CN116867486A - Use of compounds against coronaviruses - Google Patents

Use of compounds against coronaviruses Download PDF

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CN116867486A
CN116867486A CN202280013659.3A CN202280013659A CN116867486A CN 116867486 A CN116867486 A CN 116867486A CN 202280013659 A CN202280013659 A CN 202280013659A CN 116867486 A CN116867486 A CN 116867486A
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coronavirus
pharmaceutically acceptable
acceptable salt
ertapenem
virus
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饶子和
王权
王镐锋
马静静
邢天
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ShanghaiTech University
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • 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

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Abstract

The use of the compounds against coronaviruses is provided. The application is the application of a compound or pharmaceutically acceptable salt, solvate of pharmaceutically acceptable salt or crystal form thereof in preparing an anti-coronavirus preparation, wherein the compound is one or more selected from gossypol acetate, mecobalamin, ertapenem, chaetomium, netilmicin sulfate, sennoside A and ellagic acid. In the application, the compound can effectively inhibit RNA polymerase (RDRP) dependent on coronavirus RNA, further inhibit proliferation of coronavirus, and is applied to resisting coronavirus. The preparation has the advantages of strong inhibition effect, low cost and small required dosage, and can be used for effectively resisting coronaviruses.

Description

Use of compounds against coronaviruses
The present application claims priority from chinese patent application CN202110163244.1, with application date 2021, 2, 5. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The application relates to the technical field of biological medicine, in particular to application of a series of small molecular compounds in resisting coronaviruses.
Background
Coronaviruses are a class of viruses closely related to humans and animals. Common coronaviruses HCoV-229E and HCoV-OC43 cause common cold after infecting human body [1] . At the same time, infection of coronavirus in livestock can also have serious influence on livestock industry, such as Porcine Epidemic Diarrhea Virus (PEDV), gastroenteritis virus (TGEV) and porcine butyl coronavirus (PDCoV), which can cause severe enteritis, diarrhea, emesis and dehydration of pigs, and bring about great loss to pig industry [2] . Coronaviruses are used as an RNA virus, and their high mutation ability makes them always threatening to humans during evolution. Coronaviruses related to SARS-CoV-1 and SARS-CoV-2 et al SARS (severe acute respiratory syndrome) [3] Middle east respiratory syndrome caused by MERS coronavirus [4] All have a great impact on public health. The novel coronavirus (SARS-CoV-2) which is recently and widely popular worldwide has extremely strong transmission capacity, clinical manifestations after infection are mainly fever, dry cough and even dyspnea, and severe cases cause death [5] . To date, although the worldThe world has made great efforts for combating new coronaviruses, but the continuously increasing new infection cases show that the existing stage still lacks the treatment means such as medicines, vaccines, antibodies and the like for preventing and treating the new coronaviruses.
The genome of coronavirus is a single-stranded sense RNA of about 30kb in length, mainly encoding structural proteins required for viral particle assembly and nonstructural proteins responsible for transcriptional replication of the viral genome, wherein two thirds of the genes of the viral genome mainly encode nonstructural proteins nsp1-16 (the non-structural protein 1-16). The transcription replication process of the viral genome is completed by combining a plurality of reactions such as primer synthesis, nascent RNA chain extension, double-strand unwinding, and capping of the 5' -end of the nascent RNA chain. It was found that coronaviruses essentially undergo transcription replication by assembly of multiple functional subunits of nonstructural proteins to form a transcription replication complex, which takes over the viral genome, wherein nsp12 (the non-structural protein 12) is the core subunit of the complex, as an RNA-dependent RNA polymerase (RNA-dependent RNA polymerase, RDRP), essentially taking over the elongation reaction of the nascent RNA strand, and thus playing an essential role in the transcription replication of the virus, and thus became the focus of research [7] . With the deep research of coronavirus RDRP, the catalytic mechanism and the three-dimensional high-resolution atomic structure of the RDRP are revealed, and the method has important significance for researching and developing antiviral drugs based on RDRP as a target point. Meanwhile, some antiviral drugs for viral polymerase, such as ribavirin, famprivir and the like [8,9] The drug has passed FDA authentication and clinically has good treatment effect, and the side surface shows that the RDRP is taken as an antiviral target to develop inhibition capability, and the inhibitor with high safety is essential for drug development and has very good prospect. Inhibitors against coronavirus RDRP, in particular small molecule compounds targeting its catalytically active site, are likely to be potential drugs for the treatment of coronaviruses.
At present, most of clinical first-line treatment of infections caused by coronaviruses use broad-spectrum antiviral drugs, such as lopinavir/ritonavir (ritonavir), arbidol, and adefovir as anti-ebola virus drugs. But none of them is specifically designed or developed for coronaviruses or has definite and remarkable therapeutic effects, and more or less various side effects even cause bradycardia in some subjects, and therefore none of them is the optimal choice for treating coronaviruses. And no compound medicine aiming at coronavirus RDRP exists, so the development of the medicine aiming at the target point has urgency and broad prospect.
