WO2016201692A1 - 一种替考拉宁在抗中东呼吸综合征冠状病毒中的应用 - Google Patents

一种替考拉宁在抗中东呼吸综合征冠状病毒中的应用 Download PDF

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WO2016201692A1
WO2016201692A1 PCT/CN2015/081932 CN2015081932W WO2016201692A1 WO 2016201692 A1 WO2016201692 A1 WO 2016201692A1 CN 2015081932 W CN2015081932 W CN 2015081932W WO 2016201692 A1 WO2016201692 A1 WO 2016201692A1
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teicoplanin
respiratory syndrome
syndrome coronavirus
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middle east
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潘婷
周南
张辉
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Sun Yat Sen University
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin

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  • the present invention relates to new applications of antiviral drugs, and more particularly to the use of teicoplanin in anti-middle-respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) .
  • MERS-CoV anti-middle-respiratory syndrome coronavirus
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • Middle East Respiratory Syndrome an acute respiratory disease caused by a new coronavirus, was discovered in 2012. On May 23, 2013, the World Health Organization named the new coronavirus infection "Middle East Respiratory Syndrome". The virus first appeared in Saudi Arabia, and then spread in other countries in the Middle East and Europe. In early 2015, the first confirmed case was reported in South Korea and caused further spread. On May 29, according to the National Health and Family Planning Commission of China, the first confirmed case of imported Middle East respiratory syndrome occurred in Huizhou City, Guangdong province.
  • the Middle East Respiratory Syndrome Coronavirus is a human veterinary virus that is transmitted from animals to humans, and the origin of the virus is not fully understood. According to the current reported case statistics, the infection rate of the virus is about 36%. However, there are still no effective vaccines and drugs against the Middle East Respiratory Syndrome Coronavirus in the world.
  • the invention provides a new application of an old medicine, and the invention finds application of teicoplanin in anti-middle-respiratory syndrome coronavirus (MERS-CoV).
  • MERS-CoV anti-middle-respiratory syndrome coronavirus
  • Teicoplanin also known as tacromycin, was first discovered in 1975. It is a specific actinomycetes, a vancomycin-based glycopeptide antibiotic obtained after fermentation and extraction, and is an antibiotic mixture composed of a plurality of compounds having very similar chemical structures. It contains a compound of the formula: as shown in Formula I:
  • the R is,
  • Teicoplanin inhibits envelope protein of MERS-CoV MERS-CoV-S.
  • the teicoplanin inhibits the entry of the Middle East Respiratory Syndrome Coronavirus into the host cell.
  • the present invention utilizes pHIV-luciferase, pCMV- ⁇ R8.2 and MERS-CoV-S plasmids to transfect into 293T cells, and package pseudoviruses which can express the MERS-CoV envelope protein, and then use these pseudo-viruses to infect accordingly.
  • the target cell which mimics a state of MDR-infected host cells.
  • the present invention uses the cell model of the pseudovirus packaging to screen thousands of compound libraries that have been put on the market, and finds that the antibiotic teicoplanin can effectively inhibit the infection of host cells of the Middle East respiratory syndrome coronavirus, and its IC50 It is about 940nM.
  • teicoplanin is also capable of inhibiting Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), which exerts a role in inhibiting the entry of SARS virus into host cells with an IC50 of about 1.18 ⁇ M.
  • SARS-CoV Severe Acute Respiratory Syndrome Coronavirus
  • the present invention is based on a state in which a host cell of a Middle East respiratory syndrome coronavirus infection is infected, and using the cell model of the pseudovirus packaging, it is found that the antibiotic teicoplanin can effectively inhibit the Middle East Respiratory Syndrome coronavirus infection 293T cells.
  • the phenomenon confirmed by a number of experiments, the antibiotic has a good antiviral effect, IC50 is about 940nM.
  • Figure 1 Inhibitory effect of different concentrations of the antibiotic, teicoplanin, on the envelope protein S of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV).
  • Figure 2 Inhibitory effect of different concentrations of antibiotic teicoplanin on vesicular stomatitis virus envelope VSV-G.
  • Figure 4 shows the inhibitory effect of different concentrations of antibiotic teicoplanin on influenza A virus.
  • the teicoplanin used in the present invention is purchased from Shanghai Blue Wood Chemical Co., Ltd. (which is a subsidiary of Selleck Chemicals in Shanghai).
  • Example 1 Inhibitory effect of different concentrations of the compound antibiotic teicoplanin on the envelope protein S of Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
  • (1) Package virus 4.5 ⁇ g of pHIV-luciferase, 4.5 ⁇ g of pCMV- ⁇ R8.2 and 10 ⁇ g
  • the MERS-CoV-S plasmid was transfected into 293T cells (10 cm dish), and 48 hours later, the virus supernatant was collected and assayed for p24.
  • MERS-CoV-S p24-normalized MERS-CoV-S pseudovirus supernatant (containing 8 ⁇ g/ml Polybrene) was infected into 293T cells in 96-well plates, and different concentrations of teicocola were added. Ning compound.
  • Figure 1 illustrates that the antibiotic teicoplanin can specifically act on the MERS-CoV envelope protein S, inhibiting the entry of the MERS-CoV virus, and thus calculating Teicoplanin inhibits MERS-CoV-S with an IC50 of approximately 940 nM.
  • Example 2 Inhibitory effect of different concentrations of compound antibiotic teicoplanin on vesicular stomatitis virus envelope VSV-G
  • Inclusion virus 4.5 ⁇ g of pHIV-luciferase, 4.5 ⁇ g of pCMV- ⁇ R8.2 and 10 ⁇ g of VSV-G plasmid were transfected into 293T cells (10 cm dish), and 48 hours later, virus supernatant was collected, and p24 was measured.
  • VSV-G p24-normalized VSV-G pseudovirus supernatant (containing 8 ⁇ g/ml Polybrene) was infected with 293T cells in 96-well plates while different concentrations of teicoplanin compounds were added.
  • Figure 2 illustrates that the antibiotic teicoplanin does not have any inhibitory effect on the envelope protein of VSV-G.
  • Example 3 Inhibitory effect of different concentrations of compound antibiotic teicoplanin on Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) envelope protein SARS-CoV
  • Inclusion virus 6.5 ⁇ g of pHIV-luciferase, 8 ⁇ g of pCMV- ⁇ R8.2 and 20 ⁇ g of SARS-CoV-S plasmid were transfected into 293T cells (10 cm dish), and 48 hours later, virus supernatant was collected, and p24 was measured.
  • Figure 3 illustrates that the antibiotic teicoplanin can specifically act on the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) envelope protein S, inhibiting the entry of the SARS-CoV virus, and thereby calculating The IC50 for the inhibition of SARS-CoV-S by the testin was approximately 1.18 ⁇ M.
  • SARS-CoV Severe Acute Respiratory Syndrome Coronavirus
  • Example 4 Inhibitory effect of different concentrations of compound antibiotic teicoplanin on influenza A virus
  • PFU Plaque-forming unit
  • Figure 4 illustrates that the antibiotic teicoplanin does not have any inhibitory effect on influenza A virus.

