Application of tea extract and its composition in anti-coronavirus

Abstract

The present invention relates to the use of tea extracts and compositions thereof in anti-coronavirus. Specifically, the present invention relates to the use of tea extract epigallocatechin gallate and other compounds and compositions thereof as 2019 novel coronavirus (SARS-CoV-2) 3CL protease inhibitors in the preparation of drugs for treating and / or preventing and alleviating respiratory infections, pneumonia and other related diseases caused by 2019 novel coronavirus infection.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to application of tea extract and a composition thereof in resisting coronavirus. Background Art

[0002] Among acute infectious diseases, the vast majority are viral infectious diseases, which have high morbidity and mortality rates. Due to limited detection and diagnosis methods, new outbreaks caused by new viruses are often sudden, random, and unpredictable. Once an outbreak occurs, if there is no effective prevention and control method, it is very easy to cause a large-scale epidemic, seriously threatening people's health and life safety.

[0003] The transmission route of SARS-CoV-2 is not fully understood. It is known that it can be transmitted through droplets and contact, and there is a risk of human-to-human transmission, medical staff infection, and certain community transmission. The virus may mutate. There is currently no specific prevention or treatment for diseases caused by the new coronavirus.

[0004] SARS-CoV-2 coronavirus belongs to the genus Coronavirus of the family Coronavirus. It is a single-stranded positive-sense RNA virus with an envelope. Similar to other known coronaviruses, SARS-CoV-2 coronavirus also completes the proliferation of progeny viruses through several processes such as adsorption, penetration, uncoating, biosynthesis, assembly and release of progeny viruses. SARS-CoV-2 coronavirus infection of host cells begins with the binding of the spike glycoprotein on the surface of the virus envelope to the receptor on the surface of the host cell, followed by membrane fusion. The virus enters the host cell and releases the single-stranded positive-sense RNA, the genetic material of the virus, under the action of organelles such as the cell lysosome. Under the action of protein synthesis elements such as mitochondria and ribosomes of the host cell and necessary raw materials, it is translated into polyproteins. Afterwards, the two essential cysteine ​​proteases of SARS-CoV-2 coronavirus: papain-like protease (PL pro ) and 3C-like protease (3CL pro ) cuts and processes the polyprotein precursor at specific sites to produce multiple non-structural proteins that are very important for the virus life cycle. Under the action of these non-structural proteins, the viral RNA replicates the progeny viral nucleic acid material and translates the required structural proteins in large quantities to complete the assembly and release of the progeny virus. Any link or key enzyme in the life cycle of SARS-CoV-2 coronavirus infected cells can be used as a research target for antiviral drugs, such as the cysteine ​​protease PL that hydrolyzes and cuts the polyprotein precursor. pro and 3CL pro , RNA polymerase responsible for completing the replication of the genetic material of the progeny viruses, etc.

[0005] 3CL protease (3chymotrypsin-like protease, 3CL pro ), also known as the main protease (M pro ), is a key protease in the process of hydrolyzing multiple non-structural proteins after coronavirus RNA is translated into polyproteins pp1a and pp1ab, which is essential for viral replication and infection. Inhibiting the catalytic function of 3CL protease can effectively inhibit the cleavage of viral polyprotein precursors, block viral replication, and inhibit the generation of progeny viruses. 3CL pro It is a cysteine ​​protease and a key protease that catalyzes the hydrolysis of single-stranded RNA viral precursor proteins. It plays an important role in the replication activity of coronaviruses such as SARS-CoV-2. pro It is currently recognized as an ideal target for the development of anti-coronavirus drugs.

[0006] At present, there is no specific vaccine or antiviral drug for severe pneumonia caused by SARS-CoV-2 coronavirus. These infectious diseases have seriously affected people's lives and health, and the development of effective antiviral drugs is urgent. pro The development of low-toxic and highly effective antiviral drugs to meet the clinical needs of patients infected with SARS-CoV-2 coronavirus at home and abroad is of great social significance.

[0007] In summary, there is an urgent need in the art to develop inhibitors against SARS-CoV-2 coronavirus 3CL protease for the treatment of pneumonia caused by novel coronavirus infection. Summary of the invention

[0008] The purpose of the present invention is to provide an active ingredient that can effectively inhibit coronavirus 3CL protease and a new use thereof in inhibiting coronavirus.

[0009] Specifically, the present invention provides the use of main components of tea leaves and compositions thereof in combating coronaviruses, especially the new coronavirus (SARS-CoV-2).

[0010] In a first aspect of the present invention, there is provided a use (or pharmaceutical use) of an active ingredient or a preparation containing the active ingredient, wherein the active ingredient is selected from the group consisting of:

[0011] (Z1) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0012] (Z2) theaflavin-3′-gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0013] (Z3) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0014] (Z4) theaflavin-3-gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0015] (Z5) theaflavins, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0016] (Z6) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0017] (Z7) 2-gallocatechin-3-ol, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0018] (Z8) epigallocatechin-3-glucopyranoside, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0019] (Z9) epicatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0020] (Z10) epicatechin, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0021] (Z11) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0022] (Z12) catechin, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0023] (Z13) theaflavin-3,3′-digallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0024] (Z14) tea leaves or tea extracts;

[0025] (Z15) any combination of the above active ingredients Z1 to Z14;

[0026] Wherein, the active ingredient or the preparation containing the active ingredient is used to prepare (a) an inhibitor of coronavirus 3CL protease; and / or (b) a drug for treating and / or preventing and alleviating related diseases caused by coronavirus infection.

