WO2022000167A1 - 转铁蛋白、转铁蛋白受体及其抗体在制备抗SARS-CoV-2病毒的药物中的应用 - Google Patents

转铁蛋白、转铁蛋白受体及其抗体在制备抗SARS-CoV-2病毒的药物中的应用 Download PDF

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WO2022000167A1
WO2022000167A1 PCT/CN2020/098861 CN2020098861W WO2022000167A1 WO 2022000167 A1 WO2022000167 A1 WO 2022000167A1 CN 2020098861 W CN2020098861 W CN 2020098861W WO 2022000167 A1 WO2022000167 A1 WO 2022000167A1
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transferrin
cov
sars
virus
transferrin receptor
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PCT/CN2020/098861
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English (en)
French (fr)
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赖仞
彭小忠
唐小芃
廖祉亦
鲁帅尧
刘红旗
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中国科学院昆明动物研究所
中国医学科学院医学生物学研究所
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Priority to PCT/CN2020/098861 priority Critical patent/WO2022000167A1/zh
Priority to JP2021530290A priority patent/JP7397079B2/ja
Priority to US17/415,782 priority patent/US20230060040A1/en
Publication of WO2022000167A1 publication Critical patent/WO2022000167A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the invention belongs to the technical field of antiviral drugs, in particular to the application of transferrin, transferrin receptors and antibodies thereof in the preparation of drugs against SARS-CoV-2 virus.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • novel coronavirus SARS-CoV-2 have crossed the species barrier and spread to humans through animals, causing human disease. Severe pneumonia.
  • the SARS-CoV epidemic was successfully contained through public health interventions such as early detection and isolation of cases.
  • the novel coronavirus was discovered in December 2019, and sequenced and isolated in January 2020.
  • the World Health Organization declared the SARS-CoV-2 outbreak a public health emergency of international concern [1-3].
  • the SARS-CoV-2 coronavirus is an enveloped virus with a positive RNA genome and belongs to the subfamily Coronaviridae. They are grouped into 4 genera ( ⁇ , ⁇ , ⁇ , and ⁇ ), and ⁇ -CoVs are grouped into four species (A, B, C, and D).
  • Transferrin is the main iron-containing protein in plasma.
  • the molecular weight of transferrin is about 77,000. It is a single-chain glycoprotein and is responsible for carrying the iron absorbed by the digestive tract and the iron released by the degradation of red blood cells.
  • the current research on the physiological function of transferrin shows that in addition to the function of transporting iron ions, it also has important functions such as antibacterial and participation in cell growth and differentiation [4].
  • Transferrin also delivers iron to cells through the endocytic pathway of transferrin receptors, so transferrin receptors play an important role in cellular iron homeostasis [5].
  • the purpose of the present invention is to provide a new use of transferrin, that is, the application of transferrin in the preparation of medicines against SARS-CoV-2 virus.
  • the purpose of the present invention is to also provide the application of transferrin receptor or transferrin receptor antibody in preparing medicine against SARS-CoV-2 virus.
  • the invention provides the application of transferrin in the preparation of medicines against SARS-CoV-2 virus.
  • the concentration of the transferrin is not less than 250 nmol/L.
  • the invention provides the application of transferrin in anti-SARS-CoV-2 virus.
  • the present invention provides the application of transferrin receptors in preparing medicines against SARS-CoV-2 virus.
  • the concentration of the transferrin receptor is not less than 100 nmol/L.
  • the present invention provides the application of transferrin receptor in anti-SARS-CoV-2 virus.
  • the present invention provides the application of transferrin receptor antibody in preparing medicine against SARS-CoV-2 virus.
  • the concentration of the transferrin receptor antibody is not less than 70 nmol/L.
  • the invention provides the application of transferrin receptor antibody in anti-SARS-CoV-2 virus.
  • the present invention provides the application of transferrin and/or transferrin receptor antibody in the preparation of biological products that bind the spike protein of SARS-CoV-2 virus.
  • the present invention provides a biological product that binds to the spike protein of SARS-CoV-2 virus, including transferrin and/or transferrin receptor antibody.
  • the present invention provides the application of transferrin receptor in the preparation of biological products binding the spike protein of SARS-CoV-2 virus.
  • the present invention provides an anti-SARS-CoV-2 virus composition, comprising transferrin and transferrin receptor antibody; the molar ratio of transferrin and transferrin receptor antibody is not less than 1:1 .
  • the present invention provides the application of the composition in the preparation of medicines against SARS-CoV-2 virus.
  • the present invention provides a drug against SARS-CoV-2 virus, comprising active ingredients and excipients, and the active ingredients include transferrin and transferrin receptor antibodies;
  • the molar ratio of transferrin and transferrin receptor antibody is not less than 1:1.
  • the invention provides the application of transferrin in the preparation of medicines against SARS-CoV-2 virus.
  • the present invention uses two methods of surface plasmon resonance (SPR) and immunofluorescence to confirm that SARS-CoV-2 binds to the transferrin receptor through the spike protein (spike) at the cellular level. Therefore, the use of transferrin competitive It binds to the transferrin receptor of the body, blocks the active site of the transferrin receptor, inhibits the binding of SARS-CoV-2 to the transferrin receptor, thereby blocking the way that the SARS-CoV-2 virus infects cells, achieving Antiviral effects of the body.