(1) Gossypol Acetate (Gossypol Acetate, CAS number 12542-36-8) has the formula:
gossypol acetate is a phenolic, cell permeable, and inhibitors of some dehydrogenases, such as lactate dehydrogenase, NAD-linked enzymes [10] . Cell experiments show that gossypol acetate can be used for treating the disease by interfering Bcl-2 and Bcl-X L Binding to anti-apoptotic proteins, thereby inducing apoptosis of cancer cells, thereby exerting an anti-tumor effect [11] 。
(2) Mecobalamin (Methylcobalamin, CAS No. 13422-55-4) has the formula:
mecobalamin is one of the active forms of vitamin B12, and vitamin B12 can be directly involved in homocysteine metabolism. It is used to treat a number of nutritional and other clinical diseases such as Alzheimer's disease and rheumatoid arthritis.
(3) Ertapenem Sodium (Ertapenem Sodium, CAS number 153773-82-1) has the formula shown below:
ertapenem sodium is a beta-lactam antibiotic and has good inhibitory activity on most gram-positive and gram-negative bacteria. The ertapenem sodium has longer residence time in the body and can be used as a long-acting antibacterial drug.
(4) Chaetocin (Chaetocin, CAS number 28097-03-2) has the formula shown below:
chaetomium is a natural product from the genus chaetomium, a class of histone methyltransferase (histone methyltransferase) inhibitors that have half Inhibition Concentrations (IC) of histone methyltransferase dSU (VAR) 3-9, mouse histone methyltransferase (G9 a) and neurospora crassa methyltransferase (DIM 5) 50 ) 0.8. Mu.M, 2.5. Mu.M and 3. Mu.M, respectively [12] . Chaetocin is an anticancer drug which can effectively inhibit proliferation and clonality formation of a plurality of tumor cells, and IC thereof 50 2-10nM [13] 。
(5) Netilmicin sulfate (Netilmicin Sulfate, CAS number 56391-57-2) has the formula shown below:
netilmicin sulfate is an aminoglycoside antibiotic family member and is used for infection of respiratory tract, digestive tract, genitourinary system, skin and soft tissue, bone and bone segments and wound caused by Escherichia coli, klebsiella, proteus, enterobacter, citrobacter, haemophilus influenzae, salmonella, shigella [14] 。
(6) Sennoside A (Sennoside A, CAS number 81-27-6) has the formula shown below:
sennoside A is a stimulant laxative isolated from Rheum officinale rhizome and has laxative effect by regulating spontaneous movement of colon [15 ]]. It slightly regulates bovine serum monoamine oxidase, IC 50 17 mu M [16] 。
(7) Ellagic acid (Ellagic acid, CAS number 476-66-4) has the formula shown below:
ellagic acid is a class of natural compounds of polyphenols that are found in a large number of vegetables and fruits. It has antioxidant and antitumor effects. Ellagic acid can inhibit mutation of cell DNA and induce apoptosis of cancer cells, thereby resisting cancer [17] 。
Disclosure of Invention
The technical problem to be solved by the invention is to provide application of one or more compounds selected from gossypol acetate, mecobalamin, ertapenem, chaetomium globosum, netilmicin sulfate, sennoside A and ellagic acid, pharmaceutically acceptable salts thereof, solvates of crystal forms thereof or the like in resisting coronaviruses, in particular to resisting novel coronaviruses (SARS-CoV-2) aiming at the defect that no medicament for effectively treating and/or preventing diseases caused by coronaviruses exists in the prior art. The compounds can significantly inhibit the polymerase activity of RNA-dependent RNA polymerase (RDRP) of coronaviruses and are useful in the preparation of anti-coronavirus formulations or in the preparation of RDRP-inhibiting formulations, and thus are useful against coronaviruses, e.g., they can be used to prevent and/or treat patients carrying coronaviruses that do not exhibit a disease state, and they can also be used to treat and/or prevent diseases caused by coronaviruses.
One of the technical schemes provided by the invention is as follows: use of a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, for the preparation of an anti-coronavirus formulation.
Preferably, the pharmaceutically acceptable salt is a sodium salt.
More preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
In the present invention, the coronavirus may belong to the subfamily orthocoronaviridae (orthosporavarinae). The virus of the orthocoronaviridae subfamily is preferably a virus belonging to the genus alpha, beta, gamma and/or delta coronaviridae.
Preferably, the coronavirus is selected from one or more of coronavirus causing upper respiratory tract infection, coronavirus causing lower respiratory tract infection, coronavirus causing digestive tract infection, and virus causing acute respiratory syndrome.
More preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus a59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine delta coronavirus PDCoV, feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or middle east respiratory syndrome coronavirus MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
In a preferred embodiment of the invention, the compound inhibits RDRP of the coronavirus, e.g., blocks RDRP-catalyzed synthesis of viral RNA and viral replication.
The second technical scheme provided by the invention is as follows: use of a compound, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, in the preparation of an inhibitor of RDRP; the compound is selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside A and ellagic acid.
Preferably, the RDRP is a coronavirus RDRP.