[0027] In another preferred embodiment, the drug further contains one or more additional active ingredients selected from the following group:

[0028] (Y1) RNA replicase inhibitors (such as Remdesivir or GS-5734);

[0029] (Y2) Lopinavir, Ritonavir;

[0030] (Y3) Chloroquine (Sigma-C6628) or a pharmaceutically acceptable salt thereof, hydroxychloroquine, or a pharmaceutically acceptable salt thereof;

[0031] (Y4) baicalein, baicalin, forsythiaside (such as forsythiaside A, forsythiaside B), forsythiaside, or a combination thereof.

[0032] In another preferred embodiment, the coronavirus 3CL protease is selected from the following group: 2019 novel coronavirus (SARS-CoV-2) 3CL protease, SARS virus 3CL protease, MERS virus 3CL protease, or a combination thereof.

[0033] In another preferred embodiment, the active ingredient is used to prepare (a) a 2019 novel coronavirus (SARS-CoV-2) 3CL protease inhibitor; and / or (b) a drug for treating and / or preventing and alleviating related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.

[0034] In another preferred embodiment, the coronavirus is selected from the following group: alpha coronavirus, beta coronavirus, or a combination thereof.

[0035] In another preferred embodiment, the coronavirus is selected from the group consisting of HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HCoV-HKU1, MERS-CoV, SARS-CoV-2, or a combination thereof.

[0036] In another preferred embodiment, the coronavirus is selected from the group consisting of 2019 novel coronavirus (SARS-CoV-2), SARS virus, MERS virus, or a combination thereof.

[0037] In another preferred embodiment, the related diseases caused by 2019 novel coronavirus infection are selected from the following group: respiratory tract infection, pneumonia and its complications, or a combination thereof.

[0038] In another preferred embodiment, the active ingredient is selected from the following group: epigallocatechin gallate or a pharmaceutically acceptable salt thereof; theaflavin-3′-gallate or a pharmaceutically acceptable salt thereof; gallocatechin gallate or a pharmaceutically acceptable salt thereof; theaflavin-3-gallate or a pharmaceutically acceptable salt thereof; theaflavin or a pharmaceutically acceptable salt thereof; gallocatechin or a pharmaceutically acceptable salt thereof; dextrogallocatechin or a pharmaceutically acceptable salt thereof; epigallocatechin or a pharmaceutically acceptable salt thereof; epicatechin gallate or a pharmaceutically acceptable salt thereof; epicatechin or a pharmaceutically acceptable salt thereof; catechin gallate or a pharmaceutically acceptable salt thereof; catechin or a pharmaceutically acceptable salt thereof; theaflavin-3,3′-digallate or a pharmaceutically acceptable salt thereof; or a combination thereof.

[0039] In another preferred embodiment, the active ingredient is selected from the following group: epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; theaflavin-3′-gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; theaflavin-3-gallate or a pharmaceutically acceptable salt or an extract thereof; theaflavin or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin-3′-gallate or a pharmaceutically acceptable salt or an extract thereof; theaflavin or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin-3′-gallate ...

[0040] In another preferred embodiment, the active ingredient is selected from the following group: epigallocatechin gallate, theaflavin-3'-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, and epigallocatechin.

[0041] In another preferred embodiment, the active ingredient (or active compound) (any one of Z1 to Z13 or a combination thereof) is artificially synthesized and / or extracted from plants.

[0042] In another preferred embodiment, the plant is a tea tree, preferably leaves of a tea tree, or tea leaves prepared from leaves of a tea tree (preferably green tea, white tea, black tea, or oolong tea, more preferably green tea).

[0043] In another preferred embodiment, the plant or medicinal material includes roots, stems, leaves, flowers, fruits, or a combination thereof.

[0044] In another preferred embodiment, the plant or medicinal material includes leaves, flowers, fruits, or a combination thereof of tea plants.

[0045] In another preferred embodiment, the drug further comprises an additional component selected from the following group: an antiretroviral drug or an immunity enhancing drug.

[0046] In another preferred embodiment, the composition or medicine includes: an oral preparation and a parenteral preparation.

[0047] In another preferred embodiment, the preparation includes: powder, granules, capsules, injections, tinctures, oral liquids, tablets, lozenges, or pills.

[0048] In another preferred embodiment, the medicine is a traditional Chinese medicine preparation.

[0049] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0050] (a) a first active ingredient, wherein the first active ingredient is selected from the group consisting of epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; theaflavin-3′-gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epicatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epicatechin gallate or a pharmaceutically acceptable salt or an extract thereof; catechin gallate or a pharmaceutically acceptable salt or an extract thereof; catechin or a pharmaceutically acceptable salt or an extract thereof; theaflavin-3,3′-digallate or a pharmaceutically acceptable salt or an extract thereof; or a combination thereof;

[0051] and (b) a pharmaceutically acceptable carrier.

[0052] In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for inhibiting coronavirus 3CL protease.

