CN117427085A - Application of old medicines such as auranofin and the like and compositions thereof in resisting single positive strand RNA viruses - Google Patents
Application of old medicines such as auranofin and the like and compositions thereof in resisting single positive strand RNA viruses Download PDFInfo
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- CN117427085A CN117427085A CN202310418461.XA CN202310418461A CN117427085A CN 117427085 A CN117427085 A CN 117427085A CN 202310418461 A CN202310418461 A CN 202310418461A CN 117427085 A CN117427085 A CN 117427085A
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- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7024—Esters of saccharides
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to application of 73 old medicines such as auranofin and the like and a composition thereof in resisting single positive strand RNA viruses. In particular, the invention relates to application of a plurality of old medicines such as auranofin and the like and pharmaceutical compositions thereof as 2019 novel coronavirus (SARS-CoV-2) 3CL protease inhibitor in preparing medicines for treating and/or preventing and relieving respiratory tract infection, pneumonia and other related diseases caused by 2019 novel coronavirus infection.
Description
The present application is a divisional application of the invention patent application of the application date of 2020, 2 and 21, 202010109153.5, and the invention name of "application of old drugs such as auranofin and the like and compositions thereof in resisting single positive strand RNA viruses".
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 the acute infectious diseases, most of the infectious diseases are viral infectious diseases, and the incidence rate and the death rate of the viral infectious diseases are high. Because of limited detection and diagnosis means, new epidemic outbreaks caused by new viruses often have the characteristics of burstiness, randomness, unpredictability and the like, once the outbreaks are generated, if no effective prevention and treatment means exist, the outbreaks are very easy to cause large-scale epidemic, and the health and life safety of people are seriously threatened.
The SARS-CoV-2 virus transmission route is not completely known, and it is known that it can be transmitted by droplets and contact, and there is a risk of infection of people and medical staff, a certain community transmission risk, and a possibility of virus variation. There is currently no specific method of prevention or treatment for the disease 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 having an envelope. Similar to other known coronaviruses, SARS-CoV-2 coronavirus also completes the proliferation of progeny viruses through several processes of adsorption, penetration, uncoating, biosynthesis, assembly and release of progeny viruses, etc. SARS-CoV-2 coronavirus infection host cell spike glycoprotein starting from virus envelope surface is combined with host cell surface ACE2 receptor, then membrane fusion is carried out, virus enters host cell, under action of cell lysosome and other organelles, virus genetic is releasedThe single-stranded sense RNA is translated to produce polyprotein under the action of protein synthesis elements such as mitochondria and ribosomes of host cells and necessary raw materials, and then two major essential cysteine proteases of SARS-CoV-2 coronavirus: papain-like Protease (PL) pro ) And 3C-like protease (3C-like protease,3 CL) pro ) Cleavage of the multimeric protein precursor at a specific site produces a plurality of non-structural proteins that are important for the viral life cycle. Under the action of these non-structural proteins, the viral RNA replicates out the nucleic acid material of the progeny virus and numerous structural proteins are translated out to complete the assembly and release of the progeny virus. Any link or key enzyme of the life cycle of SARS-CoV-2 coronavirus infected cells can be used as a research target of antiviral drugs, such as cysteine protease PL which hydrolyzes and cleaves polyprotein precursors pro And 3CL pro RNA polymerase responsible for completing replication of progeny viral genetic material, and the like.
3CL protease (3 zymotyrpsin-like protease,3 CL) pro ) Also known as the main protease (M) pro ) Is a key protease in the process of hydrolyzing and producing a plurality of non-structural proteins after the coronavirus RNA is translated into the polyprotein pp1a and pp1ab, is critical to the replication and infection of viruses, and can effectively inhibit the cleavage of a virus polyprotein precursor, block the replication of viruses and inhibit the generation of progeny viruses by inhibiting the catalytic function of 3CL protease. 3CL pro The cysteine proteases are highly conserved in sequence and structure in all coronaviruses, are very similar to the 3C proteases in picornaviruses, and have no proteases similar thereto in humans. Thus, 3CL pro Is an ideal target for developing broad-spectrum anti-single positive strand RNA virus medicaments.