Preferably, the pharmaceutically acceptable salt is a sodium salt; more preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
In the present invention, the coronavirus may belong to the subfamily orthocoronaviridae (orthosporavarinae). The virus of the orthocoronaviridae subfamily is preferably a virus belonging to the genus alpha, beta, gamma and/or delta coronaviridae.
Preferably, the coronavirus is selected from one or more of coronavirus causing upper respiratory tract infection, coronavirus causing lower respiratory tract infection, coronavirus causing digestive tract infection, and virus causing acute respiratory syndrome.
More preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus a59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine delta coronavirus PDCoV, feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or middle east respiratory syndrome coronavirus MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
The third technical scheme provided by the invention is as follows: use of a pharmaceutical composition or kit comprising a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin sulfate, netilmicin, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, in the preparation of an anti-coronavirus formulation.
In the present invention, the coronavirus may belong to the subfamily orthocoronaviridae (orthosporavarinae).
Preferably, the virus of the orthocoronaviridae subfamily belongs to the genera alphacoronaviridae, beta coronaviridae, gamma coronaviridae and/or delta coronaviridae.
Preferably, the compound inhibits RDRP of the coronavirus, e.g., blocks RDRP-catalyzed synthesis of viral RNA and viral replication.
Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable pharmaceutical excipients.
Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
More preferably, the coronavirus is selected from one or more of coronaviruses causing upper respiratory tract infections, coronaviruses causing lower respiratory tract infections, coronaviruses causing digestive tract infections, viruses causing acute respiratory syndrome.
Further preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus a59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine delta coronavirus PDCoV, feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or middle east respiratory syndrome coronavirus MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
The technical scheme provided by the invention is as follows: use of a pharmaceutical composition or kit comprising a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, or a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, for the preparation of an inhibitor of RDRP.
Preferably, the RDRP is the RDRP of coronaviruses.
Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable pharmaceutical excipients.
Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
More preferably:
the coronavirus belongs to the subfamily orthocoronaviridae (orthotoronavir). The virus of the orthocoronaviridae subfamily is preferably a virus belonging to the genus alpha, beta, gamma and/or delta coronaviridae; and/or, the compound inhibits RDRP of the coronavirus, e.g., blocks RDRP-catalyzed synthesis of viral RNA and viral replication; and/or, the pharmaceutical composition further comprises pharmaceutically acceptable pharmaceutical excipients; and/or, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
Further preferably:
the coronavirus is selected from one or more of coronavirus causing upper respiratory tract infection, coronavirus causing lower respiratory tract infection, coronavirus causing digestive tract infection, and virus causing acute respiratory syndrome.
Even more preferably:
the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus A59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine butyl coronavirus PDCoV and feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or middle east respiratory syndrome coronavirus MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
The technical scheme provided by the invention is as follows: a method of inhibiting RDRP activity of a coronavirus comprising the step of inhibiting with a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetomium, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof.
The methods of inhibiting RDRP activity of coronaviruses are useful for diagnosing and treating inhibition of RDRP activity of interest; it can also be used for inhibition of RDRP activity for non-diagnostic and therapeutic purposes, such as scientific research of RDRP properties and functions in vitro.
Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
The technical scheme provided by the invention is as follows: use of a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, for inhibiting the RDRP activity of a coronavirus.
The methods of inhibiting RDRP activity of coronaviruses are useful for diagnosing and treating inhibition of RDRP activity of interest; it can also be used for inhibition of RDRP activity for non-diagnostic and therapeutic purposes, such as scientific research of RDRP properties and functions in vitro.
Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
Since the compounds have the ability to inhibit the activity of the RDRP of coronaviruses, and the function of RDRP is an essential condition for replication of coronaviruses, the compounds can also be used for preventing infection of coronaviruses.
The seventh technical scheme provided by the invention is as follows: a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, or a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof; it is used for the following purposes:
(1) Anti-coronavirus; (2) preparing an anti-coronavirus agent; and/or, (3) preparing an inhibitor that inhibits the activity of coronavirus RDRP.
Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
The eighth technical scheme provided by the invention is as follows: a pharmaceutical composition or kit of parts comprising a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, or a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof.
Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
The technical scheme provided by the invention is as follows: a method of combating coronavirus comprising administering to a subject in need thereof a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetomium, netilmicin sulfate, sennoside a, and ellagic acid, or a pharmaceutically acceptable salt thereof, solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof.
Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
In the present invention, the disease is preferably a mammalian or avian disease.
In the present invention, the mammal preferably includes a human, a pig and a cat.
In the present invention, the coronavirus belongs to the subfamily orthocoronaviridae (orthosporavarinae). The virus of the orthocoronaviridae subfamily is preferably a virus belonging to the genus alpha, beta, gamma and/or delta coronaviridae.
Preferably, the coronavirus is selected from one or more of coronavirus causing upper respiratory tract infection, coronavirus causing lower respiratory tract infection, coronavirus causing digestive tract infection, and virus causing acute respiratory syndrome.
More preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus a59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine delta coronavirus PDCoV, feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or middle east respiratory syndrome coronavirus MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
In a preferred embodiment of the present invention, the compounds are useful for treating diseases caused by coronaviruses such as SARS-CoV-2 (BETA-coronavirus), SARS-CoV-1 (BETA-coronavirus), MERS-CoV, etc., as well as common cold drugs, HCoV-HKU1 (Human coronavirus HKU1; β -coronavirus), HCoV-NL63 (Human coronavirus NL; α -coronavirus), HCoV-OC43 (Human coronavirus OC 43), and HCoV-229E (Human coronavirus E; α -coronavirus) in a subject; can also be used as veterinary drug for treating animal diseases such as transmissible gastroenteritis virus (Transmissible gastroenteritis virus, TGEV; alpha coronavirus), porcine epidemic diarrhea virus (Porcine epidemic diarrhea virus, PEDV; alpha coronavirus), porcine but coronavirus (Porcine delta coronavirus, PDCoV; delta coronavirus), feline infectious peritonitis virus (Feline infectious peritonitis virus, FIPV; alpha coronavirus), avian infectious bronchitis virus (Infectious bronchitis virus, IBV; gamma coronavirus). In addition, the compounds may also be used to treat subjects carrying the aforementioned viruses but not exhibiting the corresponding disorders.
The tenth technical scheme provided by the invention is as follows: use of a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin sulfate, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, against coronavirus.
Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
In all the technical schemes of the invention:
the CAS number of the gossypol acetate is 12542-36-8;
the CAS number of the mecobalamin is 13422-55-4;
the CAS number of the chaetocin is 28097-03-2;
the CAS number of the netilmicin sulfate is 56391-57-2;
the CAS number of the sennoside A is 81-27-6;
the CAS number of the ellagic acid is 476-66-4;
the CAS number of ertapenem sodium is 153773-82-1.
The pharmaceutical compositions of the present invention containing various compounds of the present invention as active ingredients may be prepared according to methods well known in the art. The compounds of the present invention may be formulated into any dosage form suitable for human or animal use. The compounds of the present invention are generally present in the pharmaceutical compositions in amounts of from 0.1 to 99.0% by weight.
The auxiliary materials can be any suitable physiologically or pharmaceutically acceptable pharmaceutical auxiliary materials. The pharmaceutical excipients are conventional pharmaceutical excipients in the art, and preferably comprise pharmaceutically acceptable excipients, fillers or diluents and the like. More preferably, the pharmaceutical composition comprises 0.01 to 99.99% of the protein and/or the antibody drug conjugate, and 0.01 to 99.99% of a pharmaceutically acceptable carrier, wherein the percentages are mass percentages of the pharmaceutical composition.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory routes, skin, vaginal, rectal and the like.
The compounds described above may be present in the form of coronavirus inhibitors, for example: conventional drugs for controlling coronaviruses.
In the present invention, "the compound is selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetomium, netilmicin sulfate, sennoside a and ellagic acid", it can be understood that: the compound is gossypol acetate, and preferably can also comprise mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside A and/or ellagic acid; or to understand: the compound is mecobalamin, and preferably can also comprise gossypol acetate, ertapenem, chaetocin, netilmicin sulfate, sennoside A and/or ellagic acid; or to understand: the compound is ertapenem, and preferably can also comprise gossypol acetate, mecobalamin, chaetocin, netilmicin sulfate, sennoside A and/or ellagic acid; or to understand: the compound is chaetocin, and preferably can also comprise gossypol acetate, mecobalamin, ertapenem, netilmicin sulfate, sennoside A and/or ellagic acid; or to understand: the compound is netilmicin sulfate, and preferably can also comprise gossypol acetate, mecobalamin, ertapenem, chaetocin, sennoside A and/or ellagic acid; or to understand: the compound is sennoside A, and preferably can also comprise gossypol acetate, mecobalamin, ertapenem, chaetomium, netilmicin sulfate and/or ellagic acid; or to understand: the compound is ellagic acid, preferably further comprises gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate and/or sennoside A; it is also understood that the compounds include 2, 3, 4, 5, 6 or 7 of these 7 compounds, and those skilled in the art will appreciate that these are within the scope of the present invention.
In the present invention, the SARS-CoV-1 can also be referred to in the art as SARS-CoV (Severe acute respiratory syndrome coronavirus).
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
Interpretation of the terms
The term "pharmaceutically acceptable" refers to salts, solvents, excipients, and the like, which are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention prepared from the medicaments, pharmaceutical compositions containing them and relatively non-toxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention, and medicaments and pharmaceutical compositions containing them, contain relatively acidic functional groups, base addition salts can be obtained by contacting neutral forms of such medicaments with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt. When the drug of the present invention contains a relatively basic functional group, the acid addition salt may be obtained by contacting the neutral form of such drug with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), and the like. When the drug of the present invention contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt. See, for example, berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: properties, selection, and Use (P.Heinrich Stahl and Camille G.Wermuth, ed., wiley-VCH, 2002).
The term "plurality of" in "one or more" may refer to 2, 3, 4, 5, 6, 7, 8, 9 or more.