[0053] In another preferred embodiment, the pharmaceutical composition does not contain other active ingredients (such as antiviral active ingredients) except epigallocatechin gallate or a pharmaceutically acceptable salt thereof, theaflavin-3′-gallate or a pharmaceutically acceptable salt thereof, gallocatechin gallate or a pharmaceutically acceptable salt thereof, theaflavin-3-gallate or a pharmaceutically acceptable salt thereof, theaflavin or a pharmaceutically acceptable salt thereof, gallocatechin or a pharmaceutically acceptable salt thereof, dextrogallocatechin or a pharmaceutically acceptable salt thereof, epigallocatechin or a pharmaceutically acceptable salt thereof, epicatechin gallate or a pharmaceutically acceptable salt thereof, epicatechin or a pharmaceutically acceptable salt thereof, catechin gallate or a pharmaceutically acceptable salt thereof, catechin or a pharmaceutically acceptable salt thereof and theaflavin-3,3′-digallate or a pharmaceutically acceptable salt thereof.

[0054] In another preferred embodiment, the pharmaceutical composition does not contain active ingredients and extracts from other medicinal materials (such as Forsythia suspensa and Honeysuckle).

[0055] In another preferred embodiment, the pharmaceutical composition contains:

[0056] (a1) a first active ingredient, wherein the first active ingredient is selected from the group consisting of epigallocatechin gallate or a pharmaceutically acceptable salt thereof or an extract thereof; theaflavin-3′-gallate or a pharmaceutically acceptable salt thereof or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt thereof or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt thereof or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt thereof or an extract thereof; epicatechin gallate or a pharmaceutically acceptable salt thereof or an extract thereof; catechin gallate or a pharmaceutically acceptable salt thereof or an extract thereof; catechin or a pharmaceutically acceptable salt thereof or an extract thereof; theaflavin-3-gallate or a pharmaceutically acceptable salt thereof or an extract thereof; theaflavin or a pharmaceutically acceptable salt thereof or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt thereof or an extract thereof; epicatechin or a pharmaceutically acceptable salt thereof or an extract thereof; catechin gallate or a pharmaceutically acceptable salt thereof or an extract thereof; catechin or a pharmaceutically acceptable salt thereof or an extract thereof; theaflavin-3,3′-digallate or a pharmaceutically acceptable salt thereof or an extract thereof; or a combination thereof;

[0057] (a2) a second active ingredient, wherein the second active ingredient is selected from the following group: RNA replicase inhibitors (such as Remdesivir or GS-5734); Lopinavir, Ritonavir; Chloroquine (Sigma-C6628), Hydroxychloroquine, or a combination thereof; and

[0058] (a3) an optional third active ingredient, wherein the third active ingredient is selected from the group consisting of baicalein, baicalin, forsythiaside, or a combination thereof;

[0059] and (b) a pharmaceutically acceptable carrier.

[0060] In another preferred embodiment, the dosage form of the drug is an oral or parenteral dosage form.

[0061] In another preferred embodiment, the oral dosage form is a tablet, powder, granule or capsule, or an emulsion or syrup.

[0062] In another preferred embodiment, the non-oral dosage form is an injection or injection.

[0063] In another preferred embodiment, the concentration of the first active ingredient (a single compound or the sum of multiple compounds) in the drug is 0.01-100 mg / ml, preferably 0.1-20 mg / ml (liquid dosage form).

[0064] In another preferred embodiment, the concentration of the first active ingredient (a single compound or the sum of multiple compounds) in the drug is 0.01-1000 mg / g, preferably 0.1-50 mg / g (solid dosage form).

[0065] In the third aspect of the present invention, the use of the pharmaceutical composition described in the second aspect of the present invention is provided, which is used to prepare (a) an inhibitor of coronavirus 3CL protease; and / or (b) a drug for treating and / or preventing and alleviating related diseases caused by coronavirus infection.

[0066] In another preferred embodiment, the pharmaceutical composition is used to prepare a drug for treating and / or preventing and alleviating related diseases caused by infection with the 2019 novel coronavirus (SARS-CoV-2).

[0067] In another preferred embodiment, the related diseases caused by 2019 novel coronavirus infection are selected from the following group: respiratory tract infection, pneumonia and its complications, or a combination thereof.

[0068] In another preferred embodiment, the coronavirus is selected from the group consisting of HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HCoV-HKU1, MERS-CoV, SARS-CoV-2, or a combination thereof.

[0069] In a fourth aspect of the present invention, a method for inhibiting coronavirus 3CL protease is provided, comprising the steps of: contacting a first active ingredient or a preparation containing the first active ingredient with a coronavirus 3CL protease, thereby inhibiting the activity of the 3CL protease;

[0070] Wherein, the first active ingredient is selected from the following group:

[0071] ((Z1) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0072] (Z2) theaflavin-3′-gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0073] (Z3) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0074] (Z4) theaflavin-3-gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0075] (Z5) theaflavins, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0076] (Z6) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0077] (Z7) 2-gallocatechin-3-ol, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0078] (Z8) epigallocatechin-3-glucopyranoside, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0079] (Z9) epicatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0080] (Z10) epicatechin, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0081] (Z11) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0082] (Z12) catechin, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0083] (Z13) theaflavin-3,3′-digallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0084] (Z14) tea leaves or tea extracts;

[0085] (Z15) any combination of the above active ingredients Z1 to Z14;

[0086] In another preferred embodiment, the inhibition method is an in vitro method and is a non-therapeutic and non-diagnostic method.

[0087] In another preferred embodiment, the inhibition method is an in vivo method and a therapeutic method.

[0088] In another preferred embodiment, the method is non-therapeutic and non-diagnostic.

[0089] In another preferred embodiment, the method is in vitro.

[0090] In another preferred embodiment, the 3CL protease is a recombinant or coronavirus-expressed 3CL protease.