  • SPR surface plasmon resonance
  • immunofluorescence to confirm that SARS-CoV-2 binds to the transferrin receptor through the spike protein (spike) at the cellular level. Therefore, the use of transferrin competitive It binds to the transferrin receptor of the body, blocks the active site of the transferrin receptor, inhibits the binding of SARS-CoV-2 to the transfer
  • transferrin is used to treat cells infected with SARS-CoV-2 virus.
  • the results show that transferrin can effectively inhibit the infection of SARS-CoV-2 virus, and the inhibition strength is strong. in a dose-dependent manner.
  • the present invention provides the application of transferrin receptors in preparing medicines against SARS-CoV-2 virus.
  • the present invention adopts two methods of surface plasmon resonance (SPR) and immunofluorescence to confirm the binding of SARS-CoV-2 to the transferrin receptor through its spike protein (spike) at the cellular level. Therefore, the transferrin receptor is used.
  • SPR surface plasmon resonance
  • spike spike protein
  • transferrin receptors are used to treat cells infected with SARS-CoV-2 virus.
  • the results show that transferrin receptors can effectively inhibit the infection of SARS-CoV-2 virus. , and the inhibitory intensity was dose-dependent.
  • the present invention provides the application of transferrin receptor antibody in preparing medicine against SARS-CoV-2 virus.
  • the present invention adopts two methods of surface plasmon resonance (SPR) and immunofluorescence to confirm the binding of SARS-CoV-2 to the transferrin receptor through its spike protein (spike) at the cellular level. Therefore, the transferrin receptor is used.
  • the antibody competitively binds to the transferrin receptor, blocks the active site of the transferrin receptor, and inhibits the binding of SARS-CoV-2 to the transferrin receptor in the body, thereby blocking the way the SARS-CoV-2 virus infects cells. To achieve the body's antiviral effect.
  • Fig. 1 shows that surface plasmon resonance (SPR) and immunofluorescence in Example 1 and Example 2 verify that SARS-CoV-2-spike (spike protein) binds to transferrin receptor;
  • A is surface plasmon resonance (SPR) ) to verify the binding of SARS-CoV-2-spike (spike protein) to the transferrin receptor, where the curves represent 250nM, 125nM, 62.5nM, 31.25nM, 15.625nM, 7.8125nM and 3.90625nM respectively from top to bottom;
  • B is the result of immunofluorescence verification of the binding of SARS-CoV-2-spike (spike protein) to transferrin receptor;
  • Figure 2 is a morphological diagram of Vero E6 cells infected with SARS-CoV-2 treated by the positive control drug Remdesivir in Comparative Example 1;
  • Figure 3 is a comparison diagram of Vero E6 cells infected with SARS-CoV-2 treated with transferrin at different concentrations (31.25nM, 62.5nM, 125nM, 250nM, 500nM and 1000nM) in Example 3;
  • Figure 4 shows the statistical results of the inhibition rate of transferrin on SARS-CoV-2 infected cells by CPE and qPCR in Example 3, wherein A is the result of using CPE to analyze the inhibition rate of transferrin on SARS-CoV-2 infected cells Statistical results; B is the statistical result of using qPCR to analyze the inhibition rate of transferrin on SARS-CoV-2 infected cells;
  • Figure 5 is a comparison diagram of Vero E6 cells infected with SARS-CoV-2 treated with transferrin receptors at different concentrations (25nM, 50nM, 100nM, 200nM, 400nM and 800nM) in Example 4;
  • Figure 6 is the statistics of the inhibition rate of transferrin receptor on SARS-CoV-2 infected cells by CPE and qPCR in Example 4, wherein, A is the analysis of transferrin on SARS-CoV-2 infected cells using CPE method The statistical results of the inhibition rate; B is the statistical results of the inhibition rate of SARS-CoV-2 infected cells by qPCR analysis of transferrin;
  • Figure 7 is a comparison diagram of Vero E6 cells infected with SARS-CoV-2 treated with different concentrations (12.5nM, 25nM, 50nM, 100nM, 200nM and 400nM) of transferrin receptor monoclonal antibody in Example 5;
  • Figure 8 shows the statistics of the inhibition rate of transferrin receptor monoclonal antibody to SARS-CoV-2 infected cells by CPE and qPCR in Example 5, wherein, A is the analysis of transferrin on SARS-CoV-2 using CPE 2 Statistical results of the inhibition rate of infected cells; B is the statistical results of the inhibition rate of transferrin on SARS-CoV-2 infected cells using qPCR method.
  • the invention provides the application of transferrin in the preparation of medicines against SARS-CoV-2 virus.
  • the present invention does not specifically limit the source of the transferrin, and the transferrin known in the art can be used.
  • the transferrin was purchased from Sigma, the product number is T4382.
  • the SARS-CoV-2 virus-infected cells were treated with transferrin in a continuous series of gradient concentrations, and the results showed that transferrin could effectively inhibit the infection of SARS-CoV-2 virus, and the inhibitory intensity was dose-dependent.
  • the results of cytopathic effect (CPE) analysis showed that the EC 50 of the transferrin was 125 nmol/L; the quantitative analysis of reverse transcription real-time PCR (qRT-PCR) showed that the EC 50 of the transferrin was 160 nmol/L. L.
  • the concentration of transferrin is preferably not lower than 250 nmol/L.
  • the present invention provides the application of transferrin receptors in preparing medicines against SARS-CoV-2 virus.
