLWong,D.Liu,J.Huang,J.He,A.Zhu,J.Zhao,X.Li,Y.Xi,R.Chen,ANAlshukairi,Z.Chen,Z.Zhang,C.Chen,X .Huang,F.Li,X.Lai,D.Chen,L.Wen,J.Zhuo,Y.Zhang,Y.Wang,S.Huang,J.Dai,Y.Shi,K.Zheng,MR Leidinger,J . Chen, Y. Li, N. Zhong, DK Meyerholz, PBMcCray, Jr., S. Perlman, J. Zhao, Generation of a broadly useful model for COVID-19 pathogenesis, vaccination, and treatment, Cell 182, 734-743 (2020) .]): The mice were intranasally administered 50 μl of 2.5×10 ⁸ FFU of Ad5-hACE2 after anesthesia, and 5 days after transfection, 1 h before SARS-Cov-2 infection, the mice in the GA group were intraperitoneally injected with 15 mg/kg. The bw GA, NS groups were given normal saline. 50 μl of DMEM containing SARS-Cov-2 (1×10 ⁵ PFU) for nasal infection of mice. After being infected with the virus, the mice received a total of 3 treatments of GA or normal saline, and the administration time was shown in Figure 12 . All mice were sacrificed on the fourth day, and the mouse body weight, SARS-COV-2 RNA copy number in the lung, changes in the pathological damage of the lung and inflammatory factors were measured.

As shown in Figure 13, a mouse model infected with SARS-COV-2 exhibited decreased body weight, high viral RNA copies, severe bronchopneumonia and interstitial pneumonia, and lymphocytic infiltration of alveoli. The mice in the GA group lost less body weight than the NS group.

As shown in Figure 14, the RNA copy of the virus in the GA treatment group was 4 x log10 ⁴ , which was significantly less than 5 x log10 ⁵ in the NS group mice.

The pathological evaluation of the lung tissue is shown in Figure 15. The pathological score of the lung injury in the mice in the NS group was about 3, and the mice infected with SARS-CoV-2 showed severe lung inflammation. The pathological score of lung injury in COVID-19 mice treated with GA was about 1.8. Treatment with GA significantly eliminated lung inflammation in SARS-CoV-2-infected mice.

As shown in Figure 16, the alveolar septa, bronchi, bronchioles, and perivascular interstitium of mice infected with SARS-CoV-2 were significantly widened, with a large number of lymphocyte infiltration and a small amount of neutrophil infiltration. In addition, a small number of lymphocytes and sloughed epithelial cells were located in the local bronchiolar lumen. Local alveolar septa, bronchi, bronchioles, and perivascular interstitial widening were significantly reduced in GA-treated mice, the mucosal epithelium of bronchi and bronchioles was intact, and no foreign bodies were observed in the lumen. The results of GA treatment were similar to the lung pathological results of virus-uninfected mice.

Taken together, GA inhibited viral replication and also directly inhibited the expression of inflammatory cytokines, thereby protecting the lungs of infected mice from inflammatory damage.

The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made. It should be regarded as the protection scope of the present invention.

Claims (17)

1. Application of gold complexes in the preparation of medicines for inhibiting the replication of SARS-COV-2 and/or inhibiting the activity of SARS-COV-2.
2. Application of gold complexes in the preparation of medicines for inhibiting pulmonary inflammatory damage induced by virus infection.
3. The application according to claim 2, wherein the virus comprises SARS-COV-2.
4. Application of gold complexes in the preparation of medicines for the treatment of novel coronavirus pneumonia.
5. The application according to any one of claims 1 to 4, wherein the gold complex comprises auranofin, gold glucosinolate or gold nanoclusters.
6. The application according to claim 5, wherein the chemical composition of the gold nanocluster is _{Aux Peptide y ;} the Peptide represents a peptide and/or a protein molecule; the x represents the number of gold atoms, the The value of x ranges from 3 to 200; the y represents the number of peptide and/or protein molecules, and the value of y ranges from 2 to 220.
7. The use according to claim 6, wherein the peptide and/or protein molecule contains free sulfhydryl groups.
8. The application according to claim 6, wherein the gold nanoclusters comprise one or more of Au ₂₉ GS ₂₇ , Au ₂₈ GS ₁₆ , Au ₂₄ C ₈ and Au ₂₅ H ₁ ; wherein, GS represents the glutathione molecule, H represents the serum protein molecule, and C represents the artificially synthesized small peptide molecule with the amino acid sequence CCY.
9. The use according to any one of claims 1 to 4, characterized in that, the dosage form of the medicine comprises injection, respiratory nebulizer or transdermal agent.
10. The application according to claim 9, wherein the content of the gold complex in the medicine is 1-20 mg/ml.
11. A medicine for inhibiting the replication of SARS-COV-2 and/or inhibiting the activity of SARS-COV-2, the active ingredient of the medicine comprises a gold complex.
12. A medicament for inhibiting pulmonary inflammatory damage induced by virus infection, wherein the active components of the medicament include gold complexes.
13. A medicine for treating novel coronavirus pneumonia, the active ingredients of the medicine include gold complexes.
14. The medicine according to any one of claims 11 to 13, wherein the gold complex comprises auranofin, gold glucosinolate or gold nanoclusters.
15. The medicament according to any one of claims 11 to 13, characterized in that, the dosage form of the medicament includes injection, respiratory nebulizer or transdermal agent.
16. A method for treating novel coronavirus pneumonia, characterized in that the drug according to any one of claims 11 to 15 is used for administration by injection therapy.
17. The method of claim 16, wherein the injection treatment comprises intraperitoneal injection.

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