The compounds of the present invention, medicaments or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, topical, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, etc., preferably by oral or topical administration.
The dosage form may be a liquid, solid or semi-solid dosage form. The liquid dosage forms can be solutions (including true solution and colloid solution), emulsions (including o/w type, w/o type and multiple emulsion), suspensions, injections (including water injection, powder injection and transfusion), eye drops, nasal drops, lotions, liniments and the like; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays; the semisolid dosage form may be an ointment, gel, paste, or the like.
The medicine or the medicine composition can be prepared into common preparations, slow release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
"pharmaceutical composition" means that one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is admixed with additional chemical ingredients, such as pharmaceutically acceptable carriers and pharmaceutical excipients. The purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
By "pharmaceutically acceptable adjuvant" is meant an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound administered, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, EZ sesame oil or hydrogenated EZ sesame oil or polyethoxy hydrogenated EZ sesame oil, corn oil, peanut oil, etc.
"pharmaceutically acceptable carrier" refers to a system that alters the manner and distribution of a drug into the human body, controls the release rate of the drug, and delivers the drug to a targeted organ, and can improve the availability, safety, and effectiveness of the drug, as conventional drug carriers in the art, such as, but not limited to: microcapsules, microspheres, nanoparticles, liposomes, and the like.
The aforementioned pharmaceutical compositions may include, in addition to pharmaceutically acceptable excipients, pharmaceutically acceptable adjuvants such as, for example: antibacterial, antifungal, antimicrobial, shelf-life agent, toner, solubilizing agent, thickener, surfactant, complexing agent, protein, amino acid, fat, saccharide, vitamin, mineral, trace element, sweetener, pigment, essence or combinations thereof, etc.
The term "treatment" refers to therapeutic therapy. When specific conditions are involved, treatment refers to: (1) alleviating a disease or one or more biological manifestations of a disorder, (2) interfering with (a) one or more points in a biological cascade that results in or causes a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of a disorder or one or more biological manifestations of a disorder.
The term "solvate" refers to a substance formed by combining a compound of the invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.
The terms "pharmaceutically acceptable salts" and "solvates" in the term "solvates of pharmaceutically acceptable salts" refer, as described above, to the compounds of the invention formed by combining 1 with 2, prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, with a stoichiometric or non-stoichiometric solvent. The "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the invention.
The terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" may exist in crystalline or amorphous form. The term "crystalline form" refers to a form in which ions or molecules are strictly and periodically arranged in three dimensions in a defined manner and have a periodic recurrence pattern at certain intervals; due to the above-mentioned periodic arrangement, there may be various crystal forms, i.e., polymorphism. The term "amorphous" refers to a state in which ions or molecules are randomly distributed, i.e., the ions and molecules do not have a periodic arrangement rule.
In the present invention, the terms "comprising," "including," or "containing" may mean that other ingredients are present in addition to those listed below; it may also be referred to as "consisting of … …", i.e. comprising only the components listed below without the presence of other components.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
the seven compounds of gossypol acetate, mecobalamin, ertapenem, chaetocin sulfate, netilmicin, sennoside A and ellagic acid disclosed by the invention can effectively inhibit the RDRP of coronaviruses, further inhibit the proliferation of coronaviruses, and are applied to resisting the coronaviruses. The preparation has the advantages of strong inhibition effect, low cost and small required dosage, and can be used for effectively resisting coronaviruses.
Drawings
FIG. 1 is a graph showing the measurement of the inhibitory activity of gossypol acetate against novel coronavirus RDRP.
FIG. 2 is a graph showing the inhibitory activity of mecobalamin on novel coronavirus RDRP.
FIG. 3 is a graph depicting the inhibition activity assay of ertapenem sodium mecobalamin against novel coronavirus RDRP.
FIG. 4 is a graph showing the inhibition activity assay of chaetomium globosum on novel coronavirus RDRP.
FIG. 5 is a graph showing the inhibition activity assay of netilmicin sulfate against novel coronavirus RDRP.
FIG. 6 is a graph showing the inhibition activity assay of sennoside A on novel coronavirus RDRP.
FIG. 7 is a graph showing the inhibitory activity of ellagic acid on novel coronavirus RDRP.
FIG. 8 is a graph showing the activity of gossypol acetate in inhibiting the replication capacity of pseudoviruses of novel coronaviruses.
FIG. 9 is a graph showing the activity of mecobalamin in inhibiting the replication capacity of pseudoviruses of the novel coronaviruses.
FIG. 10 is a graph showing the inhibition activity of ertapenem sodium mecobalamin on the replication capacity of novel coronavirus pseudoviruses.
FIG. 11 is a graph showing the inhibition activity of chaetomium globosum on the replication capacity of novel coronaviruses.
FIG. 12 is a graph showing the inhibition activity of netilmicin sulfate on the replication capacity of novel coronavirus pseudoviruses.
FIG. 13 is a graph showing the inhibition activity of sennoside A on the replication capacity of pseudoviruses of the novel coronaviruses.
