New use of small molecule compound G125-0182 in the preparation of anti-SARS-CoV-2 infection drugs

Abstract

The present invention discloses a novel use of the small molecule compound G125-0182 in the preparation of an anti-SARS-CoV-2 infection drug. Through a large number of experimental screening and verification, the present invention found that the small molecule compound G125-0182 can significantly inhibit the infection of SARS-CoV-2 without affecting cell viability. Based on this, the present invention proposes for the first time a new use of the small molecule compound G125-0182 as an anti-SARS-CoV-2 infection drug.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical technology, and specifically relates to a new use of the small molecule compound G125-0182 in the preparation of anti-SARS-CoV-2 infection drugs. Background Art

[0002] The novel coronavirus, SARS-CoV-2, is still evolving under the influence of human immune pressure and various natural factors. Sporadic or localized outbreaks caused by a mutant of the virus remain a foreseeable event. The infection process of coronaviruses includes four steps: adsorption and invasion, gene synthesis, and packaging and release of mature viruses. The key step in viral adsorption and invasion is the specificity of the viral receptor. During the coronavirus infection of host cells, the S protein specifically recognizes cell surface receptors and forms a complex, which is the key factor in determining viral invasion.

[0003] According to reports, the COVID-19 disease caused by the novel coronavirus SARS-CoV-2 has a mortality rate of approximately 3.06%, and the reproduction number (Ro) has reached 3.77. COVID-19 poses a serious threat to human survival and health, and has also had a severe impact on socioeconomic development. To date, there are no specific medications for infection with the novel coronavirus SARS-CoV-2, and clinical treatment primarily relies on symptomatic supportive care. Therefore, there is a continued need for the development of new drugs for the prevention and treatment of infection with the novel coronavirus SARS-CoV-2. Summary of the Invention

[0004] In order to overcome the technical problems currently existing in this field, the purpose of the present invention is to provide the field with a new use of the small molecule compound G125-0182 in the preparation of anti-SARS-CoV-2 infection drugs.

[0005] The present invention adopts the following technical solutions to achieve the above-mentioned invention objectives:

[0006] In one aspect, the present invention provides the use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof in the preparation of an anti-SARS-CoV-2 infection drug.

[0007] Furthermore, the structural formula of the small molecule compound G125-0182 is shown in formula (I):

[0008]

[0009] Formula (I).

[0010] Furthermore, the anti-SARS-CoV-2 infection includes treating and / or preventing SARS-CoV-2 infection.

[0011] Furthermore, the dosage form of the drug is an oral dosage form, a parenteral dosage form and / or a topical dosage form.

[0012] Furthermore, the dosage form of the drug is a solution, granules, tablets, sustained-release agents, suspensions, effervescent agents, emulsions, capsules, powders, syrups, drops and / or chewable tablets.

[0013] Furthermore, the drug is administered subcutaneously, intravenously, orally, intramuscularly, intraarterially, intranasally, intrathecally, intramucosally, intrapulmonaryly and / or rectally.

[0014] It should be understood that the present invention encompasses all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, pseudopolymorphs, hydrates, or solvates of the small molecule compound G125-0182 described herein and its pharmaceutically acceptable salts. In addition, all mixtures of such enantiomers and diastereomers are within the scope of protection of the present invention.

[0015] In the present invention, the structural formula of the small molecule compound G125-0182 is shown in formula (I) (as described above in formula (I)), and its corresponding SMILES is N(C(SC1C(=O)NCCCN(CC2)CCC2N(CC2)CCC2)=CC=1)(C=C1)C(=C1C1)C=CC=1. Currently, there is no research or report related to the small molecule compound G125-0182 as described above and its anti-SARS-CoV-2 infection.

[0016] In the present invention, the pharmaceutically acceptable salts of the small molecule compound G125-0182 refer to those carboxylate salts, amino acid addition salts, etc. of the small molecule compound G125-0182 of the present invention, which are suitable for contact with patients within the scope of reliable medical judgment, do not produce undue toxicity, irritation, allergic reactions, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended applications, including (if possible) the zwitterionic form of the compound of the present invention (the small molecule compound G125-0182).

