CN113289018A - Application of old medicine such as auranofin and composition thereof in resisting single positive strand RNA virus - Google Patents
Application of old medicine such as auranofin and composition thereof in resisting single positive strand RNA virus Download PDFInfo
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- CN113289018A CN113289018A CN202010109153.5A CN202010109153A CN113289018A CN 113289018 A CN113289018 A CN 113289018A CN 202010109153 A CN202010109153 A CN 202010109153A CN 113289018 A CN113289018 A CN 113289018A
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- 239000003814 drug Substances 0.000 title claims abstract description 72
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 title claims abstract description 30
- 229960005207 auranofin Drugs 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 title claims abstract description 28
- 241001493065 dsRNA viruses Species 0.000 title abstract description 13
- 241001678559 COVID-19 virus Species 0.000 claims abstract description 49
- 229940079593 drug Drugs 0.000 claims abstract description 47
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 206010035664 Pneumonia Diseases 0.000 claims abstract description 6
- 208000025721 COVID-19 Diseases 0.000 claims abstract description 5
- 206010057190 Respiratory tract infections Diseases 0.000 claims abstract description 5
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims abstract description 4
- 239000004480 active ingredient Substances 0.000 claims description 81
- 241000711573 Coronaviridae Species 0.000 claims description 59
- 239000004365 Protease Substances 0.000 claims description 53
- 108091005804 Peptidases Proteins 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 29
- 230000002401 inhibitory effect Effects 0.000 claims description 24
- 230000000694 effects Effects 0.000 claims description 23
- 239000000284 extract Substances 0.000 claims description 21
- 239000003112 inhibitor Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
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- ZGDLVKWIZHHWIR-UHFFFAOYSA-N 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(N2CCOCC2)N=C1 ZGDLVKWIZHHWIR-UHFFFAOYSA-N 0.000 claims description 8
- ZBFDAUIVDSSISP-UHFFFAOYSA-N 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-UHFFFAOYSA-N 0.000 claims description 8
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- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 claims description 8
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- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical compound C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-XLJNKUFUSA-N 0.000 claims description 4
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- CIKWKGFPFXJVGW-UHFFFAOYSA-N ethacridine Chemical compound C1=C(N)C=CC2=C(N)C3=CC(OCC)=CC=C3N=C21 CIKWKGFPFXJVGW-UHFFFAOYSA-N 0.000 claims description 4
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- 239000001074 1-methoxy-4-[(E)-prop-1-enyl]benzene Substances 0.000 claims description 2
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
The present invention relates to the application of 73 old medicines such as auranofin, etc. and the composition thereof in resisting single plus strand RNA virus. Specifically, the invention relates to application of a plurality of old medicines such as auranofin and pharmaceutical compositions thereof as 2019 novel coronavirus (SARS-CoV-2)3CL protease inhibitors in preparation of medicines for treating and/or preventing and relieving related diseases such as respiratory tract infection and pneumonia caused by 2019 novel coronavirus infection.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of a plurality of old medicines such as auranofin and the like and a composition thereof in resisting single positive strand RNA viruses.
Background
In acute infectious diseases, most of the infectious diseases are viral infectious diseases, the incidence rate of the viral infectious diseases is high, and the death rate is also high. Because the detection and diagnosis means are limited, the outbreak of new epidemic caused by new viruses often has the characteristics of outbreak, randomness, unpredictability and the like, once the outbreak occurs, if no effective prevention and control means exists, the outbreak is very easy to cause large-scale epidemic, and the health and life safety of people is seriously threatened.
Infection with the novel coronavirus (SARS-CoV-2) can cause severe pneumonia. The SARS-CoV-2 virus propagation path is not completely mastered, and is known to be capable of being propagated by droplets and contact, and there are human-borne and medical staff infections, certain community propagation risks, and the virus may have variation. There is currently no specific preventive or therapeutic approach for diseases caused by the novel coronavirus.
SARS-CoV-2 coronavirus belongs to the genus coronavirus of the family Coronaviridae, and is a single-stranded positive-sense RNA virus with an envelope. Similar to other known coronaviruses, SARS-CoV-2 coronaviruses also complete the proliferation of progeny viruses through several processes such as adsorption, penetration, uncoating, biosynthesis, assembly and release of progeny viruses. SARS-CoV-2 coronavirus infects host cell and starts from the binding of the spike glycoprotein on the surface of the virus envelope with the ACE2 receptor on the surface of the host cell, then the membrane fusion occurs, the virus enters the host cell, under the action of cell organelles such as cell lysosome, the single-chain positive sense RNA of the genetic material of the virus is released, under the action of protein synthesis elements such as mitochondria and ribosome of the host cell and necessary raw materials, the translation produces polyprotein, and then, the two major essential cysteine proteases of SARS-CoV-2 coronavirus: papain (PL)pro) And 3C-like protease (3C-like protease,3 CL)pro) Cleavage at specific sites processes the polyprotein precursors, producing a number of non-structural proteins that are important to the viral life cycle. Under the action of these nonstructural proteins, the viral RNA replicates the progeny viral nucleic acid material and translates into the desired structural proteins in large quantities, completing assembly and release of the progeny virus. Any link or key enzyme in the life cycle of SARS-CoV-2 coronavirus infected cell can be used as research target of antiviral medicine, such as cysteine protease PL for hydrolytic cleavage of polyprotein precursorproAnd 3CLproRNA polymerase responsible for completing replication of progeny viral genetic material, and the like.
3CL protease (3chymotrypsin-like prot)ease,3CLpro) Also known as the master protease (M)pro) The protein is a key protease in the process of hydrolyzing coronavirus RNA after translating into polyprotein pp1a and pp1ab to generate a plurality of non-structural proteins, is important for virus replication and infection, and can effectively inhibit the cutting of virus polyprotein precursors, block virus replication and inhibit the generation of progeny viruses by inhibiting the catalytic function of 3CL protease. 3CLproBelonging to the group of cysteine proteases, are highly conserved in sequence and structure in all coronaviruses, are also very similar to the 3C protease in picornaviruses, and there is no protease similar thereto in humans. Thus, 3CLproIs an ideal target point which is recognized at present for developing broad-spectrum single plus-strand RNA virus resistant medicaments.
