New application of small molecule compound G125-0182 in preparation of anti-SARS-CoV-2 infection medicine

Abstract

The invention discloses a new application of a small molecule compound G125-0182 in preparation of an anti-SARS-CoV-2 infection drug, a large number of experimental screening and verification discover that the small molecule compound G125-0182 can significantly inhibit SARS-CoV-2 infection under the condition of not influencing cell viability, and on the basis of the small molecule compound G125-0182, the small molecule compound G125-0182 can significantly inhibit SARS-CoV-2 infection. The invention provides a brand-new application of the small molecule compound G125-0182 as a medicine for resisting SARS-CoV-2 infection for the first time.

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 new coronavirus SARS-COV-2 is still in the process of continuous evolution under the influence of human immune pressure and various factors in nature. Sporadic or local outbreaks caused by a mutant of the virus are still foreseeable events. The infection steps of coronavirus include adsorption and invasion, gene synthesis, packaging and release of mature viruses. Among them, the key step of virus adsorption and invasion is the specificity of virus receptors. In the process of coronavirus infection of host cells, the S protein specifically recognizes cell surface receptors and forms a complex, which is a key factor in determining virus invasion.

[0003] According to reports, the case fatality rate of COVID-19 caused by the new coronavirus SARS-CoV-2 is about 3.06%, and the basic reproduction number Ro reaches 3.77. COVID-19 poses a serious threat to human survival and health, and also has a serious impact on social and economic development. Up to now, there is no specific drug for the new coronavirus SARS-CoV-2 infection, and clinical treatment is mainly based on symptomatic support. Therefore, there is still a need to develop new drugs for the prevention and treatment of new coronavirus SARS-CoV-2 infection in this field. Summary of the invention

[0004] In order to overcome the technical problems currently existing in the art, the purpose of the present invention is to provide the art 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 chewables.

[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 covers 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 protection scope 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. At present, there is no research or report related to the small molecule compound G125-0182 described above and anti-SARS-CoV-2 infection.

[0016] In the present invention, the pharmaceutically acceptable salts of the small molecule compound G125-0182 refer to those carboxylates, 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 inappropriate 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, those derived from a suitable base such as an alkali metal or an alkaline earth metal (e.g., Na + , Li + , K + , Ca 2+ and Mg 2+), ammonium salts. 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-phthalic 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 small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described above.

[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 for the treatment and / or prevention, or adjunctive treatment and / or adjunctive 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 non-structural 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-2nsp14 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 chewables.

[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, adhesives, etc. The aqueous preparation is prepared in a sterile form, and when intended to be delivered by non-oral administration, it will generally be isotonic. All preparations may optionally include 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 preparation includes one or more pharmaceutically acceptable excipients. The pH range of the preparation is from about 3 to about 11, but is generally from about 7 to 10. In some embodiments, the pH range of the preparation is from about 2 to about 5, but is generally from about 3 to 4.

[0026] In some embodiments, although the small molecule compound G125-0182 or its pharmaceutically acceptable salt (active ingredient) disclosed in the present invention as described above can be administered alone, it is preferably provided as a pharmaceutical preparation. The veterinary and human preparations of the present invention both include at least one active ingredient as described above, together with one or more acceptable carriers thereof and optional other therapeutic ingredients. The carrier must be acceptable, i.e., compatible with the other ingredients of the preparation and physiologically harmless to the subject thereof.

[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 preparation as described above can be administered to a person who may be exposed to a virus or has already suffered from a viral infection at any time. In the present invention, the virus refers in particular to 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 applied prophylactically to people who are in contact with people with viral infections or are at risk of contact with people with viral infections, such as healthcare providers. 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 applied to people who are positive for viral infection tests but have 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 applied to people 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 may 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 may also be administered as a pill, elixir, 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 powdered or granular) 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 also 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 may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may comprise one or more medicaments, including sweeteners, flavoring agents, coloring agents and preservatives, so as to provide a palatable preparation. Tablets containing active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents 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 sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used alone or with wax.

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

[0034] Furthermore, the method comprises: treating a system in need thereof with the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described above.

[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 combating 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 anti-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, the method comprising: administering a therapeutically and / or preventively effective amount of the small molecule compound G125-0182 of the present invention as described above or a pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation thereof to a subject in need.

[0040] In some embodiments, the specific dosage level of the small molecule compound G125-0182 or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation as described above of the present invention will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health, sex, diet, administration time, administration route and excretion rate of the subject receiving therapy, drug combination and the severity of the specific disease. For example, the dosage can be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. A dosage between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dosage between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dosage between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization according to the subject's weight is particularly useful when adjusting the dosage between subjects with large size differences (such as when using drugs in children and adults, or when converting the effective dosage of non-human subjects such as dogs to a dosage suitable for human subjects).