At present, there is no specific vaccine and antiviral drug for severe pneumonia disease (covd-19) caused by SARS-CoV-2 coronavirus. These infectious diseases seriously affect the life health of people, and the development of antiviral drugs with good effects is urgent. 3CL against SARS-CoV-2 coronavirus pro Develop low-toxicity high-efficiency antiviral drugs to meet the clinical demands of patients infected by SARS-CoV-2 coronavirus at home and abroad, and has heavy weightGreat social significance.
In view of the foregoing, there is a strong need in the art to develop inhibitors of 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 novel application thereof in inhibiting single positive strand RNA virus infection.
In particular, the present invention provides the use of several older agents such as auranofin and compositions thereof in combating single positive strand RNA viral infections, particularly novel coronavirus diseases (COVID-19).
In a first aspect of the invention there is provided the 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 one of active ingredients (old drugs) from A1 to A73, or pharmaceutically acceptable salts or extracts thereof;
(A1) Auranofin;
(A2) Sodium rabeprazole;
(A3) Heparin sodium;
(A4) Disulfiram;
(A5) Ilaprazole;
(A6) Boscalid;
(A7) Tenatoprazole;
(A8) Ethacridine;
(A9) Ethacridine;
(A10) Bromolol;
(A11) Fondaparinux sodium;
(A12) Sucralfate;
(A13) Octenedine;
(A14) Hexachlorophene;
(A15) Evan blue;
(A16) Nordihydroguaiaretic acid;
(A17) Thorium bromide;
(A18) Tannic acid;
(A19) Omeprazole;
(A20) Benzyl ziprasidac (selazimilide);
(A21) Felodipine;
(A22) Rilpivirine;
(A23) Phenoxyaniline;
(A24) Anthralin;
(A25) Dimercaptosuccinic acid;
(A26) Levothyroxine sodium;
(A27) Cefaclor;
(A28) Tela Qu Kao;
(A29) Quinine;
(A30)TIBSOVO;
(A31) Iodiplonine;
(A32) Benzbromarone;
(A33) Quinine;
(A34) Diiodoquinoline;
(A35) Granisetron;
(A36) Mianserin;
(A37) Canagliflozin;
(A38) Bedaquinoline;
(A39) Triclosan;
(A40) Ziprasidone;
(A41) Elbavir;
(A42) Bedaquinoline;
(A43) Pentachlorosalidine;
(A44) Cetyl pyridinium chloride;
(A45) Fenoldopam;
(A46) Triiodothyronine;
(A47) Anethol trithione;
(A48) Dronedarone;
(A49) Tazarotene;
(A50) 6-mercaptopurine;
(A51) Malathion;
(A52) Butoconazole;
(A53) Pexidasatinib;
(A54) Oxybutynin bromide;
(A55) Nitrooxyquinoline;
(A56) Temopofen;
(A57) Caspofungin;
(A58) Menadione;
(A59) Diacerein;
(A60) (R) -lansoprazole;
(A61) Enbei acid;
(A62) Lometapie;
(A63) Telanavir;
(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 active ingredients A1 to A73;
wherein the active ingredient or a formulation containing the active ingredient is used to prepare (a) an inhibitor that inhibits coronavirus 3CL protease; and/or (b) a medicament for treating and/or preventing, alleviating, or preventing a disease associated with a coronavirus (or single positive strand RNA virus) infection.
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 viruses or an active ingredient thereof;
(Y2) RNA replicase inhibitors (e.g., remdesivir 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 novel coronavirus (SARS-CoV-2) 3CL protease inhibitor; and/or (b) a medicament for treating and/or preventing and alleviating 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 combinations thereof.
In another preferred embodiment, the disease associated with 2019 novel coronavirus infection is selected from the group consisting of: respiratory tract infections, pneumonia, complications thereof, 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: any active ingredient (old medicine) selected from A1-A18, 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, bosupron, tenatoprazole, or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the active ingredient (or active compound) is synthesized and/or extracted from plants.