  • the source of the transferrin receptor is not specifically limited in the present invention, and a transferrin receptor known in the art may be used.
  • the transferrin receptor was purchased from Sino Biological, the product number is 11020-H07H.
  • a series of gradient concentrations of transferrin receptor were used to treat SARS-CoV-2 virus-infected cells, and the results showed that transferrin receptor could effectively inhibit the infection of SARS-CoV-2 virus in a dose-dependent manner.
  • the results of cytopathic effect (CPE) analysis showed that the EC 50 of the transferrin receptor was 80 nmol/L; the quantitative analysis of reverse transcription real-time PCR (qRT-PCR) showed that the EC of the transferrin receptor was 80 nmol/L. 50 is 93 nmol/L.
  • the concentration of the transferrin receptor is not less than 100 nmol/L.
  • the present invention provides the application of transferrin receptor antibody in preparing medicine against SARS-CoV-2 virus.
  • the present invention does not specifically limit the type of the transferrin receptor antibody, and any polyclonal antibody or monoclonal antibody known in the art can be used.
  • the present invention does not specifically limit the source of the antibody, and a transferrin receptor antibody known in the art may be used.
  • the transferrin receptor monoclonal antibody was purchased from Abcam, the product number is ab1086.
  • a series of gradient concentrations of transferrin receptor monoclonal antibodies were used to treat SARS-CoV-2 virus-infected cells. The results showed that transferrin receptor monoclonal antibodies could effectively inhibit the infection of SARS-CoV-2 virus, and the inhibition strength was in a dose-dependent manner.
  • CPE cytopathic effect
  • the antiviral effect of transferrin or transferrin receptor antibodies is to block the binding of SARS-CoV-2 to the body's transferrin receptor, which is bound by the virus through the spike protein. Binding to the body's transferrin receptor is achieved. Therefore, the present invention provides the use of transferrin and/or transferrin receptor antibodies in the preparation of biological products that bind to the spike protein of SARS-CoV-2 virus. At the same time, the present invention also provides the application of the transferrin receptor in the preparation of a biological product that binds the spike protein of the SARS-CoV-2 virus. The present invention does not specifically limit the type of the biological product, and the biological product well known in the art can be prepared.
  • the present invention provides an anti-SARS-CoV-2 virus composition, comprising transferrin and transferrin receptor antibody; the molar ratio of transferrin and transferrin receptor antibody is not less than 1:1 .
  • the sources of the transferrin and transferrin receptor antibodies are not specifically limited in the present invention, and sources of transferrin and transferrin receptor antibodies known in the art may be used.
  • the molar ratio of the transferrin and transferrin receptor antibody is preferably 2-5:1, more preferably 3-4:1.
  • the present invention provides the application of the composition in the preparation of medicines against SARS-CoV-2 virus.
  • the dosage form of the medicament is not specifically limited, and a well-known pharmaceutical dosage form in the art can be used.
  • the medicine contains different kinds of excipients according to different dosage forms.
  • the present invention does not have special restrictions on the types of the auxiliary materials, and the auxiliary materials well known in the art can be used.
  • the present invention has no special limitation on the preparation method of the medicine, and the preparation method of the medicine well-known in the art can be used.
  • the invention provides the application of transferrin, transferrin receptor or transferrin receptor antibody in anti-SARS-CoV-2 virus.
  • the present invention has no particular limitation on the source of the transferrin, transferrin receptor or transferrin receptor antibody. source can be.
  • the present invention provides a drug against SARS-CoV-2 virus, comprising active ingredients and excipients, the active ingredients include transferrin and transferrin receptor antibodies; the transferrin and transferrin receptor antibodies
  • the molar ratio is not less than 1:1, preferably 2 to 5:1, more preferably 3 to 4:1.
  • the present invention does not have special restrictions on the types and contents of the auxiliary materials, and the pharmaceutical auxiliary materials well known in the art can be used.
  • the present invention has no special limitation on the preparation method of the medicine, and the preparation method of the medicine well-known in the art can be used.
  • transferrin, transferrin receptor and its antibody in the preparation of anti-SARS-CoV-2 virus medicines provided by the present invention will be described in detail below in conjunction with the examples, but they should not be construed as the protection scope of the present invention. limited.
  • Transferrin receptor (Cat. No. 11020-H07H) was first diluted to 20 ⁇ g/ml with 200 ⁇ l of sodium acetate buffer (10 mM, pH 5), then flowed through a CM5 sensor chip (BR100012, GE) at a flow rate of 5 ⁇ l/min , reaching a resonance unit (RU) of 2000; the remaining activated sites on the chip were blocked with 75 ⁇ l of ethanolamine solution (1 M, pH 8.5).
  • Sequential concentrations of spike proteins (3.90625nM, 7.8125nM, 15.625nM, 31.25nM, 62.5nM, 125nM, 250nM; Cat. No. Z03481) were analyzed for their interaction with the immobilized transferrin receptor at a flow rate of 10 ⁇ l/min. Binding KD and Ka and Kd rate constants were determined using BIA software (GE, USA).
  • MOCK membrane surface transferrin receptor and spike protein complexes in Vero E6 cells
  • MOCK cells were fixed with 4% paraformaldehyde in PBS for 15 min, blocked with 1% BSA solution for 1 h at room temperature, and then diluted with anti-transferrin receptor antibody (1:200; 11020-MM04 , Sino Biological, China) and anti-Spike protein (1:200 dilution; 40150-R007, Sino biological, China) were incubated together for 1 h at 37°C.