[0041] Specifically, the specific dosage and frequency of administration of the small molecule compound G125-0182 or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation as described above in the present invention can be adjusted during the 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, the prevention means 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 compound disclosed in the present invention or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation can be administered to a subject (including a human) at risk of suffering from a disease or condition.

[0044] Specifically, prevention covers the administration of the small molecule compound or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical preparation according to the embodiments disclosed in the present invention before or after an individual is exposed to a virus but before the onset of symptoms of infection with the virus (in the present invention, particularly SARS-CoV-2 and its related variants) 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 prevention.

[0045] In the present invention, the subject includes one or more animals, including, for example, cattle, horses, sheep, primates, avian and rodent species. The subject can be a mammal, a bird, a fish, a reptile or an amphibian. The mammal includes a human or a non-human mammal. In other embodiments, the subject can be a mouse, a rat, a hamster, a ferret, a gerbil, a rabbit, a monkey, a chimpanzee, a horse, a pony, a donkey, a sheep, a pig, a chicken, a goat, a cat or a 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] The present invention has found through a large number of experimental screening and verification 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 : Result diagram of system verification, where A: Result diagram of verification of the constructed 293T cell line overexpressing ACE2; B: Result diagram corresponding to the good infection efficiency of the D614G mutated SARS-CoV-2 pseudovirus;

[0050] Figure 3: Screening results of small molecule compounds with good inhibitory effects on SARS-CoV-2 infection in the compound library, where A: After the preliminary screening of 1,000 small molecules, two drugs with good inhibitory effects were screened, and their drug IDs are Y020-0023 and G125-0182; 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 of the effects of drugs Y020-0023 and G125-0182 on cell viability are tested, where Figure A: G125-0182; Figure B: Y020-0023. DETAILED DESCRIPTION

[0052] The present invention is further described below in conjunction with specific examples. The following specific examples are only used to explain the present invention and cannot be construed as limiting the present invention. It can be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and purposes of the present invention, and 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 easily available to those of ordinary skill in the art, and can be obtained from commercial sources unless otherwise specified. The experimental methods for which specific conditions are not specified in the present invention are usually 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 should not limit 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 small molecule compound G125-0182 against SARS-CoV-2 infection

[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 Biology, 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 6 HEK293T cells were cultured for 12 h, and virus was ready 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, mix gently 7-8 times, and let stand for 5 min;

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

[0069] ③ Add the system evenly into the culture dish, gently shake the dish back and forth and left and right to evenly mix, 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 min 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 6HEK293T cells were cultured for 12 h, and virus was ready 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 min;

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

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

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

[0080] 4) Collect the viral supernatant 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 DMEM containing virus to the dish and infect for 48 h.

[0082] 6) Screening: Cells were passaged and cultured in DMEM containing puromycin; the overexpression effect of ACE2 was detected after 4 days of 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: Add 2 µL of 10 mM stock solution to 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 into a black 96-well plate.

[0088] 4) 48 h after infection, detect the fluorescence reading 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 skeleton library. Each compound in the library represents a class of compounds with the same skeleton as it. The 5033 compounds represent 5033 molecular skeletons. With the skeleton as a clue, after determining that a certain skeleton structure plays a role, the structure can be optimized to extend more small molecules and find "low-toxic and high-efficiency" drugs. Therefore, screening drugs by skeleton can greatly increase the efficiency of screening.

[0094] After initially completing the 1000 small molecules ( Figure 3 After screening of A), we screened out two drugs with better 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, and 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 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, 16μM, 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 cells with drugs for 1 h, and the infection efficiency was detected after 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 pharmaceutical composition for resisting SARS-CoV-2 infection, characterized in that: The pharmaceutical composition comprises the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described in claim 1.

7. A pharmaceutical preparation for resisting SARS-CoV-2 infection, characterized in that: The pharmaceutical preparation comprises the pharmaceutical composition according to claim 6.

8. The pharmaceutical preparation according to claim 7, characterized in that The dosage form of the pharmaceutical preparation is solution, granule, tablet, sustained-release agent, suspension, effervescent agent, emulsion, capsule, powder, syrup, drop and / or chewable agent.

9. 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 described in claim 1.

10. Any of the following applications: (1) Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described in claim 1 in the preparation of a pharmaceutical composition for use in combating SARS-CoV-2 infection; (2) Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described in claim 1 in the preparation of a pharmaceutical preparation for anti-SARS-CoV-2 infection; (3) Use of the small molecule compound G125-0182 or a pharmaceutically acceptable salt thereof as described in claim 1 for inhibiting SARS-CoV-2 infection for non-therapeutic purposes in vitro.

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