In another preferred embodiment, the plant or medicinal material 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: a retrovirus-resistant drug or an immunity-enhancing drug.
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 the active ingredients (old drugs) A1-A73, or pharmaceutically acceptable salts or extracts 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 any active ingredient (e.g., antiviral active ingredient) other than any active ingredient selected from A1 to a73 (old drug), or a 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 to a73 (old drugs), or pharmaceutically acceptable salts thereof or extracts thereof; or a combination thereof; and
(a2) A second active ingredient selected from the group consisting of: RNA replicase inhibitors (e.g., remdesivir 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 pharmaceutical dosage form is an oral or non-oral dosage form.
In another preferred embodiment, the oral administration form is a tablet, powder, granule or capsule, or an emulsion or syrup.
In another preferred embodiment, the non-oral administration form is an injection or an 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) an inhibitor of coronavirus 3CL protease; and/or (b) a medicament for treating and/or preventing and/or alleviating a disease associated with a coronavirus infection.
In another preferred embodiment, the pharmaceutical composition is used for preparing a medicament for treating and/or preventing and alleviating a related disease caused by 2019 novel coronavirus (SARS-CoV-2) infection.
In another preferred embodiment, the disease associated with 2019 novel coronavirus infection is selected from the group consisting of: respiratory tract infections, pneumonia, complications thereof, 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 3CL protease of a coronavirus, 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 one of active ingredients (old drugs) from A1 to A73, or pharmaceutically acceptable salts or extracts thereof;
(Z2) any combination of the above-mentioned 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 inhibition method 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 3CL protease of SARS-CoV-2 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 the active ingredients A1 to A18, or pharmaceutically acceptable salts or extracts thereof; or a combination thereof.
In another preferred embodiment, the first active ingredient is selected from the group consisting of: any one of the active ingredients A1 to A10, or pharmaceutically acceptable salts or extracts 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, bosupravid, tenatoprazole, or a pharmaceutically acceptable salt thereof; or a combination thereof.
In a fifth aspect of the invention, there is provided a method of treating, preventing, and/or alleviating a disease associated with a 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 the first active ingredient is selected from the group consisting of:
(Z1) is selected from any one of active ingredients (old drugs) from A1 to A73, or pharmaceutically acceptable salts or extracts thereof;
(Z2) any combination of the above-mentioned active ingredients A1 to A73.
In another preferred embodiment, the formulation is a non-traditional Chinese medicine formulation.
In another preferred embodiment, the method further comprises: administering to a subject in need thereof a safe and effective amount of a second active ingredient and optionally a third active ingredient, wherein
The second active ingredient is selected from the group consisting of: RNA replicase inhibitors (e.g., remdesivir 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 the active ingredients A1 to A18, or pharmaceutically acceptable salts or extracts thereof; or a combination thereof.
In another preferred embodiment, the first active ingredient is selected from the group consisting of: any one of the active ingredients A1 to A10, or pharmaceutically acceptable salts or extracts 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, bosupravid, tenatoprazole, or a pharmaceutically acceptable salt thereof; or a combination thereof.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 shows a graph of the concentration-dependent inhibition 2019 of the enzymatic activity of novel coronavirus (SARS-CoV-2) 3CL protease (SARS-CoV-2-3 CLpro) by auranofin.
FIG. 2 shows a curve of the inhibition of SARS-CoV-2-3CLpro enzyme activity in dependence of sodium rabeprazole concentration.
FIG. 3 shows a heparin sodium concentration dependent curve for inhibiting SARS-CoV-2-3CLpro enzyme activity.
FIG. 4 shows a graph of the inhibition of SARS-CoV-2-3CLpro enzyme activity in dependence of disulfiram concentration.
FIG. 5 shows a graph of the concentration-dependent inhibition of SARS-CoV-2-3CLpro enzyme activity by ilaprazole.
FIG. 6 shows a profile of the concentration-dependent inhibition of SARS-CoV-2-3CLpro enzyme activity of boscalid.