FIG. 14 is a graph showing the inhibitory activity of ellagic acid on the replication capacity of pseudoviruses of novel coronaviruses.
FIG. 15 is a graph showing the activity of pyrroloquinoline quinone disodium salt in inhibiting the replication capacity of pseudoviruses of novel coronaviruses.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
EXAMPLE 1 test of the inhibitory Effect of seven Compounds on New coronavirus RDRP
The compounds used in the examples and the instrument information are shown in Table 1.
Table 1 Compounds and instrument information
The inhibitory effect of 7 compounds on novel coronavirus RDRP was tested according to the method disclosed by Eltahla A, lackovic K, marquis C et al (A fluorescence-based high-throughput screen to identify small compound inhibitors of the genotype 3a hepatitis C virus RNA polymerase[J ]. Journal of Biomolecular Screening,2013,18 (9): 1027-1034).
The method comprises the following specific steps:
based on a dye which can generate obvious fluorescence signal difference on single-strand and double-strand nucleic acid as a detection means, the novel coronavirus RDRP activity is reflected.
Test compound is prepared by DMSO or ddH according to the requirement of respective solvent 2 O was dissolved and diluted to 1mM. Picogreen was diluted 100-fold with TE Buffer (10 mM Tris-HCl 1mM EDTA pH 8.0).
mu.M Poly (C) (Sigma-Aldrich, average chain length 300 nt) and 100. Mu.M Poly (G) 9 Mixing according to the volume ratio of 33:1, reacting at 95 ℃ for 5 minutes, and gradually annealing at room temperature to obtain the nucleic acid template for system reaction. 20. Mu.L of the reaction system was sequentially added to 384-well plates, followed by 10. Mu.L of system buffer (50mM HEPES,75mM NaCl,4mM DTT,7mM MnCl) 2 0.01% BSA), RDRP enzyme (novel coronavirus RDRP) and 2% of the reaction volume (0.4. Mu.L) were added to the test compound at a final concentration of 3. Mu.M, cofactors (novel coronaviruses nsp7 and nsp 8) were added at a final concentration of 1.8. Mu.M, 2. Mu.L of annealed nucleic acid template was added, and finally 0.5mM GTP was added as a reaction substrate (i.e.5 mM GTP substrate was used to make up to 20. Mu.L). After 120 minutes incubation at 25℃60. Mu.L PicoGreen dye was added and the system was stopped. EnVision Multimode Plate Reader (Perkinelmer) generates excitation light at 485nm and reads the fluorescence intensity signal value of the emitted light at 520nm wavelength. Converting the fluorescence intensity signal value into the inhibition rate, wherein the calculation formula is as follows:
Inhibition ratio = [1- (sample fluorescence intensity-min)/(max-min) ] ×100%
Where max is the compound-only solvent control (negative control, 0.4. Mu.L of compound in the system with 0.4. Mu.L of pure DMSO or ddH 2 O instead of) min is the signal value of fluorescence intensity of the no-enzyme-activity control (positive control, 2. Mu.L of GTP as a reaction substrate in the system with 2. Mu.L of ddH) 2 O instead of) fluorescent intensity signal value. Curves were plotted on the abscissa with compound concentration and inhibition, fitted using GraphPad Prism version8.4.3 software and IC calculated 50 。
The results show that 7 compounds in the invention have inhibitory capacity on novel coronavirus RDRP, and the inhibitory activity is shown in table 2.
The results show that most of the tested compounds of the present invention have strong inhibition of RDRP activity (IC 50 Below 20 μm), specific activity data are shown in table 2 and fig. 1-7.
TABLE 2 inhibitory Activity against novel coronavirus RDRP (half inhibitory concentration IC 50 ，μM)
Names of Compounds IC 50 ，μM
Gossypol acetate 39.71±2.76
Mecobalamin (mecobalamin) 13.91±0.73
Ertapenem sodium 29.93±0.78
Chaetomium extract 11.78±0.13
Netilmicin sulfate 19.66±0.19
Sennoside A 16.78±0.29
Ellagic acid 8.08±0.25
It can be seen that the 7 compounds all have good inhibition effect on novel coronavirus RDRP.
EXAMPLE 2 testing of the effect of eight Compounds on New coronavirus pseudovirus replication
8 compounds were tested for their anti-infective ability and cytotoxicity against novel coronaviruses according to the methods disclosed in Ju X, zhu Y, wang Y et al (A Novel Cell Culture System Modeling the SARS-CoV-2 Life cycle [ J/OL ]. PLOS Pathogens,2021,17 (3): e 1009439).
The method comprises the following specific steps:
(1) Compound cytotoxicity detection:
WST-8 in Cell Counting Kit-8 reagent can be reduced to yellow formazan product with high water solubility by dehydrogenase in cells under the action of electron carrier, the number of living cells is reflected by the absorbance of formazan at 450nm, and compound cytotoxicity analysis is carried out according to the characteristic.