  • Remdesivir was used as a positive control drug to study its effect on SARS-CoV-2 infection of African green monkey embryonic kidney cells (Vero E6).
  • Vero E6 cells were pretreated with remdesivir (4 ⁇ M) for 1 h, and then SARS-CoV-2 virus was added to infect for 1 h. Then, the virus-protein mixture was removed and the cells were further cultured with fresh medium containing 4 ⁇ M remdesivir. After 48 h of treatment, the cell supernatant was collected and lysed with lysis buffer (15596018, Thermo, USA), and the cell morphology before and after treatment was observed and photographed under a microscope.
  • lysis buffer 15596018, Thermo, USA
  • Vero E6 cells were pretreated with different concentrations (31.25nM, 62.5nM, 125nM, 250nM, 500nM and 1000nM) of transferrin for 1h, and then SARS-CoV-2 virus was added for 1h infection. Then, the virus-protein mixture was removed and the cells were further cultured with fresh medium containing different concentrations (31.25 nM, 62.5 nM, 125 nM, 250 nM, 500 nM and 1000 nM) of transferrin. After 48 h of culture, the cell supernatant was collected and lysed with lysis buffer (15596018, Thermo, USA), and the cell morphology before and after treatment was observed and photographed under a microscope.
  • lysis buffer 15596018, Thermo, USA
  • RT-qPCR Cytopathogenic effects (CPE) (refer to M. Wang et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30, 269-271 (2020)) and real-time quantitative RT- PCR (qRT-PCR) quantitative analysis.
  • CPE Cytopathogenic effects
  • qRT-PCR real-time quantitative RT- PCR
  • nucleotide sequences of the NP gene primers and probes are as follows:
  • Target-2-F 5'-ggggaacttctcctgctagaat-3' (SEQ ID No. 1);
  • Target-2-R 5'-cagacattttgctctcaagctg-3' (SEQ ID No. 2);
  • Target-2-P 5'-FAM-ttgctgctgcttgacagatt-TAMRA-3' (SEQ ID No. 3).
  • the PCR amplification program was as follows: 25°C for 2 min; 50°C for 2 min; 95°C for 2 min; 95°C for 5s, 58°C for 31s, 40 cycles.
  • the PCR amplification system is as follows: 0.5 ⁇ l each of forward primer F, reverse primer and fluorescent probe P; 4 ⁇ qPCR reaction MIX 2.5 ⁇ l, supplemented with ddH 2 O to 10 ⁇ l.

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Abstract

本发明提供转铁蛋白、转铁蛋白受体及其抗体在制备抗SARS-CoV-2病毒的药物中的应用，属于抗病毒药技术领域。转铁蛋白、转铁蛋白受体或转铁蛋白受体抗体在制备抗SARS-CoV-2的药物中的应用。表面等离子共振和免疫荧光均证实SARS-CoV-2通过其刺突蛋白与转铁蛋白受体结合，采用转铁蛋白和/或转铁蛋白受体抗体竞争性结合至机体转铁蛋白受体上，或转铁蛋白受体竞争性结合SARS-CoV-2的位点上，抑制SARS-CoV-2与机体的转铁蛋白受体结合，从而阻断SARS-CoV-2病毒感染细胞的机会，实现机体的抗病毒作用。转铁蛋白、转铁蛋白受体及其抗体在制备结合SARS-CoV-2病毒刺突蛋白的生物制品中的应用。

Description

转铁蛋白、转铁蛋白受体及其抗体在制备抗SARS-CoV-2病毒的药物中的应用 技术领域
本发明属于抗病毒药物技术领域，具体涉及转铁蛋白、转铁蛋白受体及其抗体在制备抗SARS-CoV-2病毒的药物中的应用。
背景技术
21世纪以来，严重急性呼吸道综合征冠状病毒(SARS-CoV)，中东呼吸综合征冠状病毒(MERS-CoV)和新型冠状病毒SARS-CoV-2，越过物种屏障，通过动物传播到人类，导致人类患上严重的肺炎。通过早发现和隔离病例等公共卫生干预措施，成功遏制了SARS-CoV的流行。2019年12月，发现的新型冠状病毒，并于2020年1月进行了测序和分离。2020年1月30日，世界卫生组织宣布SARS-CoV-2疫情为国际关注的突发公共卫生事件[1-3]。SARS-CoV-2冠状病毒是带有阳性RNA基因组的包膜病毒，属于冠状病毒亚科。它们分为4个属(α、β、γ和δ)，β-CoV又分为四个种(A，B，C和D)。
转铁蛋白(transferrin)是血浆中主要的含铁蛋白质，转铁蛋白的分子量约7.7万，为单链糖蛋白，负责运载由消化管吸收的铁和由红细胞降解释放的铁。转铁蛋白的生理功能在现阶段的研究显示除了具有转运铁离子的功能，还具有抗菌，参与细胞的生长分化等重要功能[4]。转铁蛋白也通过转铁蛋白受体的内吞途径将铁传递给细胞，因此转铁蛋白受体对细胞铁稳态具有重要作用[5]。
[1]A.C.Walls et al.,Structure,Function,and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.Cell 181,281-292 e286(2020).
[2]R.Li et al.,Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus(SARS-CoV-2).Science 368,489-493(2020).