At present, no specific vaccine or antiviral drug exists for severe pneumonia disease (COVID-19) caused by SARS-CoV-2 coronavirus. These infectious diseases seriously affect the life health of people, and the development of effective anti-virus drugs is imminent. Against SARS-CoV-2 coronavirus 3CLproDevelops low-toxicity and high-efficiency antiviral drugs to meet the clinical requirements of SARS-CoV-2 coronavirus infected patients at home and abroad, and has great social significance.
In view of the foregoing, there is an urgent need in the art to develop inhibitors against SARS-CoV-2 coronavirus 3CL protease for the treatment of pneumonia and other single positive strand RNA viral infections caused by novel coronavirus infections.
Disclosure of Invention
The invention aims to provide a drug molecule capable of effectively inhibiting coronavirus 3CL protease and a new application thereof in inhibiting single positive strand RNA virus infection.
Specifically, the invention provides the application of a plurality of old drugs such as auranofin and the like and compositions thereof in resisting single positive strand RNA virus infection, in particular to the application in resisting novel coronavirus diseases (COVID-19).
In a first aspect of the invention there is provided a use (or pharmaceutical use) of an active ingredient or a formulation containing said active ingredient, said active ingredient being selected from the group consisting of:
(Z1) is selected from any active ingredient (old drug) from a 1-a 73, or a pharmaceutically acceptable salt or extract thereof;
(A1) auranofin;
(A2) rabeprazole sodium;
(A3) heparin sodium;
(A4) disulfiram;
(A5) ilaprazole;
(A6) carrying out botisingwei;
(A7) tenatoprazole;
(A8) ethacridine;
(A9) ethacridine;
(A10) brobopol;
(A11) fondaparinux sodium;
(A12) sucralfate;
(A13) octenylidine;
(A14) hexachlorophene;
(A15) evans blue;
(A16) nordihydroguaiaretic acid;
(A17) thorium bromide;
(A18) tannic acid;
(A19) omeprazole;
(A20) benserazit (selazit);
(A21) felodipine;
(A22) rilpivirine;
(A23) a phenoxyaniline;
(A24) anthralin;
(A25) dimercaptosuccinic acid;
(A26) levothyroxine sodium;
(A27) cefaclor;
(A28) tirapazac;
(A29) quinine;
(A30)TIBSOVO;
(A31) liothyronine;
(A32) benzbromarone;
(A33) quinine;
(A34) a diiodoquinoline;
(A35) granisetron;
(A36) mianserin;
(A37) canagliflozin;
(A38) bedaquiline;
(A39) triclosan;
(A40) ziprasidone;
(A41) (ii) abacavir;
(A42) bedaquiline;
(A43) pentachlorsalamide;
(A44) cetylpyridinium chloride;
(A45) fenoldopam;
(A46) triiodothyronine;
(A47) anethol trithione;
(A48) dronedarone;
(A49) tazarotene;
(A50) 6-mercaptopurine;
(A51) malathion;
(A52) butoconazole;
(A53) pexidaltinib;
(A54) oxiranone bromide;
(A55) nitroxoline;
(A56) temoporfin;
(A57) caspofungin;
(A58) menadione;
(A59) diacerein;
(A60) (R) -lansoprazole;
(A61) embellic acid;
(A62) lomitapide;
(A63) tipranavir;
(A64) sofalcone;
(A65) zafirlukast;
(A66) lansoprazole;
(A67) raloxifene;
(A68) telaprevir;
(A69) riboflavin tetrabutyrate;
(A70) levothyroxine;
(A71) docusate sodium;
(A72) dronedarone;
(A73) econazole;
(Z2) any combination of the above active ingredients a1 to a 73;
wherein said active ingredient or a formulation containing said active ingredient is used in the preparation of (a) an inhibitor of coronavirus 3CL protease; and/or (b) a medicament for the treatment and/or prevention, amelioration of a disease associated with infection by a coronavirus (or single positive strand RNA virus).
In another preferred embodiment, the medicament further comprises one or more additional active ingredients selected from the group consisting of:
(Y1) a Chinese medicinal preparation for inhibiting virus or an active ingredient thereof;
(Y2) RNA replicase inhibitors (e.g., Remdesivir (redevir or GS-5734));
(Y3) Lopinavir (Lopinavir), Ritonavir (Ritonavir);
(Y4) Chloroquine (Chloroquine, Sigma-C6628), or a pharmaceutically acceptable salt thereof;
(Y5) hydroxychloroquine, or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the coronavirus 3CL protease is selected from the group consisting of: 2019 novel coronavirus (SARS-CoV-2)3CL protease, SARS virus 3CL protease, MERS virus 3CL protease, or a combination thereof.
In another preferred embodiment, the active ingredient is used to prepare (a)2019 a novel coronavirus (SARS-CoV-2)3CL protease inhibitor; and/or (b) a medicament for treating and/or preventing, relieving the related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.
In another preferred embodiment, the coronavirus is selected from the group consisting of: an alpha genus coronavirus, a beta genus coronavirus, or a combination thereof.
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.
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.
In another preferred example, the related disease caused by the 2019 novel coronavirus infection is selected from the group consisting of: respiratory infections, pneumonia and its complications, or combinations thereof.
In another preferred embodiment, the active ingredient is selected from the active compounds in table 1.
In another preferred embodiment, the active ingredient is selected from the group consisting of: is selected from any one of active ingredients A1-A18 (old drug), or pharmaceutically acceptable salt or extract thereof.
In another preferred embodiment, the active ingredient is selected from the group consisting of: auranofin, rabeprazole sodium, heparin sodium, disulfiram, ilaprazole, borciclovir, tenatoprazole, or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the active ingredient (or active compound) is artificially synthesized and/or extracted from plants.