[0017] For example, the pharmaceutically acceptable salts of the small molecule compound G125-0182 of the present invention include, but are not limited to, salts derived from a suitable base such as an alkali metal or alkaline earth metal (e.g., Na + 、Li + , K + , Ca 2+ and Mg 2+Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, but are not limited to: (a) acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.); (b) salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalactonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, o-benzoic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.; and (c) Salts formed from elemental anions such as chloride, bromide and iodide. Pharmaceutically acceptable salts of hydroxy compounds include the anion of the compound in combination with a suitable cation.

[0018] In another aspect, the present invention provides a pharmaceutical composition for use against SARS-CoV-2 infection.

[0019] Furthermore, the pharmaceutical composition comprises the aforementioned small molecule compound G125-0182 of the present invention or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the pharmaceutical composition, in addition to the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described above, may also contain other drugs that can be used to treat and / or prevent, or assist in the treatment and / or assistance prevention of SARS-CoV-2 infection.

[0021] Exemplarily, the other drugs that can be used to treat and / or prevent, or assist in the treatment and / or assist in the prevention of SARS-CoV-2 infection include but are not limited to: angiotensin converting enzyme 2 inhibitors, angiotensin converting enzyme 2 modulators, angiotensin converting enzyme 2 stimulators, angiotensin II AT-2 receptor agonists, angiotensin II AT-2 receptor antagonists, angiotensin II receptor modulators, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, SARS-CoV-2 envelope small membrane protein inhibitors, SARS-CoV-2 envelope small membrane protein modulators, SARS-CoV-2 MPro inhibitors, SARS-CoV-2 nonstructural protein 8 modulators, SARS-CoV-2 nucleoprotein inhibitors, SARS-CoV-2 nucleoprotein modulators, SARS-CoV-2 protein 3a inhibitors, SARS-CoV-2 replicase polyprotein 1a inhibitors, SARS-CoV-2 replicase polyprotein 1a modulators, SARS-CoV-2 replicase polyprotein 1ab inhibitors, SARS-CoV-2 replicase polyprotein Protein 1ab modulators, SARS-CoV-2 spike glycoprotein inhibitors, SARS-CoV-2 spike glycoprotein modulators, SARS-CoV-2 structural glycoprotein modulators, papain inhibitors, protease inhibitors, protease modulators, RNA polymerase inhibitors, RNA polymerase modulators, RNA-dependent RNA polymerase (RdRp) inhibitors, SARS coronavirus 3C protease-like inhibitors, SARS-CoV-2 nsp14 methyltransferase inhibitors, 3CLpro / Mpro inhibitors, serine protease inhibitors, transmembrane serine protease 2 inhibitors, transmembrane serine protease 2 modulators, viral envelope protein inhibitors, viral protease inhibitors, viral protease modulators, viral protein target modulators, viral ribonuclease inhibitors and / or viral structural protein modulators.

[0022] In another aspect, the present invention provides a pharmaceutical preparation for use against SARS-CoV-2 infection.

[0023] Furthermore, the pharmaceutical preparation comprises the pharmaceutical composition of the present invention as described above.

[0024] Furthermore, the dosage form of the pharmaceutical preparation is a solution, granules, tablets, sustained-release agents, suspensions, effervescent agents, emulsions, capsules, powders, syrups, drops and / or chewable tablets.

[0025] In some embodiments, the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described above of the present invention can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, glidants, fillers, binders, etc. The aqueous formulation is prepared in a sterile form and will generally be isotonic when intended for delivery by non-oral administration. All formulations may optionally contain excipients well known in the art. Pharmaceutically acceptable excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In some embodiments, the formulation comprises one or more pharmaceutically acceptable excipients. The pH range of the formulation is from about 3 to about 11, but typically from about 7 to 10. In some embodiments, the pH range of the formulation is from about 2 to about 5, but typically from about 3 to 4.