[0091] In another preferred embodiment, the SARS-CoV-2 3CL protease is a recombinant or SARS-CoV-2 expressed 3CL protease.

[0092] In another preferred embodiment, the first active ingredient is selected from the following group: epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; theaflavin-3′-gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epicatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epicatechin or a pharmaceutically acceptable salt or an extract thereof; catechin gallate or a pharmaceutically acceptable salt or an extract thereof; catechin or a pharmaceutically acceptable salt or an extract thereof; theaflavin-3,3′-digallate or a pharmaceutically acceptable salt or an extract thereof; or a combination thereof.

[0093] In another preferred embodiment, the preparation containing the first active ingredient is a traditional Chinese medicine preparation, preferably a preparation containing tea extract. In another preferred embodiment, the tea extract is a water extract of tea (such as tea) or an aqueous extract.

[0094] In another preferred embodiment, the tea extract includes liquid or solid.

[0095] In a fifth aspect of the present invention, a method for treating, preventing, and / or alleviating related diseases caused by coronavirus infection is provided, comprising the steps of: administering a safe and effective amount of a first active ingredient or a preparation containing the first active ingredient to a subject in need thereof, wherein the first active ingredient is selected from the group consisting of:

[0096] (Z1) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0097] (Z2) theaflavin-3′-gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0098] (Z3) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0099] (Z4) theaflavin-3-gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0100] (Z5) theaflavins, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0101] (Z6) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0102] (Z7) 2-gallocatechin-3-ol, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0103] (Z8) epigallocatechin-3-glucopyranoside, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0104] (Z9) epicatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0105] (Z10) epicatechin, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0106] (Z11) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0107] (Z12) catechin, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0108] (Z13) theaflavin-3,3′-digallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0109] (Z14) tea leaves or tea extracts;

[0110] (Z15) any combination of the above active ingredients Z1 to Z14;

[0111] In another preferred embodiment, the preparation is a non-traditional Chinese medicine preparation.

[0112] In another preferred embodiment, the method further comprises: administering a safe and effective amount of a second active ingredient and an optional third active ingredient to a subject in need thereof, wherein

[0113] The second active ingredient is selected from the following group: RNA replicase inhibitors (such as Remdesivir or GS-5734); Lopinavir, Ritonavir; Chloroquine (Sigma-C6628), Hydroxychloroquine, or a combination thereof;

[0114] The third active ingredient is selected from the group consisting of baicalein, baicalin, forsythiaside A, forsythiaside B, forsythiaside, or a combination thereof.

[0115] In another preferred embodiment, the subject is a mammal, preferably a primate, and more preferably a human.

[0116] In another preferred embodiment, the first active ingredient is selected from the following group: epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; theaflavin-3′-gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epigallocatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epicatechin gallate or a pharmaceutically acceptable salt or an extract thereof; epicatechin or a pharmaceutically acceptable salt or an extract thereof; catechin gallate or a pharmaceutically acceptable salt or an extract thereof; catechin or a pharmaceutically acceptable salt or an extract thereof; theaflavin-3,3′-digallate or a pharmaceutically acceptable salt or an extract thereof; or a combination thereof.

[0117] In another preferred embodiment, the preparation containing the first active ingredient is a traditional Chinese medicine preparation, preferably a preparation containing tea extract. In another preferred embodiment, the tea extract is a water extract of tea (such as tea) or an aqueous extract.

[0118] In another preferred embodiment, the tea extract includes liquid or solid.

[0119] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0120] Figure 1 The curve showing the concentration-dependent inhibition of 2019 novel coronavirus (SARS-CoV-2) 3CL protease (SARS-CoV-2-3CLpro) activity by an active compound, epigallocatechin gallate.

[0121] Figure 2The curve showing the concentration-dependent inhibition of the activity of the 2019 novel coronavirus 3CL protease (SARS-CoV-2-3CLpro) by an active compound, theaflavin-3′-gallate.

[0122] Figure 3 The curve showing the inhibition of the 2019 novel coronavirus 3CL protease (SARS-CoV-2-3CLpro) enzyme activity of an active compound, epigallocatechin gallate.

[0123] Figure 4 The curve showing the inhibition of the activity of 2019 novel coronavirus 3CL protease (SARS-CoV-2-3CLpro) by an active compound, theaflavin-3-gallate

[0124] Figure 5 A curve showing the inhibition of the activity of the 2019 novel coronavirus 3CL protease (SARS-CoV-2-3CLpro) by an active compound, theaflavins

[0125] Figure 6 The curve showing the inhibition of the activity of an active compound, 2-gallocatechin gallate, on the 2019 novel coronavirus 3CL protease (SARS-CoV-2-3CLpro). DETAILED DESCRIPTION

[0126] After extensive and in-depth research, the inventors unexpectedly developed tea leaves and their active ingredients that can effectively inhibit the 3CL protease of coronaviruses such as the 2019 novel coronavirus (SARS-CoV-2) through a large number of screenings. Experiments show that the active ingredients of the present invention (such as epigallocatechin gallate, theaflavin-3′-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin, theaflavin-3,3′-digallate, etc. or their pharmaceutically acceptable salts) can effectively inhibit the activity of 3CL proteases of coronaviruses such as the 2019 novel coronavirus (SARS-CoV-2), thereby inhibiting the replication and activity of the SARS-CoV-2 coronavirus. The present invention was completed on this basis.