In another preferred embodiment, the plant or herb comprises roots, stems, leaves, flowers, fruits, or a combination thereof.
In another preferred embodiment, the medicament further comprises an additional component selected from the group consisting of: anti-retroviral drugs or drugs for enhancing immunity.
In another preferred embodiment, the composition or medicament comprises: oral and non-oral formulations.
In another preferred embodiment, the formulation comprises: powder, granule, capsule, injection, tincture, oral liquid, tablet, buccal tablet, or dripping pill.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising:
(a) a first active ingredient selected from the group consisting of: any one of active ingredients (old drug) from A1 to A73, or a pharmaceutically acceptable salt or extract thereof; or a combination thereof;
and (b) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for inhibiting coronavirus 3CL protease.
In another preferred embodiment, the pharmaceutical composition does not contain other active ingredients (such as antiviral active ingredients) except the active ingredient (old drug) selected from any one of A1-A73, or pharmaceutically acceptable salt or extract thereof.
In another preferred embodiment, the pharmaceutical composition comprises:
(a1) a first active ingredient selected from any one of active ingredients A1-A73 (old drug), or pharmaceutically acceptable salt or extract thereof; or a combination thereof; and
(a2) a second active ingredient selected from the group consisting of: inhibitors of RNA replicase (e.g., Remdesivir (Rudexilvir or GS-5734)); lopinavir (Lopinavir), Ritonavir (Ritonavir); chloroquine (Chloroquine, Sigma-C6628), hydroxychloroquine, or a combination thereof;
and (b) a pharmaceutically acceptable carrier.
In another preferred embodiment, the dosage form of the drug is oral administration or non-oral administration.
In another preferred embodiment, the oral administration form is tablet, powder, granule or capsule, or emulsion or syrup.
In another preferred embodiment, the non-oral administration dosage form is injection or injection.
In a third aspect of the invention, there is provided the use of a pharmaceutical composition as described in the second aspect of the invention for the preparation of a medicament for the inhibition of (a) coronavirus 3CL protease; and/or (b) a medicament for treating and/or preventing, or alleviating a disease associated with coronavirus infection.
In another preferred example, the pharmaceutical composition is used for preparing a medicament for treating and/or preventing and relieving related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.
In another preferred example, the related disease caused by the 2019 novel coronavirus infection is selected from the group consisting of: respiratory infections, pneumonia and its complications, or combinations thereof.
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.
In a fourth aspect of the invention, there is provided a method of inhibiting coronavirus 3CL protease, comprising the steps of: contacting a first active ingredient or a formulation comprising said first active ingredient with a coronavirus 3CL protease, thereby inhibiting the activity of said 3CL protease;
wherein the first active ingredient is selected from the group consisting of:
(Z1) is selected from any active ingredient (old drug) from a 1-a 73, or a pharmaceutically acceptable salt or extract thereof;
(Z2) any combination of the above active ingredients A1 to A73.
In another preferred embodiment, the inhibition method is an in vitro method and is a non-therapeutic and non-diagnostic method.
In another preferred embodiment, the method of inhibition is an in vivo method and is a therapeutic method.
In another preferred embodiment, the method is non-therapeutic and non-diagnostic.
In another preferred embodiment, the method is in vitro.
In another preferred embodiment, the 3CL protease is a recombinant or coronavirus expressed 3CL protease.
In another preferred embodiment, the SARS-CoV-2 3CL protease is a recombinant or SARS-CoV-2 expressed 3CL protease.
In another preferred embodiment, the first active ingredient is selected from the group consisting of: any one of active ingredients A1-A18, or a pharmaceutically acceptable salt or extract thereof; or a combination thereof.
In another preferred embodiment, the first active ingredient is selected from the group consisting of: any one of active ingredients A1-A10, or a pharmaceutically acceptable salt or extract thereof; or a combination thereof.
In another preferred embodiment, the first active ingredient is selected from the group consisting of: auranofin, rabeprazole sodium, heparin sodium, disulfiram, ilaprazole, borrelivir, tenatoprazole, or a pharmaceutically acceptable salt thereof; or a combination thereof.
In a fifth aspect of the present invention, there is provided a method of treating, preventing, and/or ameliorating a disease associated with coronavirus infection, comprising the steps of: administering to a subject in need thereof a safe and effective amount of a first active ingredient or a formulation comprising a first active ingredient, wherein said first active ingredient is selected from the group consisting of:
(Z1) is selected from any active ingredient (old drug) from a 1-a 73, or a pharmaceutically acceptable salt or extract thereof;
(Z2) any combination of the above active ingredients A1 to A73.
In another preferred embodiment, the preparation is a non-traditional Chinese medicine preparation.
In another preferred example, the method further comprises: administering a safe and effective amount of a second active ingredient and optionally a third active ingredient to a subject in need thereof, wherein
The second active ingredient is selected from the group consisting of: inhibitors of RNA replicase (e.g., Remdesivir (Rudexilvir or GS-5734)); lopinavir (Lopinavir), Ritonavir (Ritonavir); chloroquine (Chloroquine, Sigma-C6628), hydroxychloroquine, or a combination thereof;
in another preferred embodiment, the subject is a mammal, preferably a primate, more preferably a human.
In another preferred embodiment, the first active ingredient is selected from the group consisting of: any one of active ingredients A1-A18, or a pharmaceutically acceptable salt or extract thereof; or a combination thereof.
In another preferred embodiment, the first active ingredient is selected from the group consisting of: any one of active ingredients A1-A10, or a pharmaceutically acceptable salt or extract thereof; or a combination thereof.
In another preferred embodiment, the first active ingredient is selected from the group consisting of: auranofin, rabeprazole sodium, heparin sodium, disulfiram, ilaprazole, borrelivir, tenatoprazole, or a pharmaceutically acceptable salt thereof; or a combination thereof.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the concentration-dependent inhibition of auranofin curve for 2019 novel coronavirus (SARS-CoV-2)3CL protease (SARS-CoV-2-3CLpro) enzyme activity.