[0026] In some embodiments, although the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof (active ingredient) disclosed herein can be administered alone, it is preferably provided as a pharmaceutical formulation. Both veterinary and human formulations of the present invention include at least one active ingredient as described above, together with one or more acceptable carriers thereof and optionally other therapeutic ingredients. The carrier must be acceptable, i.e., compatible with the other ingredients of the formulation and physiologically not harmful to the recipient.

[0027] In some embodiments, the administration routes of the small molecule compound G125-0182 or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation as described above of the present invention include but are not limited to: subcutaneous, intramuscular, intravenous, oral or inhalation administration.

[0028] In some embodiments, the small molecule compound G125-0182 or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical formulation as described above can be administered at any time to a person who may be exposed to a virus or already has a viral infection. In the present invention, the virus is particularly SARS-CoV-2 and its related variants.

[0029] In some embodiments, the small molecule compound G125-0182 or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation as described above of the present invention can be prophylactically administered to a person who is in contact with a person suffering from a viral infection or is at risk of contact with a person suffering from a viral infection, such as a healthcare provider. In some embodiments, the administration of the small molecule compound G125-0182 or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation as described above of the present invention can be administered to a person who tests positive for viral infection but has not yet shown symptoms of viral infection. In some embodiments, the small molecule compound G125-0182 or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation as described above of the present invention can be administered to a person at the beginning of symptoms of viral infection. In the present invention, the virus refers in particular to SARS-CoV-2 and its related variants.

[0030] In some embodiments, formulations of the invention suitable for oral administration can be provided as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a pill, electuary, or paste.

[0031] In some embodiments, tablets are prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as a powder or granular form) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom.

[0032] In some embodiments, the pharmaceutical preparation of the present invention comprises the small molecule compound G125-0182 or its pharmaceutically acceptable salt as described above and one or more pharmaceutically acceptable carriers or excipients, and may further comprise optional other therapeutic agents. The pharmaceutical preparation containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may comprise one or more medicaments, including sweeteners, flavorings, coloring agents and preservatives, so as to provide a palatable preparation. Tablets containing active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binding agents such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with a wax.

[0033] In another aspect, the present invention provides an in vitro method for inhibiting SARS-CoV-2 infection for non-therapeutic purposes.

[0034] Furthermore, the method comprises: treating a system in need thereof with the aforementioned small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof of the present invention.

[0035] In another aspect, the present invention provides any of the following applications:

[0036] (1) Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described above in the preparation of a pharmaceutical composition for use in treating SARS-CoV-2 infection;

[0037] (2) Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described above in the preparation of a pharmaceutical preparation for use in treating SARS-CoV-2 infection;

[0038] (3) Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described above in the present invention for inhibiting SARS-CoV-2 infection for non-therapeutic purposes in vitro.

[0039] On the other hand, the present invention also provides a method for treating and / or preventing SARS-CoV-2 infection, comprising administering to a subject in need thereof a therapeutically and / or prophylactically effective amount of the small molecule compound G125-0182 as described above or a pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation thereof.

[0040] In some embodiments, the specific dosage level of the small molecule compound G125-0182, or a pharmaceutically acceptable salt thereof, pharmaceutical composition, or pharmaceutical formulation described herein, will depend on a variety of factors, including the activity of the specific compound employed, the age, weight, general health, sex, diet, time of administration, route of administration, and excretion rate of the subject being treated, drug combination, and the severity of the particular disease. For example, the dosage can be expressed as milligrams of the compound described herein per kilogram of subject body weight (mg / kg). Doses between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, doses between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalizing to the subject's weight is particularly useful when adjusting dosages between subjects of widely varying sizes, such as when administering a drug in children and adults, or when converting an effective dose in a non-human subject, such as a dog, to a dose suitable for a human subject.

[0041] Specifically, the specific dosage and frequency of administration of the aforementioned small molecule compound G125-0182 or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation of the present invention can be adjusted during the course of treatment according to the judgment of the administering physician.