[0127] Specifically, the present invention discloses the use of multiple compounds such as epigallocatechin gallate (EGCG) of tea leaves and their compositions in anti-coronavirus, especially in anti-SARS-CoV-2 virus treatment. The main components of tea leaves and their compositions have excellent inhibitory effects on 3CL hydrolases that are essential for coronavirus replication and highly conserved, and have good clinical application prospects.

[0128] the term

[0129] As used herein, "active compound of the present invention" and "active compound for inhibiting 3CL protease of the present invention" are used interchangeably and refer to a compound having excellent 3CL protease inhibitory activity, especially a tea active ingredient selected from the following group: epigallocatechin gallate, theaflavin-3′-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin, theaflavin-3,3′-digallate, or a combination thereof.

[0130] As used herein, "the medicinal material of the present invention" refers to the Chinese medicinal material containing the active compound of the present invention, especially tea leaves.

[0131] As used herein, "the medicinal material extract of the present invention" or "the extract of the present invention" refers to an extract obtained by extracting Chinese medicinal materials or corresponding plants and containing one or more active compounds of the present invention, especially an extract extracted from tea leaves and containing the active compounds of the present invention. Preferably, the extract is an aqueous extract (referring to an extract extracted with water or an aqueous solvent).

[0132] As used herein, "tea extract" refers to an extract extracted from tea leaves, or an extract extracted from the root, stem, leaf or fruit of the tea plant, especially an extract containing the active compounds of the present invention (such as any one or more of Z1-Z13).

[0133] As used herein, "the preparation of the present invention" refers to a preparation containing the active compound of the present invention, including a traditional Chinese medicine preparation.

[0134] As used herein, the term “comprise” or variations thereof such as “include” or “comprising”, etc., will be understood as including the stated elements or components but not excluding other elements or components.

[0135] Coronavirus and 3CL protease

[0136] Coronavirus (CoV) belongs to the Coronaviridae family of the order Nidovirales. It is an enveloped positive-strand RNA virus, and its subfamily includes four genera: α, β, δ, and γ.

[0137] Among the currently known coronaviruses that infect humans, HCoV-229E and HCoV-NL63 belong to the alpha coronavirus family, while HCoV-OC43, SARS-CoV, HCoV-HKU1, MERS-CoV and SARS-CoV-2 are all beta coronaviruses.

[0138] The highly pathogenic coronaviruses SARS-CoV and MERS-CoV, which broke out in 2003 and 2012 respectively, are both beta coronaviruses. The new coronavirus (SARS-CoV-2) that broke out at the end of 2019 is about 80% similar to SARS-CoV and 40% similar to MERS-CoV, and is also a beta coronavirus. SARS-CoV-2 is also called 2019-nCov.

[0139] The genome of this type of virus is a single-stranded positive-strand RNA, which is one of the largest RNA viruses. It encodes replicase, spike protein, envelope protein, envelope protein and nucleocapsid protein, etc. In the initial stage of virus replication, the genome is translated into two peptide chains of several thousand amino acids, namely precursor polyproteins. Subsequently, the precursor proteins are cleaved by proteases to generate non-structural proteins (such as RNA polymerase and helicase) and structural proteins (such as spike protein) and auxiliary proteins.

[0140] 3CL protease (3Chymotrypsin-like protease, 3CLpro) is the main protease responsible for cleaving the precursor protein in coronavirus (so it is also called M pro ), which is indispensable for the replication of the virus.

[0141] 3CLpro is a cysteine ​​hydrolase that is highly conserved among various coronaviruses and is similar to the 3C protease in small RNA viruses. However, there is no similar protease in the human body. Therefore, it is an ideal target for the development of broad-spectrum anti-single positive-strand RNA virus drugs including coronaviruses.

[0142] Active compounds and active ingredients of the invention

[0143] In the present invention, an active ingredient is provided that can effectively inhibit the replication of coronaviruses such as the 2019 novel coronavirus (SARS-CoV-2). The active ingredient is selected from the following group:

[0144] (Z1) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0145] (Z2) theaflavin-3′-gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0146] (Z3) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0147] (Z4) theaflavin-3-gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0148] (Z5) theaflavins, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0149] (Z6) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0150] (Z7) 2-gallocatechin-3-ol, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0151] (Z8) epigallocatechin-3-glucopyranoside, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0152] (Z9) epicatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0153] (Z10) epicatechin, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0154] (Z11) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0155] (Z12) catechin, or a pharmaceutically acceptable salt thereof or an extract thereof;

[0156] (Z13) theaflavin-3,3′-digallate, or a pharmaceutically acceptable salt thereof, or an extract thereof;

[0157] (Z14) tea leaves or tea extracts;

[0158] (Z15) any combination of the above active ingredients Z1 to Z14;

[0159] In the present invention, the "tea extract" is an extract (or effective part) rich in epigallocatechin gallate, theaflavin-3'-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin and / or theaflavin-3,3'-digallate.

[0160] Experiments have shown that the active ingredients of the present invention can effectively inhibit the 3CL protease of the 2019 novel coronavirus (SARS-CoV-2), thereby inhibiting the replication of the 2019 novel coronavirus (SARS-CoV-2), and further preventing, treating and / or alleviating SARS-CoV-2 related diseases.

[0161] As used herein, "active compound of the present invention" and "active compound for inhibiting 3CL protease of the present invention" are used interchangeably and refer to compounds having excellent 3CL protease inhibitory activity, especially epigallocatechin gallate, theaflavin-3'-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin, theaflavin-3,3'-digallate, or a combination thereof.