[3]W.Wang et al.,Detection of SARS-CoV-2 in Different Types of Clinical Specimens.JAMA,(2020).
[4]P.T.Gomme,K.B.McCann,J.Bertolini,Transferrin:structure, function and potential therapeutic actions.Drug Discov Today 10,267-273(2005).
[5]H.Fuchs,U.Lucken,R.Tauber,A.Engel,R.Gessner,Structural model of phospholipid-reconstituted human transferrin receptor derived by electron microscopy.Structure 6,1235-1243(1998).
发明内容
有鉴于此，本发明的目的在于提供一种转铁蛋白的新用途，即转铁蛋白在制备抗SARS-CoV-2病毒的药物中的应用。
本发明的目的在于还提供转铁蛋白受体或转铁蛋白受体抗体在制备抗SARS-CoV-2病毒的药物中的应用。
本发明提供了转铁蛋白在制备抗SARS-CoV-2病毒的药物中的应用。
优选的，所述转铁蛋白的浓度不低于250nmol/L。
本发明提供了转铁蛋白在抗SARS-CoV-2病毒中的应用。
本发明提供了转铁蛋白受体在制备抗SARS-CoV-2病毒的药物中的应用。
优选的，所述转铁蛋白受体的浓度不低于100nmol/L。
本发明提供了转铁蛋白受体在抗SARS-CoV-2病毒中的应用。
本发明提供了转铁蛋白受体抗体在制备抗SARS-CoV-2病毒的药物中的应用。
优选的，所述转铁蛋白受体抗体的浓度不低于70nmol/L。
本发明提供了转铁蛋白受体抗体在抗SARS-CoV-2病毒中的应用。
本发明提供了转铁蛋白和/或转铁蛋白受体抗体在制备结合SARS-CoV-2病毒的刺突蛋白的生物制品中的应用。
本发明提供了一种结合SARS-CoV-2病毒的刺突蛋白的生物制品，包括转铁蛋白和/或转铁蛋白受体抗体。
本发明提供了转铁蛋白受体在制备结合SARS-CoV-2病毒的刺突蛋白的生物制品中的应用。
本发明提供了一种抗SARS-CoV-2病毒的组合物，包括转铁蛋白和转铁蛋白受体抗体；所述转铁蛋白和转铁蛋白受体抗体的摩尔比不低于1:1。
本发明提供了所述组合物在制备抗SARS-CoV-2病毒的药物中的应用。
本发明提供了一种抗SARS-CoV-2病毒的药物，包括活性成分和辅料，所述活性成分包括转铁蛋白和转铁蛋白受体抗体；
所述转铁蛋白和转铁蛋白受体抗体的摩尔比不低于1:1。
本发明提供了转铁蛋白在制备抗SARS-CoV-2病毒的药物中的应用。本发明采用表面等离子共振(SPR)和免疫荧光两种方法证实，在细胞水平上SARS-CoV-2通过刺突蛋白(spike)与转铁蛋白受体的结合，因此，采用转铁蛋白竞争性结合至机体的转铁蛋白受体上，封闭转铁蛋白受体活性位点，抑制SARS-CoV-2与转铁蛋白受体结合，从而阻断SARS-CoV-2病毒感染细胞的途径，实现机体的抗病毒作用。实验证明，以瑞德西韦作为阳性对照药，采用转铁蛋白来治疗感染SARS-CoV-2病毒的细胞，结果表明，转铁蛋白能有效抑制SARS-CoV-2病毒的感染，且抑制强度呈剂量依赖性。
本发明提供了转铁蛋白受体在制备抗SARS-CoV-2病毒的药物中的应用。本发明采用表面等离子共振(SPR)和免疫荧光两种方法证实在细胞水平上SARS-CoV-2通过其刺突蛋白(spike)与转铁蛋白受体的结合，因此，采用转铁蛋白受体通过竞争性结合至SARS-CoV-2病毒上，封闭SARS-CoV-2病毒结合位点，抑制SARS-CoV-2与机体的转铁蛋白受体结合，从而阻断SARS-CoV-2病毒感染细胞的途径，实现机体的抗病毒作用。实验证明，以瑞德西韦作为阳性对照药，采用转铁蛋白受体来治疗感染SARS-CoV-2病毒的细胞，结果表明，转铁蛋白受体能有效抑制SARS-CoV-2病毒的感染，且抑制强度呈剂量依赖性。
本发明提供了转铁蛋白受体抗体在制备抗SARS-CoV-2病毒的药物中的应用。本发明采用表面等离子共振(SPR)和免疫荧光两种方法证实在细胞水平上SARS-CoV-2通过其刺突蛋白(spike)与转铁蛋白受体的结合，因此，采用转铁蛋白受体抗体竞争性结合至转铁蛋白受体，封闭转铁蛋白受体活性位点，抑制SARS-CoV-2与机体中转铁蛋白受体结合，从 而阻断SARS-CoV-2病毒感染细胞的途径，实现机体的抗病毒作用。实验证明，以瑞德西韦作为阳性对照药，采用转铁蛋白受体单克隆抗体来治疗感染SARS-CoV-2病毒的细胞，结果表明，转铁蛋白受体单克隆抗体能有效抑制SARS-CoV-2病毒的感染，且抑制强度呈剂量依赖性。
附图说明