FIG. 7 shows a curve of the concentration-dependent inhibition of SARS-CoV-2-3CLpro enzyme activity by tenatoprazole.
Detailed Description
Through extensive and intensive studies, the present inventors have unexpectedly developed a number of old drugs such as auranofin which effectively inhibit the activity of 3CL protease of coronaviruses such as 2019 novel coronavirus (SARS-CoV-2) for the first time by screening 2000 drug molecules approved for marketing. Experiments show that the active molecules (such as a plurality of old drugs such as auranofin and the like or pharmaceutically acceptable salts thereof) can effectively inhibit the activity of 3CL protease of coronaviruses such as 2019 novel coronavirus (SARS-CoV-2) and the like, thereby inhibiting the replication and activity of the SARS-CoV-2 coronavirus. The present invention has been completed on the basis of this finding.
In particular, the invention discloses the use of several older agents such as auranofin and their compositions against single positive strand RNA viruses, especially in anti-COVID-19 therapy. The novel 3CL hydrolase has excellent inhibition effect on the 3CL hydrolase which is essential for the replication of coronaviruses and is highly conserved, and has good clinical application prospect.
Terminology
As used herein, "active compound of the present invention", "active compound of the present invention that inhibits 3CL protease" are used interchangeably to refer to compounds having excellent 3CL protease inhibitory activity, particularly known pharmaceutically active ingredients (old drugs) such as auranofin, or combinations thereof.
As used herein, "medicinal material of the present invention" refers to a traditional Chinese medicinal material containing an active compound of the present invention.
As used herein, "the medicinal extract of the present invention" or "the extract of the present invention" refers to an extract obtained by extraction of a Chinese medicinal material or a corresponding plant and containing one or more active compounds of the present invention.
As used herein, "formulations of the present invention" refers to formulations containing the active compounds of the present invention, including both traditional Chinese medicine formulations and non-traditional Chinese medicine formulations.
As used herein, the terms "comprises," "comprising," or variations thereof such as "comprises" or "comprising," etc., are to be construed as including the stated element or component without excluding other elements or other components.
Coronavirus and 3CL protease
Coronaviruses (CoV) belong to the family of Coronaviridae (coroneaviridae) of the order monoviridae (Nidovirales), which are enveloped positive-strand RNA viruses whose subfamilies comprise four genera α, β, δ and γ.
Among the currently known human-infected coronaviruses, 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 coronaviruses.
The highly pathogenic coronaviruses "SARS-CoV and" middle east respiratory syndrome "MERS-CoV, which have exploded in 2003 and 2012, respectively, are among the beta coronaviruses. The new coronavirus (SARS-CoV-2) from the late 2019 outbreak has about 80% similarity to SARS-CoV and 40% similarity to MERS-CoV, and is also a beta coronavirus.
The genome of the virus is a single-strand positive-strand RNA, is one of the RNA viruses with the largest genome, and codes for replicase, spike protein, envelope protein, nucleocapsid protein and the like. In the initial stages of viral replication, the genome is translated into two peptide chains of up to several thousand amino acids, the precursor polyproteins (polyproteins), which are then cleaved by proteases to produce nonstructural proteins (e.g., RNA polymerase and helicase) and structural proteins (e.g., spike proteins) and helper proteins.
The 3CL protease (3 Chymotypsin-like protease,3 CLpro) is the main protease responsible for cleavage of the precursor protein in coronaviruses (hence the name M) pro ) Is essential for replication of the virus.
3CLpro belongs to cysteine hydrolase, is highly conserved in various coronaviruses, is similar to 3C protease in picornaviruses, and does not have protease similar to the picornaviruses in human body, so that it is an ideal target for developing broad-spectrum anti-single positive strand RNA virus drugs.
The active compounds and active ingredients of the invention
In the present invention, an active ingredient capable of effectively inhibiting replication of coronaviruses such as 2019 novel coronavirus (SARS-CoV-2) is provided. The active ingredient is selected from the group consisting of:
(Z1) an active ingredient selected from any one of A1 to A73, or a pharmaceutically acceptable salt or extract thereof;
(Z2) any combination of the above-mentioned active ingredients A1 to A73 (including any combination of two or more of the above-mentioned active ingredients Z1).