[0162] It should be understood that the active ingredients of the present invention include the active compounds of the present invention that inhibit 3CL proteases, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, or prodrugs thereof. It should be understood that the active ingredients of the present invention also include crystalline forms, amorphous compounds, and deuterated compounds of the active compounds of the present invention.

[0163] The "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by the reaction of the active compound of the present invention with an inorganic acid or an organic acid. For example, conventional non-toxic salts can be prepared by the reaction of the active compound of the present invention with an inorganic acid or an organic acid, wherein the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, and the organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, Ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or the active compound of the present invention forms an ester with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid, and then forms a sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt with an inorganic base; or the active compound of the present invention forms a methylamine salt, ethylamine salt or ethanolamine salt with an organic base; or the active compound of the present invention forms an ester with lysine, arginine, or ornithine, and then forms an inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, or forms an organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.

[0164] In addition, the active ingredients of the present invention are particularly suitable for use in combination with other antiviral drugs. Representative other antiviral drugs include (but are not limited to): reverse transcriptase inhibitors, protease inhibitors, coreceptor antagonists, retroviral integrase inhibitors, viral adsorption inhibitors, specific viral transcription inhibitors, antibodies, or combinations thereof.

[0165] The active ingredients of the present invention can inhibit the infection activity of new coronaviruses such as SARS-CoV-2. Therefore, when the active ingredients of the present invention are applied or administered therapeutically, the activity of 3CL protease can be inhibited, thereby inhibiting the infection of the 2019 new coronavirus (SARS-CoV-2), thereby achieving an antiviral effect.

[0166] Pharmaceutical compositions and applications

[0167] The present invention also provides the use of the active compound for inhibiting 3CL protease of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or an extract thereof, or a mixture of one or more of its medicinal materials as an effective ingredient in the preparation of a drug for treating and / or preventing or alleviating respiratory tract infections, pneumonia and other related diseases caused by 2019 novel coronavirus infection.

[0168] The pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 0.001-99wt%, preferably a ratio of 0.1-90wt% or 1-50wt% of the total weight of the active compound of the present invention as an active ingredient, and the rest is a pharmaceutically acceptable carrier, diluent or solution or saline solution.

[0169] When necessary, one or more pharmaceutically acceptable carriers may be added to the drug of the present invention, including conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

[0170] The compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be present in suitable solid or liquid carriers or diluents and suitable sterile devices for injection or infusion.

[0171] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the preparation formula generally contains 0.05-400 mg of the active compound of the present invention, preferably, the unit dosage of the preparation formula contains 1-500 mg of the active compound of the present invention.

[0172] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered by oral, nasal, skin, lung or gastrointestinal tract administration. Oral administration is most preferred. The most preferred daily dose is 0.01-400 mg / kg body weight, taken at one time, or 0.01-200 mg / kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Usually, a small dose is started and the dose is gradually increased until the most suitable dose is found.

[0173] The drugs or inhibitors of the present invention can be administered in various ways, for example, by injection, spraying, nasal drops, eye drops, penetration, absorption, physical or chemical mediated methods such as introduction into the body, such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue; or mixed or encapsulated in other substances and introduced into the body.

[0174] The main advantages of the present invention include:

[0175] (a) The active compounds of the present invention can effectively inhibit SARS-CoV-2 3CL protease. The IC 50 The value reached about 0.285 μM.

[0176] (b) Due to the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, the active compounds of the present invention are expected to inhibit other coronavirus 3CLpro and exert broad-spectrum antiviral activity.

[0177] (c) The active compounds of the present invention have low toxicity and side effects and good drugability.

[0178] (d) The technical platform of the present invention can quickly and effectively discover inhibitors of coronavirus 3CL hydrolase, and the method was used to discover the inhibitory effect of tea extract and its composition on SARS-CoV-2 virus 3CL hydrolase.

[0179] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0180] The analytical data of the samples were measured by the following instruments: nuclear magnetic resonance was measured by GEMINI-300, Bruker AMX-400 and INVOA-600 nuclear magnetic resonance instruments, TMS (tetramethylsilane) was used as the internal standard, the chemical shift unit was ppm, and the coupling constant unit was Hz; mass spectrometry was measured by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.

[0181] Silica gel 200-300 mesh (produced by Qingdao Ocean Chemical Plant) was used for column chromatography; TLC silica gel plate was HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Plant; petroleum ether boiling range was 60-90°C; ultraviolet lamp and iodine cylinder were used for color development. Unless otherwise specified, conventional reagents and drugs used in the following examples were purchased from Sinopharm Group. The reagents and solvents used in the experiment were handled according to the specific conditions of the reaction.

[0182] Example 1: Establishment of a method for discovering SARS-CoV-2-3 CLpro inhibitors

[0183] The fluorescence resonance energy transfer method was used to evaluate the inhibitory activity of various samples such as compounds and mixtures on the 2019-nCoV3CLpro enzyme activity. The volume of the entire enzymatic reaction system was 120 μL, the final concentration of the protease was 30 nM, and the final concentration of the substrate was 20 μM. The buffer of the reaction system included 50 mM Tris pH 7.3 and 1 mM EDTA. SARS-CoV-2 3CLpro protease and samples such as compounds or mixtures of different concentrations were added to a 96-well plate, incubated at 30 ° C for 10 minutes, added the substrate and quickly placed in the microplate reader for reading. The excitation light and emission light were 340 nm and 405 nm, respectively. The test time was 10 minutes, and the fluorescence value was read every 30 seconds. The final result took the readings of the first 2 minutes to fit the reaction rate, and compared with the control group (DMSO), and the inhibition rate was calculated. The IC was fitted using the software GraphPad Prism 8 50 value.