图1为实施例1和实施例2中表面等离子共振(SPR)和免疫荧光验证SARS-CoV-2-spike(刺突蛋白)与转铁蛋白受体结合；其中，A为表面等离子共振(SPR)验证SARS-CoV-2-spike(刺突蛋白)与转铁蛋白受体结合，其中，曲线由上到下分别代表250nM、125nM、62.5nM、31.25nM、15.625nM、7.8125nM和3.90625nM；B为免疫荧光验证SARS-CoV-2-spike(刺突蛋白)与转铁蛋白受体结合结果图；
图2为对比例1中阳性对照药瑞德西韦治疗SARS-CoV-2感染的Vero E6细胞的形态图；
图3为实施例3中不同浓度(31.25nM、62.5nM、125nM、250nM、500nM和1000nM)转铁蛋白治疗SARS-CoV-2感染的Vero E6细胞的对比图；
图4为实施例3中以CPE和qPCR对转铁蛋白对SARS-CoV-2感染细胞的抑制率进行统计结果，其中A为采用CPE分析转铁蛋白对SARS-CoV-2感染细胞抑制率的统计结果；B为采用qPCR分析转铁蛋白对SARS-CoV-2感染细胞抑制率的统计结果；
图5为实施例4中不同浓度(25nM、50nM、100nM、200nM、400nM和800nM)转铁蛋白受体治疗SARS-CoV-2感染的Vero E6细胞对比图；
图6为实施例4中以CPE和qPCR对转铁蛋白受体对SARS-CoV-2感染细胞的抑制率进行统计，其中，A为采用CPE方法分析转铁蛋白对SARS-CoV-2感染细胞抑制率的统计结果；B为采用qPCR分析转铁蛋白对SARS-CoV-2感染细胞抑制率的统计结果；
图7为实施例5中不同浓度(12.5nM、25nM、50nM、100nM、200nM和400nM)转铁蛋白受体单克隆抗体治疗SARS-CoV-2感染的Vero E6细胞对比图；
图8为实施例5中以CPE和qPCR对转铁蛋白受体单克隆抗体对SARS-CoV-2感染细胞的抑制率进行统计，其中，A为采用CPE方法分析转铁蛋白对SARS-CoV-2感染细胞抑制率的统计结果；B为采用qPCR方法分析转铁蛋白对SARS-CoV-2感染细胞抑制率的统计结果。
具体实施方式
本发明提供了转铁蛋白在制备抗SARS-CoV-2病毒的药物中的应用。
本发明对所述转铁蛋白的来源不做具体限定，采用本领域所熟知的转铁蛋白即可。在本发明实施例中，所述转铁蛋白购自Sigma，货号为T4382。采用连续系列梯度浓度的转铁蛋白治疗SARS-CoV-2病毒感染的细胞，结果表明，转铁蛋白能有效抑制SARS-CoV-2病毒的感染，且抑制强度呈剂量依赖性。细胞致病作用(CPE)分析结果表明，所述转铁蛋白的EC 50为125nmol/L；反转录实时定量PCR(qRT-PCR)定量分析表明，所述转铁蛋白的EC 50为160nmol/L。所述转铁蛋白的浓度优选不低于250nmol/L。
本发明提供了转铁蛋白受体在制备抗SARS-CoV-2病毒的药物中的应用。
本发明对所述转铁蛋白受体的来源不做具体限定，采用本领域所熟知的转铁蛋白受体即可。在本发明实施例中，所述转铁蛋白受体购自Sino Biological，货号为11020-H07H。采用系列梯度浓度的转铁蛋白受体治疗SARS-CoV-2病毒感染的细胞，结果表明，转铁蛋白受体能有效抑制SARS-CoV-2病毒的感染，且抑制强度呈剂量依赖性。细胞致病作用(CPE)分析结果表明，所述转铁蛋白受体的EC 50为80nmol/L；反转录实时定量PCR(qRT-PCR)定量分析表明，所述转铁蛋白受体的EC 50为93nmol/L。所述转铁蛋白受体的浓度不低于100nmol/L。
本发明提供了转铁蛋白受体抗体在制备抗SARS-CoV-2病毒的药物中的应用。
本发明对所述转铁蛋白受体抗体的种类不做具体限定，采用本领域所熟知的多克隆抗体或单克隆抗体均可。本发明对所述抗体的来源不做具体限定，采用本领域所熟知的转铁蛋白受体抗体即可。在本发明实施例中， 所述转铁蛋白受体单克隆抗体购自Abcam，货号为ab1086。采用系列梯度浓度的转铁蛋白受体单克隆抗体治疗SARS-CoV-2病毒感染的细胞，结果表明，转铁蛋白受体单克隆抗体能有效抑制SARS-CoV-2病毒的感染，且抑制强度呈剂量依赖性。细胞致病作用(CPE)分析结果表明，所述转铁蛋白受体单克隆抗体的EC 50为80nmol/L；反转录实时定量PCR(qRT-PCR)定量分析表明，所述转铁蛋白受体的EC 50为50nmol/L。所述转铁蛋白受体的浓度不低于16.6nmol/L。所述转铁蛋白受体抗体的浓度不低于70nmol/L。
实验证明，转铁蛋白或转铁蛋白受体抗体发挥抗病毒作用是通过阻断SARS-CoV-2与机体的转铁蛋白受体的结合发挥作用，而其结合是所述病毒通过刺突蛋白与机体的转铁蛋白受体的结合实现的。因此，本发明提供了转铁蛋白和/或转铁蛋白受体抗体在制备结合SARS-CoV-2病毒的刺突蛋白的生物制品中的应用。同时本发明还提供了转铁蛋白受体在制备结合SARS-CoV-2病毒的刺突蛋白的生物制品中的应用。本发明对所述生物制品的种类不做具体限制，制备本领域所熟知的生物制品即可。