[0042] In the present invention, treating means reversing, alleviating or inhibiting the progression of the disorder or condition to which the term applies or one or more symptoms of such disorder or condition.

[0043] In the present invention, prevention refers to any treatment of any disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the small molecule compounds disclosed herein, or pharmaceutically acceptable salts thereof, pharmaceutical compositions, or pharmaceutical formulations, can be administered to subjects (including humans) at risk of developing a disease or condition.

[0044] Specifically, prevention encompasses administering the small molecule compound or a pharmaceutically acceptable salt, pharmaceutical composition, or pharmaceutical formulation according to the embodiments disclosed herein before or after an individual is exposed to a virus, but before symptoms of infection with the virus (in the present invention, particularly SARS-CoV-2 and its related variants) appear and / or before the virus is detected in the blood. The term also refers to preventing the onset of disease symptoms and / or preventing the virus from reaching detectable levels in the blood. The term includes pre-exposure prophylaxis (PrEP) as well as post-exposure prophylaxis (PEP) and event-driven or on-demand prophylaxis.

[0045] In the present invention, the subject includes one or more animals, including, for example, cattle, horses, sheep, primates, birds, and rodent species. The subject can be a mammal, bird, fish, reptile, or amphibian. The mammal includes a human or a non-human mammal. In other embodiments, the subject can be a mouse, rat, hamster, ferret, gerbil, rabbit, monkey, chimpanzee, horse, pony, donkey, sheep, pig, chicken, goat, cat, or dog. In a preferred embodiment, the subject is a human.

[0046] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0047] Through a large number of experimental screening and verification, the present invention found that the small molecule compound G125-0182 can significantly inhibit the infection of SARS-CoV-2 without affecting cell viability. Based on this, the present invention proposes for the first time a new use of the small molecule compound G125-0182 as an anti-SARS-CoV-2 infection drug. The small molecule compound G125-0182 can be used as an active ingredient to prepare a drug for treating and / or preventing SARS-CoV-2 infection. The present invention provides a new strategy and solution for the treatment and / or prevention of SARS-CoV-2 infection. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 : Schematic diagram of pseudovirus system construction;

[0049] Figure 2 : Graphs showing the validation results of the constructed system, including: Figure A: Validation results of the constructed 293T cell line overexpressing ACE2; Figure B: Result graph showing that the D614G mutant SARS-CoV-2 pseudovirus has a better infection efficiency;

[0050] Figure 3: Screening results of small molecule compounds with good inhibitory effects on SARS-CoV-2 infection in the compound library. Among them, Figure A: After the preliminary screening of 1,000 small molecules, two drugs with good inhibitory effects were screened out, and their drug IDs are Y020-0023 and G125-0182; Figure B: The corresponding results of drugs Y020-0023 and G125-0182 that can significantly and effectively inhibit SARS-CoV-2 infection;

[0051] Figure 4 : While testing the efficiency of drugs Y020-0023 and G125-0182 in inhibiting SARS-CoV-2 pseudovirus, the corresponding result graphs are also testing the effects of drugs Y020-0023 and G125-0182 on cell viability, among which, Figure A: G125-0182; Figure B: Y020-0023. DETAILED DESCRIPTION

[0052] The present invention will be further described below in conjunction with specific examples. The following specific examples are only used to explain the present invention and are not to be construed as limiting the present invention. Those of ordinary skill in the art will appreciate that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and purpose of the present invention, and that the scope of the present invention is defined by the claims and their equivalents. The reagents and raw materials used in the present invention are readily available to those of ordinary skill in the art and are commercially available unless otherwise specified. The experimental methods for which specific conditions are not specified in the present invention are typically tested under conventional conditions or under conditions recommended by the manufacturer. In particular, the following examples are only used to illustrate the present invention and are not to be construed as limiting the scope of the present invention in any way. It should be noted that the experimental conditions and results described in the following examples are only used to illustrate the present invention and should not and will not limit the present invention described in detail in the claims.