FIG. 2 shows the curve of inhibition of SARS-CoV-2-3CLpro enzyme activity depending on the concentration of rabeprazole sodium.
FIG. 3 shows the curve of inhibition of SARS-CoV-2-3CLpro enzyme activity depending on the concentration of heparin sodium.
FIG. 4 shows a graph of the concentration-dependent inhibition of SARS-CoV-2-3CLpro enzyme activity by disulfiram.
FIG. 5 shows the curve of inhibition of SARS-CoV-2-3CLpro enzyme activity depending on the concentration of ilaprazole.
FIG. 6 shows the concentration-dependent inhibition of SARS-CoV-2-3CLpro enzyme activity by bosbevir.
FIG. 7 shows the concentration-dependent inhibition of SARS-CoV-2-3CLpro enzyme activity by tenatoprazole.
Detailed Description
The present inventors have conducted extensive and intensive studies and, as a result of screening 2000 drug molecules approved for the market, have unexpectedly developed, for the first time, a number of old drugs such as auranofin which effectively inhibit the activity of 3CL protease of a coronavirus such as 2019, a novel coronavirus (SARS-CoV-2). Experiments show that the active molecule (such as a plurality of old drugs such as auranofin and the like or pharmaceutically acceptable salts thereof) can effectively inhibit 2019 activity of 3CL protease of coronavirus such as SARS-CoV-2 and the like, thereby inhibiting the replication and the activity of the SARS-CoV-2 coronavirus. The present invention has been completed based on this finding.
Specifically, the invention discloses the application of a plurality of old drugs such as auranofin and the like and compositions thereof in resisting single positive strand RNA viruses, in particular to the application in resisting COVID-19 treatment. A plurality of old medicines such as auranofin and the like and compositions thereof have excellent inhibition effect on 3CL hydrolase which is indispensable for coronavirus replication and highly conserved, and have good clinical application prospect.
Term(s) for
As used herein, "active compound of the present invention", "active compound of the present invention which inhibits 3CL protease" are used interchangeably and refer to a compound having excellent 3CL protease inhibitory activity, particularly a known pharmaceutically active ingredient (old drug) such as auranofin or a combination thereof.
As used herein, "medicinal material of the present invention" refers to a Chinese medicinal material containing the active compound of the present invention.
As used herein, "extract of medicinal material of the present invention" or "extract of the present invention" refers to an extract obtained by extraction of a Chinese medicinal material or corresponding plant and containing one or more active compounds of the present invention.
As used herein, "a formulation of the invention" refers to a formulation containing an active compound of the invention, including both traditional Chinese medicine formulations and non-traditional Chinese medicine formulations.
As used herein, the term "comprising" or variations thereof, such as "comprises" or "comprising," etc., will be understood to imply the inclusion of stated elements or components but not the exclusion of any other elements or components.
Coronavirus and 3CL protease
Coronaviruses (CoV) belong to the family of the Nidovirales (Nidovirales) Coronaviridae (Coronaviridae), a enveloped positive-strand RNA virus, a subfamily of which contains four genera, alpha, beta, delta and gamma.
Among the coronaviruses currently known to infect humans, HCoV-229E and HCoV-NL63 belong to the genus alpha coronavirus, and HCoV-OC43, SARS-CoV, HCoV-HKU1, MERS-CoV and SARS-CoV-2 are all the genus beta coronavirus.
Highly pathogenic coronaviruses SARS-CoV and MERS-CoV, which outbreak in 2003 and 2012, respectively, both belong to the genus beta coronavirus. The novel coronavirus (SARS-CoV-2) which is outbreak in 2019 and has 80% similarity with SARS-CoV and 40% similarity with MERS-CoV, and also belongs to the beta genus coronavirus.
The genome of the virus is a single-strand positive-strand RNA, is one of RNA viruses with the largest genome, and codes comprise replicase, spike protein, envelope protein, nucleocapsid protein and the like. In the initial stage of viral replication, the genome is translated into two peptide chains of up to several thousand amino acids, the precursor Polyprotein (Polyprotein), which is subsequently cleaved by proteases to yield nonstructural proteins (e.g., RNA polymerase and helicase) and structural proteins (e.g., spike protein) and accessory proteins.
3CL protease (3Chymotrypsin-like protease,3CLpro) is the main protease responsible for cleavage of the precursor protein in coronaviruses (so also called Mpro) Is essential for virus replication.
The 3CLpro belongs to cysteine hydrolase, is highly conserved in various coronaviruses, is similar to 3C protease in small RNA viruses, and does not have the similar protease in human bodies, so the 3CLpro is an ideal target for developing broad-spectrum anti-single plus-strand RNA virus medicines.
Active Compounds and active ingredients of the invention
The present invention provides an active ingredient which is effective in inhibiting the replication of a novel coronavirus (SARS-CoV-2) of 2019. The active ingredient is selected from the group consisting of:
(Z1) is selected from any one of a 1-a 73, or a pharmaceutically acceptable salt or extract thereof;
(Z2) any combination of the above active ingredients A1 to A73 (including any combination of two or more of the above active ingredients Z1).
Experiments show that the active compound 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 relieving SARS-CoV-2 related diseases.
As used herein, "an active compound of the present invention", "an active compound of the present invention which inhibits 3CL protease" are used interchangeably and refer to a compound having excellent 3CL protease inhibitory activity, particularly any one of active ingredients a1 to a73 represented by auranofin, or a combination thereof.
It is to be understood that the active ingredients of the present invention include the active compounds of the present invention which inhibit the 3CL protease, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, or a prodrug thereof. It is to be understood that the active ingredients of the present invention also include crystalline, amorphous, deuterated, solvates, hydrates, and the like forms of the active compounds of the present invention.