本发明提供了一种抗SARS-CoV-2病毒的组合物，包括转铁蛋白和转铁蛋白受体抗体；所述转铁蛋白和转铁蛋白受体抗体的摩尔比不低于1:1。
本发明对所述转铁蛋白和转铁蛋白受体抗体的来源不做具体限定，采用本领域所熟知的转铁蛋白和转铁蛋白受体抗体的来源即可。所述转铁蛋白和转铁蛋白受体抗体的摩尔比优选为2～5:1，更优选为3～4:1。
本发明提供了所述组合物在制备抗SARS-CoV-2病毒的药物中的应用。
在本发明中，所述药物的剂型不做具体限定，采用本领域所熟知的药物剂型即可。所述药物根据剂型的不同包含不同种类的辅料。本发明对所述辅料的种类没有特殊限制，采用本领域所熟知的辅料即可。本发明对所述药物的制备方法没有特殊限制，采用本领域所熟知的药物的制备方法即可。
本发明提供了转铁蛋白、转铁蛋白受体或转铁蛋白受体抗体在抗SARS-CoV-2病毒中的应用。本发明对所述转铁蛋白、转铁蛋白受体或转 铁蛋白受体抗体的来源没有特殊限制，采用本领域所熟知的转铁蛋白、转铁蛋白受体或转铁蛋白受体抗体的来源即可。
本发明提供了一种抗SARS-CoV-2病毒的药物，包括活性成分和辅料，所述活性成分包括转铁蛋白和转铁蛋白受体抗体；所述转铁蛋白和转铁蛋白受体抗体的摩尔比不低于1:1，优选为2～5:1，更优选为3～4:1。本发明对所述辅料的种类和含量没有特殊限制，采用本领域所熟知的药品辅料即可。本发明对所述药物的制备方法没有特殊限制，采用本领域所熟知的药物的制备方法即可。
下面结合实施例对本发明提供的转铁蛋白、转铁蛋白受体及其抗体在制备抗SARS-CoV-2病毒的药物中的应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
表面等离子共振(SPR)验证SARS-CoV-刺突蛋白(spike)与转铁蛋白受体结合
使用BIAcore 2000(美国通用电气公司)分析转铁蛋白受体与刺突蛋白(spike)的相互作用。首先将转铁蛋白受体(货号11020-H07H)用200μl乙酸钠缓冲液(10mM，pH值5)稀释至20μg/ml，然后流过CM5传感器芯片(BR100012，GE)以5μl/min的流速流动，达到2000的共振单位(RU)；芯片上剩余的活化位点用75μl乙醇胺溶液(1M，pH值8.5)封闭。刺突蛋白(3.90625nM，7.8125nM，15.625nM，31.25nM，62.5nM，125nM，250nM；货号Z03481)的连续浓度以10μl/min的流速分析它们与固定化转铁蛋白受体的相互作用。使用BIA软件(GE，美国)确定结合的KD以及Ka和Kd速率常数。
结果见图1A。由图1A可知，SARS-CoV-2刺突蛋白与转铁蛋白受体结合，结合能力强。
实施例2
免疫荧光验证细胞水平SARS-CoV-2-刺突蛋白与转铁蛋白受体结合
为了检测Vero E6细胞的膜表面转铁蛋白受体和刺突蛋白复合物，将细胞(MOCK)感染SARS-CoV-2(MOI＝0.2)2h，以未感染的MOCK作为对照。用PBS洗涤后，将MOCK细胞用PBS中的4％多聚甲醛固定 15分钟，在室温下用1％BSA溶液封闭1h，然后与抗转铁蛋白受体抗体(1：200稀释；11020-MM04,Sino Biological,China)和抗刺突蛋白(1：200稀释；40150-R007,Sino biological,China)的抗体一起孵育在37℃下孵育1h。用PBS洗涤3次以去除多余的一抗后，将切片与荧光标记的二抗一起37℃下孵育1h。用PBS洗涤以去除多余的二抗后，将细胞用DAPI(P36941，Life Technologies，美国)染色，并用共聚焦显微镜(FluoView TM1000，Olympus，美国)成像。
结果见图1中B。SARS-CoV-2刺突蛋白与转铁蛋白受体在细胞水平结合。
对比例1
瑞德西韦作为阳性对照药研究其对SARS-CoV-2感染非洲绿猴胚肾细胞(Vero E6)的影响。
具体步骤如下：将Vero E6细胞用瑞德西韦(4μM)预处理1h，然后加入SARS-CoV-2病毒感染1h。然后，除去病毒-蛋白质混合物，并用新鲜的含4μM瑞德西韦的培养基进一步培养细胞。在处理48h时，收集细胞上清液，并用裂解缓冲液(15596018，Thermo，USA)裂解，在显微镜下观察并拍照处理前与处理后的细胞形态。
结果见图2。处理前后的细胞形态对比发现，瑞德西韦能够抑制SARS-CoV-2感染细胞。
实施例3
不同浓度转铁蛋白治疗SARS-CoV-2感染的Vero-E6细胞。
将Vero E6细胞用不同浓度(31.25nM、62.5nM、125nM、250nM、500nM和1000nM)转铁蛋白预处理1h，然后加入SARS-CoV-2病毒感染1h。然后，除去病毒-蛋白质混合物，并用新鲜的含不同浓度(31.25nM、62.5nM、125nM、250nM、500nM和1000nM)转铁蛋白的培养基进一步培养细胞。在培养48h时，收集细胞上清液，并用裂解缓冲液(15596018，Thermo，USA)裂解，在显微镜下观察并拍照处理前与处理后的细胞形态。