[0053] Experimental verification of the anti-SARS-CoV-2 infection effect of the small molecule compound G125-0182 in the example

[0054] 1. Experimental Materials

[0055] Plasmids: psPAX2, pCDNA3.1-SARS-CoV-2-spike-Δ19 D614G, pLVX-luc2, pCMV VSVG, pLVX-3×flag-hACE2;

[0056] Cells: 293T;

[0057] Culture medium: DMEM (MACGENE, CM10013);

[0058] Calcium phosphate transfection reagents (MACGENE, CTK001);

[0059] Steady-Glo® Luciferase Assay System (Promega, E2520);

[0060] Mini Scaffold Library (Taoshu Biological, L5600);

[0061] HBSS (MACGENE, CC016).

[0062] 2. Experimental methods

[0063] (1) Construction of SARS-CoV-2 pseudovirus

[0064] 1) Seed cells

[0065] 2.5 × 10 cells were seeded per 10 cm dish. 6 HEK293T cells were cultured for 12 h and virus was encapsulated when the cell density reached about 50%.

[0066] 2) Matching system

[0067] ① Solution A: 3 µg psPAX2 + 3 µg pCDNA3.1-SARS-CoV-2-spike-Δ19 D614 + 6 µg pLVX-luc2 + 1 mL HBS, gently mix 7-8 times, and let stand for 5 minutes;

[0068] ② Slowly add 67 µL of CaCl2 to Solution A, gently mix while adding, gently pipette 7-8 times, and let it stand for 15 minutes;

[0069] ③ Add the system evenly to the culture dish, shake the dish gently from front to back and left to right, and return it to the incubator between viruses.

[0070] 3) Replace the culture medium with fresh one every 6 hours.

[0071] 4) Collect the viral supernatant after 48 h, centrifuge at 800 × g for 5 minutes to remove cell debris, filter through a 0.45 µm filter, and store at -80°C.

[0072] (2) Construction of ACE2 overexpression cell line

[0073] 1) Seed cells

[0074] 2.5 × 10 cells were seeded per 10 cm dish. 6HEK293T cells were cultured for 12 h and virus was encapsulated when the cell density reached about 50%.

[0075] 2) Matching system

[0076] ① Solution B: 5 µg psPAX2 + 5 µg pCMV VSVG + 5 µg pLVX-3×flag-hACE2 + 1 mL HBS, gently mix 7-8 times, and let stand for 5 minutes;

[0077] ② Slowly add 67 µL of CaCl2 to Solution B, gently mix while adding, gently pipette 7-8 times, and let it stand for 15 minutes;

[0078] ③ Add the system evenly to the culture dish, shake the dish gently from front to back and left to right, and return it to the incubator between viruses.

[0079] 3) Replace the culture medium with fresh one every 6 hours.

[0080] 4) Collect viral supernatants at 48 h and 72 h, centrifuge at 800 × g for 5 min to remove cell debris, filter through a 0.45 µm filter, and store at -80°C.

[0081] 5) Virus-infected cells: 1.5×10 cells per 10 cm dish 6 For each HEK293T cell, add 5 mL of DMEM and 5 mL of virus-containing DMEM to the dish and infect for 48 h.

[0082] 6) Screening: Cells were passaged and cultured in DMEM containing puromycin. ACE2 overexpression was detected 4 days after screening.

[0083] 7) Construct 293T cells overexpressing ACE2.

[0084] (3) SARS-CoV-2 pseudovirus infection of cells and detection of infection efficiency

[0085] 1) Dilute the drug to 100 µM: Dispense 2 µL of the 10 mM stock solution into 198 µL of HBSS and pipette to mix.

[0086] 2) Drug pretreatment of cells: Pipette 10 µL of the diluted cells into a black 96-well plate and seed 1.6×10 4 cells / 40µL DMEM in a 96-well plate.