Seeding 10 in 96 well cell culture plates 5 Caco-2-N cells with a volume of 100. Mu.l were placed in 5% CO at 37℃ 2 After 24 hours of stationary culture in a cell incubator, the precursor compound powder was sufficiently dissolved with DMSO to 200mM, and then diluted 10-fold at a concentration gradient of 200mM, 20mM, 2mM, 200. Mu.M, 20. Mu.M, 2. Mu.M, 200nM; after 100-fold dilution of the compounds at different concentrations with complete medium (10% fbs, 1% ps), 100 μl was added to each cell culture well to give DMSO content of 0.5% per experimental well, 5 duplicate wells per concentration; placing in 37 ℃ and 5% CO 2 Cell incubatorAfter further incubation at rest for 48 hours, the liquid in the cell culture plate was aspirated, 10. Mu. L Cell Counting Kit-8 and 90. Mu.l of a mixture of maintenance medium (2% FBS, 1% PS) was added to each well, and the mixture was left at 37℃with 5% CO 2 Immediately after incubation of the cell incubator for 1.5 hours, the absorbance at 450nm was read with EnVision Multimode Plate Reader (PerkinElmer). Absorbance was converted into cell activity data (% cell viability= (ABS per well) 450nm Value-min)/(max-min) ×100). Wherein max is ABS of cells treated with only 0.5% DMSO 450nm The value of min is the ABS of only Cell Counting Kit-8 450nm Values. Error bar was the standard deviation between cell viability calculated for the three replicates after discarding the maximum and minimum assays for each concentration. And drawing a curve by taking the logarithm of the concentration of the compound and the cell survival rate as the abscissa, and obtaining cell activity data and standard deviation by Excel treatment.
(2) Compound anti-novel coronavirus particle infection assay:
novel coronavirus-like particles (Transcription and Replication-complete SARS-CoV-2 virus-like-particles, trVLP) with transcriptional replication capability are capable of expressing green fluorescent proteins instead of viral capsid proteins, and a complete life cycle can only be performed by infecting cell lines capable of ectopically expressing SARS-CoV or SARS-CoV-2 capsid proteins. The inhibition capacity of the compound on the trVLP is reflected by detecting the green fluorescence intensity difference, so that the anti-novel coronavirus activity of the compound is further characterized.
1.25X10 cells were seeded in 96 well plates 5 Caco-2-N cells with a volume of 100. Mu.l were placed in 5% CO at 37℃ 2 The cells were allowed to stand in an incubator for 24 hours. The compound powder was dissolved well to 200mM with DMSO, after which it was diluted every 10-fold to a concentration gradient of 200mM, 20mM, 2mM, 200. Mu.M, 20. Mu.M, 2. Mu.M, 200nM; after 100-fold dilution of the compounds at different concentrations with complete medium (10% fbs, 1% ps), 100 μl was added to each cell culture well to give DMSO content of 0.5% per experimental well, 5 duplicate wells per concentration; placing in 37 ℃ and 5% CO 2 Cell cultureAfter further incubation in the incubator for 12 hours, the liquid in the cell culture plate was aspirated, trVLP was diluted with maintenance medium (2% FBS, 1% PS) and inoculated into each well at a volume of 100 μl at MOI=2.0, and further placed at 37℃with 5% CO 2 After the cells were cultured in a cell incubator for 48 hours, imaging analysis was performed using a high content cell imaging system Operetta (PerkinElmer), and fluorescence intensity quantitative analysis was performed using long-term dynamic live cell imaging intycyte Zoom HD/2CLR (BioScience). The green fluorescence intensity was converted into virus infectivity data (% virus infection rate=1- (max-total fluorescence intensity value per well)/max×100). max refers to the average of the total fluorescence intensity values of the five parallel groups treated with 0.5% dmso alone. Error bar is the standard deviation between the viral infection rates calculated for the three replicates after discarding the maximum and minimum assays for each concentration. And drawing a curve by taking the logarithm of the compound concentration and the virus infection rate as the abscissa, and obtaining virus infection rate data and standard deviation by Excel treatment.
TABLE 3 inhibition of replication Capacity of novel coronavirus pseudoviruses (EC 50 Mu M) and cytotoxicity (CC 50 ,μM)
Names of Compounds EC 50 (μM) CC 50 (μM) SI
Gossypol acetate 34.68 22.75 0.66
Mecobalamin (mecobalamin) 437.46 288.79 0.66
Ertapenem sodium 456.38 1232.70 2.70
Chaetomium extract 0.05 0.14 2.67
Netilmicin sulfate 375.22 970.84 2.59
Sennoside A 79.40 n.d. n.a.
Ellagic acid 61.88 n.d. n.a.
Pyrroloquinoline quinone disodium salt 95.05 n.d. n.a.
The results show that most tested compounds of the invention show obvious inhibition capability in a system for inhibiting the replication of new coronavirus pseudoviruses, and specific data are shown in fig. 8-15 and table 3.
Reference to the literature
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Claims (14)

  1. Use of a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, for the preparation of an anti-coronavirus formulation.