Experiments show that the active compound can effectively inhibit 3CL protease of 2019 novel coronavirus (SARS-CoV-2), thereby inhibiting replication of 2019 novel coronavirus (SARS-CoV-2) and further preventing, treating and/or relieving SARS-CoV-2 related diseases.
As used herein, "active compound of the present invention", "active compound of the present invention that inhibits 3CL protease" are used interchangeably to refer to a compound having excellent 3CL protease inhibitory activity, in particular, any one of the active ingredients A1 to a73 typified 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 that inhibit 3CL protease, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, or prodrugs thereof. It is to be understood that the active ingredients of the present invention also include crystalline, amorphous, deuterated, solvated, hydrated forms of the active compounds of the present invention.
The "pharmaceutically acceptable salts" are those of the active compounds of the present invention which react with inorganic or organic acids to form conventional non-toxic salts. 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 with 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 the active compounds of the invention form esters 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 form sodium, potassium, calcium, aluminum or ammonium salts with inorganic bases; or the active compounds of the invention form methylamine salts, ethylamine salts or ethanolamine salts with organic bases; or the active compounds according to the invention form esters with lysine, arginine, ornithine and then with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid or with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.
In addition, the active ingredients of the invention are also 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 retrovirus integrase inhibitor, a virus adsorption inhibitor, a specific virus transcription inhibitor, an antibody, or a combination thereof.
The active ingredient of the present invention can inhibit the infection activity of novel coronaviruses such as SARS-CoV-2, etc. Thus, when the active ingredients of the present invention are administered or administered therapeutically, the 3CL protease activity can be inhibited, thereby inhibiting infection of 2019 novel coronavirus (SARS-CoV-2) and thus achieving antiviral effect.
Pharmaceutical composition and application
The invention also provides application of the active compound for inhibiting the 3CL protease, or pharmaceutically acceptable salt thereof, or prodrug thereof, or extract thereof, or a mixture of one or more of medicinal materials thereof as an active ingredient in preparing medicines for treating and/or preventing and relieving related diseases such as respiratory tract infection, pneumonia and the like caused by 2019 novel coronavirus infection.
The pharmaceutical composition provided by the invention preferably contains 0.001-99wt% of active ingredient, the preferable proportion is that the active compound of the invention is 0.1wt% -90wt% or 1% -50wt% of the total weight of the active ingredient, and the rest is 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 promoters, 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, aerosols and the like, and may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterilization apparatus for injection or infusion.
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 dosage unit of the formulation generally comprises from 0.05 to 400mg of the active compound according to the invention, preferably from 1mg to 500mg of the active compound according to the invention.
The compounds and pharmaceutical compositions of the present invention may be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably orally. Most preferably, the daily dosage is 0.01-400mg/kg body weight, and the medicine is administered once or in divided doses 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. Typically starting from a small dose, the dose is gradually increased until the most suitable dose is found.
The agents or inhibitors of the invention may be administered by a variety of different means, for example, by injection, spraying, nasal drops, eye drops, permeation, absorption, physical or chemical mediated methods, into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue; or mixed or wrapped by other materials and introduced into the body.
The main advantages of the invention include:
(a) The active compound of the invention can inhibit SARS-CoV-23CL proteinase with high efficiency, and part of the IC of the active compound 50 Values of less than 5 μm or less.
(b) Because of the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, the active compounds of the present invention are expected to inhibit 3CLpro of other coronaviruses 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 pharmaceutical property.
(d) The technical platform of the invention can rapidly and effectively find out the inhibitor of coronavirus 3CL hydrolase, and the method is applied to find out the inhibition effect of a plurality of old drugs 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 specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Analytical data for the samples were determined by the following instrument: nuclear magnetic resonance is measured by GEMINI-300 type, bruker AMX-400 type and INVOA-600 type nuclear magnetic resonance apparatus, TMS (tetramethylsilane) is an internal standard, chemical displacement unit is ppm, and coupling constant unit is Hz; mass spectra were determined by Finnigan type MAT-711, MAT-95 and LCQ-DECA mass spectrometers and ion spec 4.7Tesla mass spectrometers.