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Abstract

替考拉宁在抗中东呼吸综合征冠状病毒中的应用。

Description

一种替考拉宁在抗中东呼吸综合征冠状病毒中的应用 技术领域
本发明涉及抗病毒药物的新应用，更具体地，涉及一种替考拉宁在抗中东呼吸综合征冠状病毒(MERS-CoV)以及严重急性呼吸综合征冠状病毒(SARS-CoV)中的应用。
背景技术
中东呼吸综合征，是2012年发现的一种由新型冠状病毒引起的急性呼吸道疾病，2013年5月23日，世界卫生组织将这种新型冠状病毒感染命名为“中东呼吸综合征”。该病毒首现于沙特，继而在中东其他国家及欧洲等地区蔓延，2015年初在韩国报告了首例确诊病例，并引起进一步传播。5月29日，根据我国国家卫生和计划生育委员会通报，广东省惠州市出现首例输入性中东呼吸综合征确诊病例。
中东呼吸综合征冠状病毒是从动物传染给人的人兽共患病毒，然后该病毒的起源尚不完全清楚。就目前的报告病例统计发现，该病毒的感染病死率约为36％。然而，目前世界上仍缺乏有效的抗中东呼吸综合征冠状病毒的疫苗和药物。
发明内容
目前针对中东呼吸综合征冠状病毒，市场尚没有明确抗病毒药物可以使用，并有效抑制该病毒。
本发明提供一种老药新的应用，本发明发现替考拉宁在抗中东呼吸综合征冠状病毒(MERS-CoV)中的应用。
替考拉宁，又名太古霉素，1975年被首次发现。它是特定的游动放线菌，经发酵、提取后得到的一种万古霉素族糖肽类抗生素，为多个化学结构非常相似的化合物组成的抗生素混合物。其中含有如下结构式的化合物，如式I所示：
Figure PCTCN2015081932-appb-000001
所述的R为，
Figure PCTCN2015081932-appb-000002
Figure PCTCN2015081932-appb-000003
Figure PCTCN2015081932-appb-000004
Figure PCTCN2015081932-appb-000005
Figure PCTCN2015081932-appb-000006
所述的替考拉宁能够抑制中东呼吸综合征冠状病毒的包膜蛋白 MERS-CoV-S。
所述的替考拉宁抑制中东呼吸综合征冠状病毒进入宿主细胞。
本发明利用pHIV-luciferase、pCMV-ΔR8.2和MERS-CoV-S质粒转染至293T细胞，包装出可以表达中东呼吸综合征冠状病毒包膜蛋白的假病毒，再用这些假病毒来感染相应的靶细胞，从而模拟中东呼吸综合征冠状病毒感染宿主细胞的一种状态。
然后，本发明运用此种假病毒包装的细胞模型，筛选上千个已经上市使用的化合物库，发现了抗菌素替考拉宁可以有效的抑制中东呼吸综合征冠状病毒感染宿主细胞的现象，其IC50约为940nM。
另外，本发明发现，替考拉宁也能够抑制严重急性呼吸综合征冠状病毒(SARS-CoV)，其通过抑制SARS病毒进入宿主细胞发挥作用，IC50约为1.18μM。
本发明的优点在于：
1.本发明根据模拟中东呼吸综合征冠状病毒感染宿主细胞的一种状态，并利用该假病毒包装的细胞模型，发现了抗菌素替考拉宁可以有效的抑制中东呼吸综合征冠状病毒感染293T细胞的现象，经多个实验证实，该抗菌素替考拉宁具有良好的抗病毒作用，IC50约为940nM。
2.该抗菌素替考拉宁对人体的安全性早已经过了临床实践的检验，我们目前确定了替考拉宁抗中东呼吸综合征冠状病毒的明显药效，即可在国家药监局紧急备案和批准后，直接用于临床治疗的第一线，避免了新药研发的漫长周期，这 为我们进一步的研发抗中东呼吸综合征冠状病毒提供的强有力的理论基础和实践基础，具有重要的开发价值和推广意义。
3.根据本发明的研究发现替考拉宁对中东呼吸综合征冠状病毒(MERS-CoV)和严重急性呼吸综合征冠状病毒(SARS-CoV)的包膜蛋白有抑制作用。
附图说明
图1不同浓度的抗菌素替考拉宁对中东呼吸综合征冠状病毒(MERS-CoV)包膜蛋白S的抑制效果。
图2不同浓度的抗菌素替考拉宁对水疱性口炎病毒包膜VSV-G的抑制效果。
图3不同浓度的抗菌素替考拉宁对严重急性呼吸综合征冠状病毒(SARS-CoV)包膜蛋白S的抑制效果。
图4不同浓度的抗菌素替考拉宁对A型流感病毒的抑制效果。
具体实施方式
下面结合附图和具体实施例进一步详细说明本发明。除非特别说明，本发明采用的试剂、设备和方法为本技术领域常规市购的试剂、设备和常规使用的方法。