The "pharmaceutically acceptable salts" are conventional non-toxic salts formed by reacting the active compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts can be prepared by reacting the active compounds of the present invention with inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid, and the like, or organic acids including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic 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, isethionic acid, and the like; or sodium, potassium, calcium, aluminum or ammonium salts of the active compounds of the invention which are esterified 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 with an inorganic base; or the methylamine, ethylamine or ethanolamine salt of an active compound of the invention with an organic base; or the corresponding inorganic acid salt formed by the active compound of the invention and lysine, arginine and ornithine and then hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, or the corresponding organic acid salt formed by the active compound of the invention and formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.
Furthermore, the active ingredients of the invention are particularly suitable for use in combination with other antiviral drugs. Representative other antiviral drugs include (but are not limited to): a reverse transcriptase inhibitor, a protease inhibitor, a co-receptor antagonist, a retroviral integrase inhibitor, a viral adsorption inhibitor, a specific viral transcription inhibitor, an antibody, or a combination thereof.
The active ingredient of the invention can inhibit the infection activity of novel coronavirus such as SARS-CoV-2. Therefore, when the active ingredient of the present invention is therapeutically administered or administered, 3CL protease activity can be inhibited, thereby inhibiting 2019 infection by a novel coronavirus (SARS-CoV-2), and further achieving antiviral effects.
Pharmaceutical composition and application
The invention also provides application of the active compound inhibiting the 3CL protease, or pharmaceutically acceptable salt, prodrug, extract or mixture of one or more of medicinal materials thereof as an active ingredient in preparing a medicament for treating and/or preventing and relieving relevant diseases such as respiratory tract infection, pneumonia and the like caused by 2019 novel coronavirus infection.
The pharmaceutical composition provided by the present invention preferably contains 0.001-99 wt% of active ingredient, preferably 0.1-90 wt% or 1-50 wt% of active compound of the present invention as active ingredient, the rest being pharmaceutically acceptable carrier, diluent or solution or salt solution.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier comprises diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical field.
The compounds and pharmaceutical compositions provided herein may be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the like, and may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterile vehicle for injection or instillation.
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 dose of the formulation generally comprises 0.05 to 400mg of active compound according to the invention, preferably 1 to 500mg of active compound according to the invention.
The compounds and pharmaceutical compositions of the present invention may be administered to mammals in clinical use, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably oral. Most preferably, the daily dose is 0.01-400mg/kg body weight, and is administered once or in portions of 0.01-200mg/kg body weight. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.
The drug or inhibitor of the present invention can be administered by a variety of different means, e.g., by injection, spray, nasal drop, eye drop, osmotic, absorption, physical or chemical mediated methods, into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue; or mixed with other materials or encapsulated and introduced into body.
The main advantages of the invention include:
(a) the active compound of the invention can effectively inhibit SARS-CoV-23 CL protease, and IC of partial active compound50Values below 5 μ M or lower are achieved.
(b) Due to the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, the active compounds of the invention are expected to inhibit 3CLpro of other coronaviruses and to exert broad-spectrum antiviral activity.
(c) The active compounds of the invention are all old medicines, have low toxic and side effects and good patent medicine property.
(d) The technical platform of the invention can quickly and effectively discover the inhibitor of coronavirus 3CL hydrolase, and the method discovers the inhibition effect of a plurality of old medicines such as auranofin and the like and the composition thereof on SARS-CoV-2 virus 3CL hydrolase.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures in the following examples, where specific conditions are not indicated, are generally carried out according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.
Analytical data for the samples were determined by the following instruments: the nuclear magnetic resonance is measured by GEMINI-300 type, Bruker AMX-400 type and INVOA-600 type nuclear magnetic resonance instruments, TMS (tetramethylsilane) is an internal standard, the unit of chemical shift is ppm, and the unit of coupling constant is Hz; mass spectra were determined on a Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometer and an IonSpec 4.7Tesla mass spectrometer.
Silica gel 200-300 mesh for column chromatography (produced by Qingdao ocean factory); the TLC silica gel plate is an HSGF-254 thin-layer chromatography prefabricated plate produced by a cigarette-table chemical plant; the boiling range of petroleum ether is 60-90 ℃; an ultraviolet lamp and an iodine cylinder are adopted for color development. Unless otherwise indicated, conventional reagents and drugs used in the following examples were purchased from the national institutes of medicine. Reagents and solvents used in the experiment are all processed according to the specific conditions of the reaction.
Example 1: establishment of SARS-CoV-2-3CLpro inhibitor discovery method
The inhibition activity of single compound and mixture on the activity of SARS-CoV-23 CLpro enzyme is evaluated and determined by fluorescence resonance energy transfer method. The volume of the whole enzymatic reaction system was 120. mu.L, the final concentration of protease was 30nM and the final concentration of substrate was 20. mu.M. The buffer of the reaction system included 50mM Tris pH7.3, 1mM EDTA. Adding SARS-CoV-23 CLpro protease and compounds or mixture with different concentrations into 96-well plate, incubating at 30 deg.C for 10min, adding substrate, and rapidly placing into microplate reader for reading. The excitation light and the emission light were 340nm and 405nm, respectively. The test time was 10min and the fluorescence was read every 30 s. The reading of the last 2min is taken to fit the reaction rate and compared with the control group (DMSO) to calculate the inhibition rate. IC was obtained by fitting with the software GraphPad Prism 850The value is obtained.
The method is simple, convenient and sensitive, and can screen SARS-CoV-2-3CLpro inhibitor (including monomer and mixture etc. various entity samples) in high flux. Furthermore, due to the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, the method is also applicable to the discovery of inhibitors of 3CLpro of other coronaviruses, such as SARS-nCoV-3 CLpro.
Example 2: determination of SARS-CoV-2-3CLpro inhibiting effect of auranofin and other old medicine
The 2000 old drugs tested in this example were obtained by purchase, confirming their structure and purity (> 90%). The compound is firstly dissolved in DMSO to prepare a mother solution, and the DMSO mother solution is diluted by adopting an enzyme activity test buffer solution to prepare compound samples with various concentrations.