Silica gel for column chromatography (produced by Qingdao ocean chemical plant) 200-300 mesh; the TLC silica gel plate is an HSGF-254 thin layer chromatography precast plate produced by a smoke laboratory chemical plant; petroleum ether boiling range is 60-90 ℃; an ultraviolet lamp and an iodine cylinder are adopted for color development. Conventional reagents, medicines, used in the following examples, were purchased from the national drug group unless otherwise indicated. The reagents and solvents used in the experiment are all treated according to the specific reaction conditions.
Example 1: establishment of SARS-CoV-2-3CLpro inhibitor discovery method
The inhibition activity of individual compounds and mixtures on SARS-CoV-23CLpro enzyme activity was evaluated using 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. Samples such as SARS-CoV-23CLpro protease and different concentrations of compounds or mixtures are added to a 96-well plate, incubated at 30℃for 10min, substrate is added and rapidly placed into an microplate reader for reading.The excitation light and the emission light were 340nm and 405nm, respectively. The test time was 10min, and fluorescence values were read every 30 s. The final results were fitted to the read out values for the first 2min to the reaction rate and compared to the control group (DMSO) to calculate the inhibition. IC was obtained by fitting with software GraphPad Prism 8 50 Values.
The method is simple and sensitive, and can screen SARS-CoV-2-3CLpro inhibitor (including monomer and mixture and other solid 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 other coronaviruses 3CLpro such as SARS-nCoV-3 CLpro.
Example 2: inhibition of SARS-CoV-2-3CLpro by several old drugs such as auranofin
The 2000 old drugs tested in this example were obtained by purchase and their structure and purity (> 90%) were confirmed. The compound is firstly dissolved in DMSO to prepare mother liquor, and the mother liquor of the DMSO is diluted by enzyme activity test buffer to prepare compound samples with various concentrations.
The inhibition of SARS-CoV-2-3CLpro by compounds (multiple old drugs such as auranofin) in 2000 old drug libraries was measured by the SARS-CoV-2-3CLpro inhibitor discovery method established in example 1, inhibition rates of compounds on SARS-CoV-2-3CLpro and IC at different concentrations 50 As shown in table 1.
The experimental results are shown in table 1.
TABLE 1 inhibition of 2019 novel coronavirus 3CL protease by several old drugs such as auranofin
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As a result, it was revealed that several old drugs (A1 to A73) such as auranofin had extremely remarkable inhibitory effects on SARS-CoV-2-3CLpro (Table 1). Several old drugs such as auranofin are SARS-CoV-2-3CLpro inhibitor and IC 50 Reaching the order of single digit micromolar, the optimal compounds of auranofin, rabeprazole sodium, heparin sodium, disulfiram, ilaprazole, bosupravid, tenatoprazole and the like 50 1.1. 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. 1-7).
Due to the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, these newly discovered inhibitors are expected to inhibit 3CLpro of other coronaviruses to exert a broad spectrum of antiviral activity.
Example 3: evaluation of novel coronavirus replication inhibitory Activity of Compound 2019
Measurement of replication inhibitory Activity of active Compounds (A1-A73) against each 2019 novel coronavirus (SARS-CoV-2): cells were grown at a density of 5X 10 4 Cells/well 48 well cell culture dishes were incubated overnight, the cells were pre-treated with various concentrations of active compound (several old drugs such as auranofin) for 1 hour, then infected with virus (multiple infections MOI 0.05) for 2 hours, then the virus compound mixture was removed and the cells were further incubated with fresh medium containing the active compound. At 48h p.i., cell supernatants were collected and lysed in lysis buffer, and viral copy number in cell supernatants was quantified by quantitative real-time RT-PCR (qRT-PCR)Evaluation, calculation of EC of compounds to inhibit virus 50 。
The results show that the active compound (a plurality of old drugs such as auranofin and the like) can effectively inhibit the replication of 2019 novel coronaviruses, and has a certain inhibition on different isolated virus strains.