[0087] 3) SARS-CoV-2 pseudovirus infection of cells: After 1 h of drug pretreatment, add 50 µL of DMEM containing SARS-CoV-2 pseudovirus to a black 96-well plate.

[0088] 48 h after infection, the fluorescence reading was detected according to the Steady-Glo instructions.

[0089] 3. Experimental results

[0090] (1) Build system

[0091] Schematic diagram of the construction of the SARS-CoV-2 pseudovirus system Figure 1 As shown, the construction results are as follows Figure 2 As shown, the results showed that the 293T cell line overexpressing ACE2 was successfully constructed ( Figure 2 A), SARS-CoV-2 pseudovirus with D614G mutation has better infection efficiency ( Figure 2 B).

[0092] (2) Screening results

[0093] The compound library used for screening is a molecular scaffold library. Each compound in the library represents a class of compounds with the same scaffold. The 5,033 compounds represent 5,033 different molecular scaffolds. Using the scaffold as a clue, after determining that a particular scaffold structure is effective, the structure can be optimized to extend to more small molecules, thereby identifying "low-toxic, high-efficiency" drugs. Therefore, drug screening based on scaffolds can greatly increase screening efficiency.

[0094] After initially completing the 1000 small molecules ( Figure 3 After screening of A), we screened out two drugs with good inhibitory effects, whose drug IDs are Y020-0023 and G125-0182. Both drugs Y020-0023 and G125-0182 can significantly and effectively inhibit the infection of SARS-CoV-2 (P < 0.05) ( Figure 3 B), in which the dosage of drugs in each group was 10 μM. The treatment method of the three groups was that the cells were pretreated with drugs for 1 h, and the infection efficiency was detected after the cells were infected with SARS-CoV-2 pseudovirus.

[0095] (3) Drug toxicity testing

[0096] While testing the efficiency of drugs Y020-0023 and G125-0182 in inhibiting SARS-CoV-2 pseudovirus, we also tested the effects of drugs Y020-0023 and G125-0182 on cell viability. The results are as follows: Figure 4As shown in Figure AB, the results showed that drugs Y020-0023 and G125-0182 had good inhibitory effects on SARS-CoV-2 infection without significantly affecting cell viability. The concentration gradient of drug Y020-0023 was 0 μM, 0.25 μM, 0.5 μM, 1 μM, 2 μM, 4 μM, 8 μM, 16 μM, and 32 μM, and the concentration gradient of drug G125-0182 was 0 μM, 12.5 μM, 25 μM, 50 μM, and 100 μM. The treatment method of both drugs was to pretreat the cells with the drugs for 1 hour, and the infection efficiency was detected after the cells were infected with SARS-CoV-2 pseudovirus.

Claims

1. Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof in the preparation of an anti-SARS-CoV-2 infection drug, characterized in that: The structural formula of the small molecule compound G125-0182 is shown in formula (I): Formula (I).

2. The use according to claim 1, characterized in that The anti-SARS-CoV-2 infection includes treating and / or preventing SARS-CoV-2 infection.

3. The use according to claim 1, characterized in that The dosage form of the drug is an oral dosage form, a parenteral dosage form and / or a topical dosage form.

4. The use according to claim 1, characterized in that The dosage form of the drug is solution, granule, tablet, sustained-release agent, suspension, effervescent agent, emulsion, capsule, powder, syrup, drop and / or chewable agent.

5. The use according to claim 1, characterized in that The drug is administered subcutaneously, intravenously, orally, intramuscularly, intraarterially, intranasally, intrathecally, intramucosally, intrapulmonaryly and / or rectally.

6. A method for inhibiting SARS-CoV-2 infection in vitro for non-therapeutic purposes, characterized in that: The method comprises: treating a system in need thereof with the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as claimed in claim 1.

7. Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a pharmaceutical composition for anti-SARS-CoV-2 infection.

8. Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a pharmaceutical preparation for anti-SARS-CoV-2 infection.

9. Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as claimed in claim 1 in inhibiting SARS-CoV-2 infection for non-therapeutic purposes in vitro.

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