Using the method for discovering SARS-CoV-2-3CLpro inhibitor established in example 1, the inhibitory effect of compounds (multiple old drugs such as auranofin) in 2000 old drug libraries on SARS-CoV-2-3CLpro was measured, and the inhibitory rate and IC of compounds on SARS-CoV-2-3CLpro were determined at different concentrations50As shown in table 1.
The results of the experiment are shown in table 1.
TABLE 1. auranofin et al multiple old drugs against 2019 novel coronavirus 3CL protease inhibitory activity
The results show that a plurality of old drugs (A1-A) such as auranofin73) Has very obvious inhibition effect on SARS-CoV-2-3CLpro (Table 1). A plurality of old drugs such as auranofin are SARS-CoV-2-3CLpro inhibitor and IC from newly discovered old drugs50To reach the single digit micromolar level, the IC of the compounds of auranofin, rabeprazole sodium, heparin sodium, disulfiram, ilaprazole, borescopic and tenatoprazole, etc. is optimized501.1. mu.M, 1.5. mu.M, 1.6. mu.M, 2.6. mu.M, 4.8. mu.M and 6.5. mu.M, respectively (FIGS. 1 to 7).
Due to the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, these newly discovered inhibitors are expected to inhibit other coronaviruses 3CLpro to exert broad spectrum antiviral activity.
Example 3: evaluation of novel coronavirus replication inhibitory Activity of Compound 2019
Determination of the replication-inhibiting activity of the active compounds (A1-A73) against the novel coronavirus (SARS-CoV-2) of 2019: cells were grown at a density of 5X 104Cells/well in 48-well cell culture dishes overnight, cells were pretreated with different concentrations of active compounds (multiple old drugs such as auranofin) for 1 hour, then infected with virus (multiplicity of infection MOI 0.05) for 2 hours, then the virus compound mixture was removed and the cells were further cultured with fresh medium containing the active compounds. At 48h p.i., cell supernatants were collected and lysed in lysis buffer, viral copy number in cell supernatants was quantitatively assessed by quantitative real-time RT-PCR (qRT-PCR), and EC of compounds inhibiting virus was calculated50。
The results show that the active compounds (a plurality of old drugs such as auranofin and the like) can effectively inhibit the replication of 2019 novel coronavirus, and have certain inhibition on different separated virus strains.
Discussion of the related Art
The sequence identity of SARS-CoV-23 CLpro and SARS-CoV 3CLpro is up to 96%, while the substrate binding pocket portion is more 100% conserved. After SARS-CoV outbreak in 2003, a plurality of inhibitors are designed and discovered aiming at SARS-CoV 3CLpro, and most of the inhibitors are peptide-like and polypeptide inhibitors with covalent action, and meanwhile, a small amount of heterocyclic esters, pyrazoles and large-ring non-covalent inhibitors are reported. This is achieved byThe biological activity of some known inhibitors is mainly measured by in vitro enzyme levels, and a small amount of inhibitor has a certain inhibitory Efficiency (EC) at the cellular level50On the order of micromoles at most).
The search for compounds with anti-SARS-CoV-2 activity from the old drugs that have been approved for marketing is currently the most rapid strategy to find for clinical treatment of COVID-19.
Prior to the present invention, the inhibitory effect of many old drugs such as auranofin on coronavirus 3CL hydrolase has not been reported.
In the invention, the inventor firstly discloses that a plurality of old drugs such as auranofin and the like have obvious inhibition effect on SARS-CoV-23 CLpro (Table 1), and a novel SARS-CoV-23 CLpro inhibitor, IC, which is a source of the old drugs50On the single digit micromolar scale. Due to the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, the SARS-CoV-23 CLpro inhibitor of the present invention is expected to inhibit 3CLpro of other coronaviruses to exert broad-spectrum antiviral activity.
Therefore, a plurality of old drugs such as auranofin provide important candidate drugs for the research and development of broad-spectrum single positive strand RNA virus resistant drugs, and have good clinical application prospects.
All documents referred to herein are incorporated by reference into this application as if each had been individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined in the appended claims.
Claims (10)
1. Use of an active ingredient or a formulation containing said active ingredient, wherein said active ingredient is selected from the group consisting of:
(Z1) any one of active ingredients (old drug) a 1-a 73, or a pharmaceutically acceptable salt or extract thereof;
(A1) auranofin;
(A2) rabeprazole sodium;
(A3) heparin sodium;
(A4) disulfiram;
(A5) ilaprazole;
(A6) carrying out botisingwei;
(A7) tenatoprazole;
(A8) ethacridine;
(A9) ethacridine;
(A10) brobopol;
(A11) fondaparinux sodium;
(A12) sucralfate;
(A13) octenylidine;
(A14) hexachlorophene;
(A15) evans blue;
(A16) nordihydroguaiaretic acid;
(A17) thorium bromide;
(A18) tannic acid;
(A19) omeprazole;
(A20) benserazit (selazit);
(A21) felodipine;
(A22) rilpivirine;
(A23) a phenoxyaniline;
(A24) anthralin;
(A25) dimercaptosuccinic acid;
(A26) levothyroxine sodium;
(A27) cefaclor;
(A28) tirapazac;
(A29) quinine;
(A30)TIBSOVO;
(A31) liothyronine;
(A32) benzbromarone;
(A33) quinine;
(A34) a diiodoquinoline;
(A35) granisetron;
(A36) mianserin;
(A37) canagliflozin;
(A38) bedaquiline;
(A39) triclosan;
(A40) ziprasidone;
(A41) (ii) abacavir;
(A42) bedaquiline;
(A43) pentachlorsalamide;
(A44) cetylpyridinium chloride;
(A45) fenoldopam;
(A46) triiodothyronine;
(A47) anethol trithione;
(A48) dronedarone;
(A49) tazarotene;
(A50) 6-mercaptopurine;
(A51) malathion;
(A52) butoconazole;
(A53) pexidaltinib;
(A54) oxiranone bromide;
(A55) nitroxoline;
(A56) temoporfin;
(A57) caspofungin;
(A58) menadione;
(A59) diacerein;
(A60) (R) -lansoprazole;
(A61) embellic acid;
(A62) lomitapide;
(A63) tipranavir;
(A64) sofalcone;
(A65) zafirlukast;
(A66) lansoprazole;
(A67) raloxifene;
(A68) telaprevir;
(A69) riboflavin tetrabutyrate;
(A70) levothyroxine;
(A71) docusate sodium;
(A72) dronedarone;
(A73) econazole;
(Z2) any combination of the above active ingredients a1 to a 73;
and said active ingredient or a formulation containing said active ingredient is used in the preparation of (a) an inhibitor of coronavirus 3CL protease; and/or (b) a medicament for the treatment and/or prevention, amelioration of a related disease caused by a coronavirus infection.