Discussion of the invention
The sequence identity of SARS-CoV-23CLpro to SARS-CoV 3CLpro is up to 96%, while the substrate binding pocket portion is more 100% conserved. After the explosion of SARS-CoV in 2003, several inhibitors were designed and found for SARS-CoV 3CLpro, most of which are covalent peptide and polypeptide inhibitors, and few non-covalent inhibitors of heterocyclic esters, pyrazoles and macrocycles were reported. The biological activity of these known inhibitors is mainly measured by in vitro enzyme levels, and small amounts of inhibitors have a certain inhibition efficiency (EC 50 At the micromolar level).
Finding compounds with anti-SARS-CoV-2 activity from the old drugs already approved for the market is currently the best strategy to quickly find for clinical treatment of covd-19.
Prior to the present invention, the inhibition of coronavirus 3CL hydrolase by several old drugs such as auranofin has not been reported.
In the present invention, the present inventors have disclosed for the first time that several old drugs such as auranofin have remarkable inhibitory effect on SARS-CoV-23CLpro (Table 1), which are novel inhibitors of SARS-CoV-23CLpro derived from old drugs, IC 50 Reaching the single digit micromolar scale. Because of the high conservation of 3CLpro and its substrate binding pocket in various coronaviruses, the SARS-CoV-23CLpro inhibitors of the present invention are expected to inhibit other coronaviruses 3CLpro and exert broad-spectrum antiviral activity.
Therefore, a plurality of old medicines such as auranofin and the like provide important candidate medicines for developing broad-spectrum single positive strand RNA virus resistant medicines, and have good clinical application prospects.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. Use of an active ingredient or a formulation containing said active ingredient, characterized in that said active ingredient is selected from the group consisting of: tannic acid, or a pharmaceutically acceptable salt thereof;
and the active ingredient or a formulation containing the active ingredient is used to prepare (a) an inhibitor that inhibits coronavirus 3CL protease; and/or (b) a medicament for treating and/or preventing and/or alleviating a disease associated with 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 novel coronavirus (SARS-CoV-2) 3CL protease inhibitor; and/or (b) a medicament for treating and/or preventing and alleviating the related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.
4. The use according to claim 1, wherein the related disease caused by 2019 novel coronavirus infection is selected from the group consisting of: respiratory tract infections, pneumonia, complications thereof, or combinations thereof.
5. A pharmaceutical composition comprising:
(a) A first active ingredient selected from the group consisting of: tannic acid, or a pharmaceutically acceptable salt thereof;
and (b) a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises:
(a1) A first active ingredient selected from the group consisting of: tannic acid, or a pharmaceutically acceptable salt thereof;
(a2) A second active ingredient selected from the group consisting of: RNA replicase inhibitors (e.g., remdesivir or GS-5734); lopinavir (Lopinavir), ritonavir (Ritonavir); chloroquine (Chloroquine, sigma-C6628), hydroxychloroquine, or a combination thereof;
and (b) a pharmaceutically acceptable carrier.
7. The use of a pharmaceutical composition according to claim 5 or 6 for the preparation of (a) an inhibitor of coronavirus 3CL protease; and/or (b) a medicament for treating and/or preventing and/or alleviating a disease associated with a coronavirus infection.
8. The use according to claim 7, wherein the pharmaceutical composition is for the preparation of a medicament for the treatment and/or prevention and alleviation of related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.
9. The use of claim 7, wherein 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.
10. A method of non-therapeutically inhibiting a coronavirus 3CL protease in vitro comprising the steps of: contacting a first active ingredient or a formulation comprising said first active ingredient with a 3CL protease of a coronavirus, thereby inhibiting the activity of said 3CL protease;
wherein the first active ingredient is selected from the group consisting of: tannic acid, or a pharmaceutically acceptable salt thereof.
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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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