[0184] This method is simple and sensitive, and can be used for high-throughput screening of SARS-CoV-2-3CLpro inhibitors (including various entity samples such as monomers and mixtures). In addition, due to the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, this method is also applicable to the discovery of inhibitors of other coronavirus 3CLpro such as SARS-nCoV-3CLpro.

[0185] Example 2: Determination of the inhibitory effect of tea extract on SARS-CoV-2-3CLpro

[0186] The SARS-CoV-2-3CLpro inhibitor discovery method established in Example 1 was used to test the inhibitory effect of tea extract (tea water) on SARS-CoV-2-3CLpro. The method is as follows: Weigh 1 g of various commercially available tea leaves, add 20 ml of pure water heated to boiling in a microwave oven, that is, the initial concentration of each tea water is 50 mg / ml. Leave at room temperature for 30 minutes. Aspirate the liquid, centrifuge at high speed at 12000 rpm, and dilute the test directly after 5 minutes. The inhibition rates of various tea extracts on SARS-CoV-2-3CLpro at different concentrations are shown in Table 1, among which most green tea extracts can effectively inhibit the activity of SARS-CoV-2-3CLpro.

[0187] Table 1. Inhibitory activity of tea on 2019 novel coronavirus 3CL protease

[0188]

[0189] Example 3: Determination of the inhibitory effect of tea extract monomers on SARS-CoV-2-3CLpro

[0190] The compounds tested in this example were isolated or purchased by conventional methods, and compared with reference products and tested by nuclear magnetic resonance spectroscopy to confirm their structure and purity (>90%). The compounds were first dissolved in DMSO to prepare a mother solution, and the DMSO mother solution was diluted with enzyme activity test buffer to prepare compound samples of various concentrations.

[0191] The SARS-CoV-2-3CLpro inhibitor discovery method established in Example 1 was used to determine the inhibitory effects of multiple compound monomers in tea extract (epigallocatechin gallate, theaflavin-3′-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin, theaflavin-3,3′-digallate) on SARS-CoV-2-3CLpro. The inhibition rates and IC values ​​of different concentrations of the compounds on SARS-CoV-2-3CLpro were determined. 50 As shown in Table 2 and Figures 1 to 6 shown.

[0192] The experimental results are shown in Table 2.

[0193] Table 2. Inhibitory activity of tea extract monomers on 2019-nCoV 3CL protease

[0194]

[0195]

[0196] The results showed that tea extracts and their monomer compounds have extremely significant inhibitory effects on SARS-CoV-2-3CLpro (Table 1 and Table 2). Among them, epigallocatechin gallate, theaflavin-3′-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin, and theaflavin-3,3′-digallate are all newly discovered SARS-CoV-2-3CLpro inhibitors from Chinese herbal medicine or plants, IC 50 Reaching nanomolar level, the best compound epigallocatechin gallate IC 50 Reach 0.285μM( Figure 1 ).

[0197] Due to the high conservation of 3CLpro and its substrate binding pocket among various coronaviruses, these newly discovered inhibitors are expected to inhibit other coronavirus 3CLpro and exert broad-spectrum antiviral activity.

[0198] Example 4: Evaluation of the 2019-nCoV replication inhibitory activity of active compounds

[0199] Determine the inhibitory activity of active compounds on the replication of each 2019 novel coronavirus (SARS-CoV-2): Vero E6 cells were cultured at a density of 5×10 4 Cells were cultured overnight in 48-well cell culture dishes at 10 cells / well. Cells were pre-treated with different concentrations of active compounds for 1 hour, and then virus (multiplicity of infection MOI of 0.05) was added to infect for 2 hours. The virus compound mixture was then removed and the cells were further cultured with fresh medium containing active compounds. At 48h pi, the cell supernatant was collected and lysed in lysis buffer, and the number of viral copies in the cell supernatant was quantitatively evaluated by quantitative real-time RT-PCR (qRT-PCR), and the EC of the compound to inhibit the virus was calculated. 50 In addition, the cytotoxicity of the active compounds to Vero E6 cells was determined by CCK8 assay (CCK8 50 ).

[0200] The results show that the active compounds of the present invention can effectively inhibit the replication of the 2019 novel coronavirus and have low cytotoxicity.

[0201] discuss

[0202] The sequence identity between SARS-CoV-2-3CLpro and SARS-CoV-3CLpro is as high as 96%, and the substrate binding pocket is 100% conserved. After the outbreak of SARS-CoV in 2003, several inhibitors were designed and discovered for SARS-CoV-3CLpro, most of which were covalent peptidomimetics and polypeptide inhibitors. At the same time, a small number of heterocyclic esters, pyrazoles and macrocyclic non-covalent inhibitors were reported. The biological activity of these known inhibitors is mainly detected at the in vitro enzyme level, and a small number of inhibitors have a certain inhibitory efficiency at the cellular level (EC 50 Mostly in micromole level).

[0203] Chinese herbal medicine is a treasure trove for new drug research and development. Tu Youyou, a professor at the China Academy of Chinese Medical Sciences, won the Nobel Prize for isolating artemisinin from Artemisia annua for the treatment of malaria, inspired by traditional Chinese medicine classics.