然后采用细胞致病作用(CPE)(参考M.Wang et al.,Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus(2019-nCoV)in vitro.Cell Res 30,269-271(2020))和实时定量RT-PCR (qRT-PCR)定量分析。其中，RT-qPCR按照说明书操作，分别使用RNA提取试剂盒(DP419)和反转录试剂盒(A5000)进行RNA提取和cDNA反转录程序。RT-qPCR的检测方法如下：
NP基因引物和探针的核苷酸序列如下：
Target-2-F:5'-ggggaacttctcctgctagaat-3'(SEQ ID No.1)；
Target-2-R:5'-cagacattttgctctcaagctg-3'(SEQ ID No.2)；
Target-2-P:5'-FAM-ttgctgctgcttgacagatt-TAMRA-3'(SEQ ID No.3)。
PCR扩增的程序如下25℃2min；50℃2min；95℃2min；95℃5s，58℃31s，进行40个循环。PCR扩增的体系如下：正向引物F、反向引物和荧光探针P各0.5μl；4×qPCR反应MIX 2.5μl，用ddH 2O补充至10μl。
结果参见图3和图4。由上述结果可知，CPE统计的转铁蛋白的EC 50为125nM，RT-qPCR结果统计的转铁蛋白的EC 50为160nM。随着转铁蛋白的浓度增大，对SARS-CoV-2病毒的抑制作用强。转铁蛋白能够抑制SARS-CoV-2感染。
实施例4
不同浓度(25nM、50nM、100nM、200nM、400nM和800nM)转铁蛋白受体治疗SARS-CoV-2感染的Vero-E6细胞。具体步骤参见实施例3记载。
结果参见图5和图6。由上述结果可知，CPE统计的转铁蛋白的EC 50为80nM，RT-qPCR结果统计的转铁蛋白的EC 50为93nM。随着转铁蛋白的浓度增大，对SARS-CoV-2病毒的抑制作用强。转铁蛋白受体能够抑制SARS-CoV-2感染。
实施例5
不同浓度转铁蛋白受体单克隆抗体治疗SARS-CoV-2感染的Vero-E6细胞。具体步骤参见实施例3记载。
结果参见图7和图8。由上述结果可知，CPE统计的转铁蛋白的EC 50为50nM，RT-qPCR结果统计的转铁蛋白的EC 50为16.6nM。随着转铁蛋白的浓度增大，对SARS-CoV-2病毒的抑制作用强。转铁蛋白受体单克隆抗体能够抑制SARS-CoV-2感染。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的 普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (15)

  1. 转铁蛋白在制备抗SARS-CoV-2病毒的药物中的应用。
  2. 根据权利要求1所述应用，其特征在于，所述转铁蛋白的浓度不低于250nmol/L。
  3. 转铁蛋白在抗SARS-CoV-2病毒中的应用。
  4. 转铁蛋白受体在制备抗SARS-CoV-2病毒的药物中的应用。
  5. 根据权利要求4所述应用，其特征在于，所述转铁蛋白受体的浓度不低于100nmol/L。
  6. 转铁蛋白受体在抗SARS-CoV-2病毒中的应用。
  7. 转铁蛋白受体抗体在制备抗SARS-CoV-2病毒的药物中的应用。
  8. 根据权利要求7所述应用，其特征在于，所述转铁蛋白受体抗体的浓度不低于70nmol/L。
  9. 转铁蛋白受体抗体在抗SARS-CoV-2病毒中的应用。
  10. 转铁蛋白和/或转铁蛋白受体抗体在制备结合SARS-CoV-2病毒的刺突蛋白的生物制品中的应用。
  11. 一种结合SARS-CoV-2病毒的刺突蛋白的生物制品，其特征在于，包括转铁蛋白和/或转铁蛋白受体抗体。
  12. 转铁蛋白受体在制备结合SARS-CoV-2病毒的刺突蛋白的生物制品中的应用。
  13. 一种抗SARS-CoV-2病毒的组合物，其特征在于，包括转铁蛋白和转铁蛋白受体抗体；所述转铁蛋白和转铁蛋白受体抗体的摩尔比不低于1:1。
  14. 权利要求13所述组合物在制备抗SARS-CoV-2病毒的药物中的应用。
  15. 一种抗SARS-CoV-2病毒的药物，包括活性成分和辅料，其特征在于，所述活性成分包括转铁蛋白和转铁蛋白受体抗体；
    所述转铁蛋白和转铁蛋白受体抗体的摩尔比不低于1:1。
PCT/CN2020/098861 2020-06-29 2020-06-29 转铁蛋白、转铁蛋白受体及其抗体在制备抗SARS-CoV-2病毒的药物中的应用 WO2022000167A1 (zh)

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