Application of CC-115 in preparation of medicine for resisting new coronavirus
Through in vitro Vero cell infection model studies, it was found that CC-115 can inhibit the novel coronavirus (SARS-CoV-2 and Omicron variants) with IC50 values of 0.004 μM and 0.005 μM, respectively. This solves the problem that CC-115 has not been involved in the development of existing anti-COVID-19 drugs and provides an effective solution for combating COVID-19 infection.
Patent Information
- Application Number
- CN202511451396.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2025-07-30
- Filing Date
- 2025-10-11
- Publication Date
- 2026-02-10
AI Technical Summary
Existing anti-COVID-19 drug development strategies have not yet included the application of CC-115 in COVID-19 infection, and the potential therapeutic effects of CC-115 have not been studied.
In vitro Vero cell infection model studies have shown that CC-115 can inhibit the replication of SARS-CoV-2 and Omicron variants, with IC50 values of 0.004 μM and 0.005 μM, respectively, indicating that it has anti-SARS-CoV-2 activity.
CC-115 significantly inhibited the replication of SARS-CoV-2 in an in vitro model, providing a potential approach for developing drugs against SARS-CoV-2 infection.
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Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of antiviral drugs, and particularly relates to application of CC-115 in preparation of an anti-novel coronavirus drug. BACKGROUND
[0002] The current anti-novel coronavirus drug research and development strategies mainly include target drug design and development of key viral molecules (such as Mpro, RdRP, PLpro, etc.) and host factors (such as ACE2, TMPRSS2, etc.), and drug screening based on viral infection models. The former develops small molecule, polypeptide, aptamer, etc. inhibitors through virtual screening or experimental screening based on molecular interaction, and develops neutralizing antibodies through antigen immune screening or antibody gene sequencing, etc. The latter tests various existing drugs and compound libraries (including known active compound libraries, natural product compound libraries, etc.), and screens drugs or compounds that can inhibit viral replication. The present application discovers that CC-115 has the activity of inhibiting novel coronavirus replication through screening of a kinase inhibitor library.
[0003] CC-115 is a dual inhibitor of DNA-dependent protein kinase DNA-PK and mammalian target of rapamycin mTOR (including mTORC1 and mTORC2) with IC50 of 0.013 μM and 0.021 μM, respectively. DNA-dependent protein kinase (DNA-PK) is a key component of DNA damage repair mechanism and is important for maintaining genome integrity. mTOR is a key mediator of the phosphoinositide 3-kinase / protein kinase B (PI3K / Akt) pathway and plays an important role in cell proliferation, apoptosis, metabolism, and other processes. CC-115 has potential anti-tumor activity. In vitro studies found that CC-115 inhibited the proliferation of PC-3 human prostate cancer cells with an IC50 value of 138 nM. CC-115 has good pharmacokinetic distribution in multiple species, with oral bioavailability of 53%, 76%, and ~100% in mice, rats, and dogs, respectively. In mouse tests, CC-115 was tested at lower doses of 0.25, 0.5, and 1 mg / kg bid or 1 mg / kg qd, and the corresponding tumor volumes were observed to be reduced by 46%, 57%, 66%, and 57%, respectively (Mortensen DS, et al. Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115. J Med Chem. 2015 Jul 23;58(14):5599-5608.). In chronic lymphocytic leukemia patients (CLL patients), CC-115 reduced lymphadenopathy (Thijssen R, et al. Dual TORK / DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood. 2016 Jul 28;128(4):574-83.). CC-115 has drug safety in in vitro and in vivo experiments and is suitable for clinical drug development. However, the therapeutic effect of CC-115 in COVID-19 infection has not been studied. The research results of the present application found that CC-115 can inhibit the replication of COVID-19, and the specific mechanism needs to be further studied. SUMMARY
[0004] The application aims to provide the application of CC-115 in the preparation of an anti-novel coronavirus drug. The novel coronavirus is SARS-CoV-2, and the CC-115 includes a pharmaceutically acceptable salt thereof or a derivative thereof, the chemical name of the CC-115 is: 1-ethyl-7-[2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl]-3,5-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, the molecular formula is: C16H16N8O, and the structural formula is as shown below: .