2. The use according to claim 1, wherein the coronavirus 3CL protease is selected from the group consisting of: 2019 novel coronavirus (SARS-CoV-2)3CL protease, SARS virus 3CL protease, MERS virus 3CL protease, or a combination thereof.
3. The use according to claim 1, wherein the active ingredient is used for the preparation of (a)2019 a novel coronavirus (SARS-CoV-2)3CL protease inhibitor; and/or (b) a medicament for treating and/or preventing, alleviating related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.
4. The use of claim 1, wherein the related disease caused by the 2019 novel coronavirus infection is selected from the group consisting of: respiratory infections, pneumonia and its complications, or combinations thereof.
5. The use according to claim 1, wherein the active ingredient is selected from the group consisting of: is selected from any one of A1-A18, or pharmaceutically acceptable salt or extract thereof.
6. Use according to claim 1, wherein the active ingredient is selected from the group consisting of: auranofin, rabeprazole sodium, heparin sodium, disulfiram, ilaprazole, borciclovir, tenatoprazole, or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition, comprising:
(a) a first active ingredient selected from any one of active ingredients A1-A73 (old drug), or pharmaceutically acceptable salt or extract thereof;
and (b) a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 7, wherein said pharmaceutical composition comprises:
(a1) a first active ingredient selected from the group consisting of: any one of active ingredients (old drug) from A1 to A73, or a pharmaceutically acceptable salt or extract thereof;
(a2) a second active ingredient selected from the group consisting of: inhibitors of RNA replicase (e.g., Remdesivir (Rudexilvir or GS-5734)); lopinavir (Lopinavir), Ritonavir (Ritonavir); chloroquine (Chloroquine, Sigma-C6628), hydroxychloroquine, or combinations thereof.
9. Use of a pharmaceutical composition according to claim 7 or 8 for the preparation of (a) an inhibitor of coronavirus 3CL protease; and/or (b) a medicament for the treatment and/or prevention, amelioration of a related disease caused by a coronavirus infection.
10. A method for non-therapeutic inhibition of coronavirus 3CL protease in vitro comprising the steps of: contacting a first active ingredient or a formulation comprising said first active ingredient with a coronavirus 3CL protease, thereby inhibiting the activity of said 3CL protease;
wherein the first active ingredient is selected from the group consisting of:
(Z1) any one of active ingredients (old drug) a 1-a 73, or a pharmaceutically acceptable salt or extract thereof;
(Z2) any combination of the above active ingredients A1 to A73.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114246854A (en) * | 2020-09-24 | 2022-03-29 | 中国科学院大连化学物理研究所 | Application of Succimer in preparation of anti-coronavirus infection medicine and medicine |
CN114432280A (en) * | 2020-11-05 | 2022-05-06 | 山东大学 | Application of Bronopol in preparation of anti-coronavirus infection medicine |
CN114452271A (en) * | 2022-01-29 | 2022-05-10 | 中国医学科学院药用植物研究所 | Application of diarylbutane compounds in preparation of drugs for inhibiting new coronavirus |
CN114796264A (en) * | 2021-01-27 | 2022-07-29 | 北京北工大科技园有限公司 | Application of gold complex in preparation of medicine for treating novel coronavirus pneumonia |
CN117003813A (en) * | 2021-04-16 | 2023-11-07 | 福建广生中霖生物科技有限公司 | Ring-modified proline short peptide compound and application thereof |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1628664A (en) * | 2004-08-27 | 2005-06-22 | 江苏正大天晴药业股份有限公司 | Pharmaceutical preparation of Tenatoprazole and preparation method thereof |
CN1878769A (en) * | 2003-09-11 | 2006-12-13 | 凯米亚公司 | Cytokine inhibitors |
CN101066245A (en) * | 2007-05-25 | 2007-11-07 | 朱芳海 | Orally taken emulsion and its prepn |
CN101212970A (en) * | 2005-06-02 | 2008-07-02 | 先灵公司 | Combination of HCV protease inhibitors with a surfactant |
CN101966161A (en) * | 2010-09-06 | 2011-02-09 | 海南美兰史克制药有限公司 | Rabeprazole sodium liposome enteric-coated tablets |
CN102525990A (en) * | 2010-12-23 | 2012-07-04 | 丽珠医药集团股份有限公司 | Ilaprazole enteric-coated tablets and preparation method thereof |
US20130039928A1 (en) * | 2010-01-28 | 2013-02-14 | The Johns Hopkins University | Compositions and methods for reversing corticosteroid resistance or treating respiratory infections |
CN103127511A (en) * | 2013-02-07 | 2013-06-05 | 中美华世通生物医药科技(武汉)有限公司 | Novel drug composition for curing hepatitis c virus |
CN103961311A (en) * | 2014-05-26 | 2014-08-06 | 成都市海通药业有限公司 | Heparin sodium injection and preparation method thereof |
CN104083763A (en) * | 2014-07-16 | 2014-10-08 | 中国人民解放军军事医学科学院野战输血研究所 | Application of histone deacetylase inhibitor in preparation of latent virus activator |