本发明所使用的替考拉宁均采购自上海蓝木化工有限公司(其是美国Selleck Chemicals在上海设立的子公司)。
实施例1 不同浓度的化合物抗菌素替考拉宁对中东呼吸综合征冠状病毒(MERS-CoV)包膜蛋白S的抑制效果
(1)包病毒：将4.5μg pHIV-luciferase、4.5μg pCMV-ΔR8.2和10μg  MERS-CoV-S质粒转染至293T细胞(10cm dish)，48小时后，收集病毒上清，测p24。
(2)针对MERS-CoV-S的化合物筛选：将p24-normalized MERS-CoV-S假病毒上清(含8μg/ml Polybrene)感染96孔板中的293T细胞，同时加入不同浓度的替考拉宁化合物。
(3)换液：感染12小时后，更换新鲜的DMEM培养基。
(4)检测luciferase活性：感染48小时后，每孔用PBS洗一次，然后加入100μl裂解液，震荡30min，取10μl裂解液检测luciferase活性。
根据实施例1的结果图1说明，抗菌素替考拉宁可以特异性的作用于中东呼吸综合征冠状病毒(MERS-CoV)包膜蛋白S，抑制MERS-CoV病毒的进入，并由此计算出替考拉宁抑制MERS-CoV-S的IC50约为940nM。
实施例2 不同浓度的化合物抗菌素替考拉宁对水疱性口炎病毒包膜VSV-G的抑制效果
(1)包病毒：将4.5μg pHIV-luciferase、4.5μg pCMV-ΔR8.2和10μg VSV-G质粒转染至293T细胞(10cm dish)，48小时后，收集病毒上清，测p24。
(2)针对VSV-G的化合物筛选：将p24-normalized VSV-G假病毒上清(含8μg/ml Polybrene)感染96孔板中的293T细胞，同时加入不同浓度的替考拉宁化合物。
(3)换液：感染12小时后，换新鲜的DMEM培养基。
(4)检测luciferase活性：感染48小时后，每孔用PBS洗一次，然后加入 100ul裂解液，震荡30min,取10ul裂解液检测luciferase活性。
根据实施例2的结果图2说明，抗菌素替考拉宁对VSV-G的包膜蛋白没有任何抑制作用。
实施例3 不同浓度的化合物抗菌素替考拉宁对严重急性呼吸综合征冠状病毒(SARS-CoV)包膜蛋白S的抑制效果
(1)包病毒：将6.5μg pHIV-luciferase、8μg pCMV-ΔR8.2和20μg SARS-CoV-S质粒转染至293T细胞(10cm dish)，48小时后，收集病毒上清，测p24。
(2)针对SARS-CoV-S的化合物筛选：将p24-normalized SARS-CoV-S假病毒上清(含8μg/ml Polybrene)感染96孔板中的293T细胞，同时加入不同浓度的替考拉宁化合物。
(3)换液：感染12小时后，更换新鲜的DMEM培养基。
(4)检测luciferase活性：感染48小时后，每孔用PBS洗一次，然后加入100μl裂解液，震荡30min，取10μl裂解液检测luciferase活性。
根据实施例3的结果图3说明，抗菌素替考拉宁可以特异性的作用于严重急性呼吸综合征冠状病毒(SARS-CoV)包膜蛋白S，抑制SARS-CoV病毒的进入，并由此计算出替考拉宁抑制SARS-CoV-S的IC50约为1.18μM。
实施例4 不同浓度的化合物抗菌素替考拉宁对A型流感病毒的抑制效果
(1)加药与感染：将5×104 A549细胞铺于24孔板中，于37℃培养12小时后，加入不同浓度的化合物，并且每孔以MOI＝0.1的A型流感病毒进行感染， 感染4小时后换液，24小时后收取上清液。
(2)测定空斑形成单位(Plaque-forming unit,PFU)：准备细胞融合度≥95％的MDCK细胞12孔培养板，弃去细胞培养液，用PBS洗2遍，将收取的上清液10倍梯度稀释至需要的稀释度，每个细胞孔接种500μl上清稀释液，置于37℃孵育1小时。将2×MEM培养基置于37℃下预热，同时配置2％低熔点琼脂糖凝胶，完全溶解后置于50℃水浴锅中防止凝固。1小时后弃去病毒上清液，用PBS清洗2次，2％低熔点琼脂糖凝胶和2×MEM培养基1:1混合并加入终浓度为2μg/ml的TPCK胰酶、0.2％牛血清白蛋白(BSA)及100U/ml的青-链霉素，混匀。每孔加入1ml琼脂糖-MEM培养基，待其完全凝固后，倒扣放置于37℃的CO2培养箱，48小时后对空斑进行观察计数。
根据实施例4的结果图4说明，抗菌素替考拉宁对A型流感病毒没有任何抑制作用。