[0204] Prior to the present invention, the inhibitory effects of epigallocatechin gallate, theaflavin-3′-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin, and theaflavin-3,3′-digallate on coronavirus 3CL hydrolase have not been reported.

[0205] In the present invention, the inventors disclosed for the first time that the active ingredients of tea, epigallocatechin gallate, theaflavin-3′-gallate, gallocatechin gallate, theaflavin-3-gallate, theaflavin, gallocatechin, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin, and theaflavin-3,3′-digallate, have significant inhibitory effects on SARS-CoV-2-3CLpro (Table 1 and Table 2), and are new SARS-CoV-2-3CLpro inhibitors derived from Chinese herbal medicine, IC 50 It reaches the nanomolar level and effectively inhibits the viral replication of SARS-CoV-2 in cells. Due to the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, the SARS-CoV-2-3CLpro inhibitor of the present invention is expected to inhibit other coronavirus 3CLpro and exert a broad-spectrum antiviral activity.

[0206] Therefore, the active ingredients from tea leaves, such as epigallocatechin gallate, theaflavin-3′-gallate, epigallocatechin gallate, theaflavin-3-gallate, theaflavin, epigallocatechin gallate, dextrogallocatechin, epigallocatechin, epicatechin gallate, epicatechin, catechin gallate, catechin, theaflavin-3,3′-digallate, etc., provide important candidate compounds and candidate drugs for the development of broad-spectrum anti-coronavirus drugs and have good clinical application prospects.

[0207] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A use of an active ingredient, characterized in that: The active ingredient is selected from the following group: (Z1) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof; (Z2) 2-hydroxygallocatechin-3-ol, or a pharmaceutically acceptable salt thereof; (Z3) epigallocatechin-3-ol, or a pharmaceutically acceptable salt thereof; (Z4) any combination of the above active ingredients Z1 to Z3; And the active ingredients are used to prepare (a) 2019 novel coronavirus (SARS-CoV-2) 3CL protease inhibitors; and / or (b) drugs for treating and / or preventing and alleviating related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.

2. The use according to claim 1, characterized in that The related diseases caused by 2019 novel coronavirus infection are selected from the following groups: respiratory tract infection, pneumonia and its complications, or a combination thereof.

3. The use according to claim 1, characterized in that The drug further comprises an additional component selected from the following group: RNA replicase inhibitor; Lopinavir, Ritonavir; Chloroquine (Sigma-C6628), hydroxychloroquine, or a combination thereof.

4. A pharmaceutical composition for use in the preparation of (a) an inhibitor of 2019 novel coronavirus (SARS-CoV-2) 3CL protease; and / or (b) a drug for treating and / or preventing or alleviating related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection, characterized in that: The pharmaceutical composition contains: (a1) a first active ingredient, wherein the first active ingredient is selected from the group consisting of: epigallocatechin gallate or a pharmaceutically acceptable salt thereof; epigallocatechin gallate or a pharmaceutically acceptable salt thereof; (a2) a second active ingredient, wherein the second active ingredient is selected from the group consisting of: RNA replicase inhibitors; Lopinavir, Ritonavir; Chloroquine, Hydroxychloroquine, or a combination thereof; and (a3) an optional third active ingredient, wherein the third active ingredient is selected from the group consisting of baicalein, baicalin, forsythiaside, forsythiaside, or a combination thereof; and (b) a pharmaceutically acceptable carrier.

5. The use according to claim 4, characterized in that The RNA replicase inhibitor is Remdesivir.

6. The use according to claim 4, characterized in that The pharmaceutical composition is a pharmaceutical composition for inhibiting the 2019 novel coronavirus (SARS-CoV-2) 3CL protease.

7. The use according to claim 4, characterized in that The concentration of the first active ingredient in the drug is 0.01-100 mg / ml, and the pharmaceutical composition is in liquid dosage form, wherein the first active ingredient is a single compound or a sum of multiple compounds.

8. The use according to claim 7, characterized in that The concentration of the first active ingredient in the drug is 0.1-20 mg / ml.

9. The use according to claim 4, characterized in that The concentration of the first active ingredient in the drug is 0.01-1000 mg / g, and the pharmaceutical composition is a solid dosage form, wherein the first active ingredient is a single compound or a sum of multiple compounds.

10. The use according to claim 9, characterized in that The concentration of the first active ingredient in the drug is 0.1-50 mg / g.

11. A method for non-therapeutic in vitro inhibition of 2019 novel coronavirus (SARS-CoV-2) 3CL protease, characterized in that: The method comprises the steps of: contacting a first active ingredient or a preparation containing the first active ingredient with a 3CL protease of the 2019 novel coronavirus (SARS-CoV-2), thereby inhibiting the activity of the 3CL protease; Wherein, the first active ingredient is selected from the following group: (Z1) epigallocatechin gallate, or a pharmaceutically acceptable salt thereof; (Z2) 2-hydroxygallocatechin-3-ol, or a pharmaceutically acceptable salt thereof; (Z3) epigallocatechin-3-ol, or a pharmaceutically acceptable salt thereof; (Z4) Any combination of the above active ingredients Z1 to Z3.

12. The method according to claim 11, characterized in that The SARS-CoV-2 3CL protease is a recombinant 3CL protease or a SARS-CoV-2 expressed 3CL protease.

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