  2. The use of claim 1, wherein the pharmaceutically acceptable salt is a sodium salt;
    preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
  3. The use according to claim 1 or 2, wherein the coronavirus belongs to the subfamily orthocoronaviridae (orthosporavirinae); the virus of the orthocoronaviridae subfamily is preferably a virus belonging to the genus alpha, beta, gamma and/or delta coronaviridae;
    Preferably, the coronavirus is selected from one or more of a coronavirus causing upper respiratory tract infection, a coronavirus causing lower respiratory tract infection, a coronavirus causing digestive tract infection and a coronavirus causing acute respiratory syndrome;
    more preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus a59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine delta coronavirus PDCoV, feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
  4. The use according to any one of claims 1 to 3, wherein the compound inhibits the RDRP of the coronavirus.
  5. Use of a compound, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, in the preparation of an inhibitor of RDRP; the compound is selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside A and ellagic acid;
    Preferably, the RDRP is that of a coronavirus;
    and/or, the pharmaceutically acceptable salt is sodium salt; preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
  6. The use according to claim 5, wherein the coronavirus belongs to the subfamily orthocoronaviridae (orthoonavirina); the virus of the orthocoronaviridae subfamily is preferably a virus belonging to the genus alpha, beta, gamma and/or delta coronaviridae;
    preferably, the coronavirus is selected from one or more of coronavirus causing upper respiratory tract infection, coronavirus causing lower respiratory tract infection, coronavirus causing digestive tract infection, and virus causing acute respiratory syndrome;
    more preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus a59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine delta coronavirus PDCoV, feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
  7. Use of a pharmaceutical composition or kit comprising a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin sulfate, netilmicin, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, in the preparation of an anti-coronavirus formulation;
    preferably, the coronavirus belongs to the subfamily orthocoronaviridae (orthosporavairina); the virus of the orthocoronaviridae subfamily is a virus belonging to the genus alpha, beta, gamma and/or delta coronaviridae; and/or, the compound inhibits RDRP of the coronavirus; and/or, the pharmaceutical composition further comprises pharmaceutically acceptable pharmaceutical excipients; and/or, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium;
    more preferably, the coronavirus is selected from one or more of coronavirus causing upper respiratory tract infection, coronavirus causing lower respiratory tract infection, coronavirus causing digestive tract infection, virus causing acute respiratory syndrome;
    Further preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus a59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine delta coronavirus PDCoV, feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
  8. Use of a pharmaceutical composition or kit comprising a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a, and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, in the preparation of an inhibitor of RDRP;
    preferably:
    the RDRP is RDRP of coronavirus; and/or, the pharmaceutical composition further comprises pharmaceutically acceptable pharmaceutical excipients; and/or, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium;
    More preferably:
    the coronavirus belongs to the subfamily orthocoronaviridae (orthotoronavir); the virus of the orthocoronaviridae subfamily is preferably a virus belonging to the genus alpha, beta, gamma and/or delta coronaviridae; and/or, the compound inhibits RDRP of the coronavirus; and/or, the pharmaceutical composition further comprises pharmaceutically acceptable pharmaceutical excipients; and/or, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium;
    further preferably:
    the coronavirus is selected from one or more of coronavirus causing upper respiratory tract infection, coronavirus causing lower respiratory tract infection, coronavirus causing digestive tract infection, and virus causing acute respiratory syndrome;
    even more preferably:
    the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and/or mouse hepatitis virus A59, the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV, the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine butyl coronavirus PDCoV and feline transmissible peritonitis virus FIPV, and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or MERS-CoV; further preferably, the SARS-associated coronavirus is SARS-CoV-1 or SARS-CoV-2.
  9. A method of inhibiting RDRP activity of a coronavirus comprising the step of inhibiting with a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetomium, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof;
    preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
  10. Use of a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, for inhibiting the RDRP activity of a coronavirus;
    preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
  11. A compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof; it is used for the following purposes:
    (1) Anti-coronavirus; (2) preparing an anti-coronavirus agent; and/or, (3) preparing an inhibitor that inhibits the activity of coronavirus RDRP;
    preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
  12. A pharmaceutical composition or kit of parts comprising a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin, netilmicin sulfate, sennoside a and ellagic acid, or a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof;
    preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
  13. A method of combating coronavirus comprising administering to a subject in need thereof a compound, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, said compound being selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetomium, netilmicin sulfate, sennoside a and ellagic acid;
    preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
  14. Use of a compound selected from one or more of gossypol acetate, mecobalamin, ertapenem, chaetocin sulfate, netilmicin sulfate, sennoside a and ellagic acid, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, against coronavirus;
    Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.
CN202280013659.3A 2021-02-05 2022-01-30 Use of compounds against coronaviruses Pending CN116867486A (en)

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CN102451154A (en) * 2010-10-14 2012-05-16 山东方明药业股份有限公司 Netilmicin sulfate injection and preparation method thereof
CN103622940B (en) * 2013-11-06 2016-02-24 中国医学科学院药用植物研究所 The application of gossypol acetate in pharmacy
CN107163067B (en) * 2017-07-05 2019-05-17 山东省科学院生物研究所 Wide spectrum antimicrobial agent lead compound and preparation and application
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