Claims (6)

  1. 一种替考拉宁在抗中东呼吸综合征冠状病毒中的应用。
  2. 根据权利要求1所述的替考拉宁在抗中东呼吸综合征冠状病毒中的应用，其特征在于，所述的替考拉宁抑制中东呼吸综合征冠状病毒的包膜蛋白S。
  3. 根据权利要求1所述的替考拉宁在抗中东呼吸综合征冠状病毒中的应用，其特征在于，所述的替考拉宁抑制中东呼吸综合征冠状病毒进入宿主细胞。
  4. 一种替考拉宁在制备抗严重急性呼吸综合征冠状病毒药物中的应用。
  5. 根据权利要求4所述的替考拉宁在制备抗严重急性呼吸综合征冠状病毒药物中的应用，其特征在于，所述的替考拉宁类化合物抑制严重急性呼吸综合征冠状病毒进入宿主细胞中的应用。
  6. 一种替考拉宁在抗中东呼吸综合征和严重急性呼吸综合征冠状病毒药物中的应用，其特征在于，所述的替考拉宁抑制冠状病毒进入宿主细胞。
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Publication number Priority date Publication date Assignee Title
CN1741810A (zh) * 2002-08-30 2006-03-01 鲁汶天主教大学研究开发部 糖肽类抗生素衍生物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1741810A (zh) * 2002-08-30 2006-03-01 鲁汶天主教大学研究开发部 糖肽类抗生素衍生物

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