CN104146978A (en) * | 2013-05-13 | 2014-11-19 | 沈阳药科大学 | Disulfiram enteric coated tablet and preparation method thereof |
WO2018057618A1 (en) * | 2016-09-20 | 2018-03-29 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for identification, assessment, prevention, and treatment of aml using usp10 biomarkers and modulators |
-
2020
- 2020-02-21 CN CN202310415534.XA patent/CN116236580A/en active Pending
- 2020-02-21 CN CN202010109153.5A patent/CN113289018B/en active Active
- 2020-02-21 CN CN202310418461.XA patent/CN117427085A/en active Pending
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1878769A (en) * | 2003-09-11 | 2006-12-13 | 凯米亚公司 | Cytokine inhibitors |
CN1628664A (en) * | 2004-08-27 | 2005-06-22 | 江苏正大天晴药业股份有限公司 | Pharmaceutical preparation of Tenatoprazole and preparation method thereof |
CN101212970A (en) * | 2005-06-02 | 2008-07-02 | 先灵公司 | Combination of HCV protease inhibitors with a surfactant |
CN101066245A (en) * | 2007-05-25 | 2007-11-07 | 朱芳海 | Orally taken emulsion and its prepn |
US20130039928A1 (en) * | 2010-01-28 | 2013-02-14 | The Johns Hopkins University | Compositions and methods for reversing corticosteroid resistance or treating respiratory infections |
CN101966161A (en) * | 2010-09-06 | 2011-02-09 | 海南美兰史克制药有限公司 | Rabeprazole sodium liposome enteric-coated tablets |
CN102525990A (en) * | 2010-12-23 | 2012-07-04 | 丽珠医药集团股份有限公司 | Ilaprazole enteric-coated tablets and preparation method thereof |
CN103127511A (en) * | 2013-02-07 | 2013-06-05 | 中美华世通生物医药科技(武汉)有限公司 | Novel drug composition for curing hepatitis c virus |
CN104146978A (en) * | 2013-05-13 | 2014-11-19 | 沈阳药科大学 | Disulfiram enteric coated tablet and preparation method thereof |
CN103961311A (en) * | 2014-05-26 | 2014-08-06 | 成都市海通药业有限公司 | Heparin sodium injection and preparation method thereof |
CN104083763A (en) * | 2014-07-16 | 2014-10-08 | 中国人民解放军军事医学科学院野战输血研究所 | Application of histone deacetylase inhibitor in preparation of latent virus activator |
WO2018057618A1 (en) * | 2016-09-20 | 2018-03-29 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for identification, assessment, prevention, and treatment of aml using usp10 biomarkers and modulators |
Non-Patent Citations (10)
Title |
---|
ANTI-SARS AND ANTI-HCV DRUGS REPURPOSING AGAINST THE PAPAIN-LIKE: "Anti-SARS and anti-HCV drugs repurposing against the Papain-like protease of the newly emerged coronavirus (2019-nCoV)", 《SEMANTIC SCHOLAR》 * |
ANTI-SARS AND ANTI-HCV DRUGS REPURPOSING AGAINST THE PAPAIN-LIKE: "Anti-SARS and anti-HCV drugs repurposing against the Papain-like protease of the newly emerged coronavirus (2019-nCoV)", 《SEMANTIC SCHOLAR》, 11 February 2020 (2020-02-11), pages 8 * |
GUANGDI LI,等: "Therapeutic options for the 2019 novel coronavirus (2019-nCoV)", 《NATURE REVIEWS DRUG DISCOVERY》 * |
GUANGDI LI,等: "Therapeutic options for the 2019 novel coronavirus (2019-nCoV)", 《NATURE REVIEWS DRUG DISCOVERY》, 19 February 2020 (2020-02-19), pages 2 * |
SHANNON STONE,等: "The FDA-approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells", 《RESEARCHGATE》 * |
SHANNON STONE,等: "The FDA-approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells", 《RESEARCHGATE》, 8 February 2020 (2020-02-08), pages 3 * |
佚名: "药品说明书 金诺芬片", 《网页证据:HTTPS://JINGYAN.BAIDU.COM/ARTICLE/FA4125AC9A64A528AC7092DC.HTML》 * |
佚名: "药品说明书 金诺芬片", 《网页证据:HTTPS://JINGYAN.BAIDU.COM/ARTICLE/FA4125AC9A64A528AC7092DC.HTML》, 4 March 2013 (2013-03-04), pages 1 * |
学协会: "新型冠状病毒肺炎相关静脉血栓栓塞症防治建议(试行)", 《网址:HTTPS://JSP.365HEART.COM/DETAIL/988431A5-E169-40F8-961B-AF452E6993F7》 * |
学协会: "新型冠状病毒肺炎相关静脉血栓栓塞症防治建议(试行)", 《网址:HTTPS://JSP.365HEART.COM/DETAIL/988431A5-E169-40F8-961B-AF452E6993F7》, 16 February 2020 (2020-02-16), pages 4 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114246854A (en) * | 2020-09-24 | 2022-03-29 | 中国科学院大连化学物理研究所 | Application of Succimer in preparation of anti-coronavirus infection medicine and medicine |
CN114432280A (en) * | 2020-11-05 | 2022-05-06 | 山东大学 | Application of Bronopol in preparation of anti-coronavirus infection medicine |
CN114796264A (en) * | 2021-01-27 | 2022-07-29 | 北京北工大科技园有限公司 | Application of gold complex in preparation of medicine for treating novel coronavirus pneumonia |
CN117003813A (en) * | 2021-04-16 | 2023-11-07 | 福建广生中霖生物科技有限公司 | Ring-modified proline short peptide compound and application thereof |
CN117003813B (en) * | 2021-04-16 | 2024-03-08 | 福建广生中霖生物科技有限公司 | Ring-modified proline short peptide compound and application thereof |
CN114452271A (en) * | 2022-01-29 | 2022-05-10 | 中国医学科学院药用植物研究所 | Application of diarylbutane compounds in preparation of drugs for inhibiting new coronavirus |
CN114452271B (en) * | 2022-01-29 | 2023-03-14 | 中国医学科学院药用植物研究所 | Application of diarylbutane compounds in preparation of drugs for inhibiting new coronavirus |
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