[0005] The application discloses that CC-115 has the effect of inhibiting the replication of the novel coronavirus, and through the study of a Vero cell infection model in vitro, it is shown that CC-115 can inhibit the replication of the original strain and the Omicron mutant strain (EG.5.1) of the novel coronavirus (SARS-CoV-2) and has the activity of resisting the novel coronavirus. In the Vero cell infection model, the IC50 for the original strain of SARS-CoV-2 is 0.004 μM, and the IC50 for the Omicron mutant strain (EG.5.1) is 0.005 μM. CC-115 can be used for the research and development of an anti-novel coronavirus infection drug and has good development prospects. BRIEF DESCRIPTION OF DRAWINGS
[0006] Figure 1 In the Vero cell infection model, CC-115 can significantly inhibit the replication of the novel coronavirus, the IC50 for the original strain of SARS-CoV-2 is 0.004 μM, and the IC50 for the Omicron mutant strain (EG.5.1) is 0.005 μM. DETAILED DESCRIPTION
[0007] The technical solutions of the application will be described clearly and completely below in combination with the drawings and examples, the application examples include but are not limited to the following conditions, and can be modified within the acceptable range in the art, and all other examples obtained by the person skilled in the art without creative labor on the basis of the examples in the application all belong to the protection range of the application.
[0008] Example 1: Anti-novel coronavirus drug screening model Vero cells were cultured in MEM medium at 37°C in a 5% CO2 incubator. The day before drug screening, the appropriate number of Vero cells were inoculated in a 48-well plate so that the density reached more than 90% the next day. The small molecule kinase inhibitor library was purchased from a commercial company, and the initial concentration was 10 mM. First, dilute to 100 μM initial concentration with MEM medium, then dilute to 10 concentrations with 3.33 and 3-fold cross gradient, so that the drug concentration reaches 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003 and 0.001 μM. 500 μL of drug-containing medium was added to the Vero cells at each concentration. Next, in a biosafety level 3 laboratory, the new coronavirus was infected, and the original virus liquid was diluted with MEM medium at an appropriate ratio, and 10 μL of diluted virus liquid was added to the culture well to be infected, so that the final infection titer reached about 100 TCID50. At the same time, set up no virus infection negative control, and add virus without drug positive control, all with 3 repeats. After 3 days of virus infection, the cell culture supernatant was aspirated to detect the virus amplification and evaluate the inhibitory effect of the drug on virus replication, and the cell pathology was observed under a microscope. If high-concentration drugs cause severe cell lesions, the drug concentration is considered invalid.
[0009] Example 2: Anti-new coronavirus effect evaluation After the culture ended, 200 μL of culture supernatant was aspirated, and the viral nucleic acid was extracted by a magnetic bead method nucleic acid extraction kit and a full-automatic nucleic acid extractor (Shanghai Zhijiang Biology). The new coronavirus nucleic acid detection kit (fluorescence PCR method) was used to detect the viral RNA level: by one-step RT-PCR combined with TaqMan technology, specific primers and probes were designed on ORF1a / b and N genes, respectively, the ORF1a / b gene probe was labeled with FAM fluorescein, the N gene probe was labeled with VIC fluorescein, and the internal standard probe was labeled with ROX fluorescein. After denaturation, annealing and extension by PCR, the light signals emitted after the hydrolysis of different fluorescein-labeled probes were collected by the PCR instrument, and the amplification curve was presented on the instrument, realizing the detection of new coronavirus ORF1a / b and N genes. The Ct value represents the level of virus, and the relative amount of viral nucleic acid of each concentration of drug treatment group and drug-free group is calculated by 2 -ΔΔCt Method to obtain the virus inhibition percentage and evaluate the anti-new coronavirus activity of the drug. See Figure 1 In this example, 100 μM and 30 μM CC-115 caused cell lesions and obvious morphological changes, although they inhibited virus replication, but were not counted as effective concentrations.
[0010] In summary, the present application provides a new use of CC-115 against new coronavirus. CC-115 is a potential drug for treating new coronavirus infection.
Claims
1. The application of CC-115 in the preparation of anti-COVID-19 drugs, characterized in that, CC-115 includes its pharmaceutically acceptable salts. The chemical name of CC-115 is 1-ethyl-7-[2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl]-3,5-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, with the molecular formula C16H16N8O, and the structural formula shown below: 。 2. The application according to claim 1, characterized in that, The novel coronavirus mentioned is SARS-CoV-2.
3. The application according to claim 1, characterized in that, CC-115 exhibits anti-SARS-CoV-2 activity by inhibiting the replication of the original SARS-CoV-2 strain and the Omicron mutant strain EG.5.1.