WO2017092698A1 - 一种能够抑制流感病毒聚合酶亚基pa与pb1相互作用的化合物 - Google Patents
一种能够抑制流感病毒聚合酶亚基pa与pb1相互作用的化合物 Download PDFInfo
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- the present invention relates to a compound, and in particular to a compound capable of inhibiting the interaction of influenza virus polymerase subunit PA with PB1.
- influenza viruses can evade the effects of vaccines and antiviral effects against drugs through genetic mutations or genetic recombination between different subtypes. Therefore, new drug targets and innovative therapeutic strategies are urgently needed to advance anti-influenza therapy.
- Influenza virus RNA polymerase contains three subunits, PB1, PB2 and PA, and is responsible for transcription and replication of the viral genome. These three subunits form a ternary complex with each other through non-covalent bonds before they enter the host's nucleus.
- the major protein-protein interaction is through the binding of the amino-terminal domain of the PB1 subunit (PB1 N ) to the carboxy-terminal domain of the PA subunit (PA C ) and the carboxy-terminal domain of the PB1 subunit (PB1 C ).
- the amino terminal domain (PB2 N ) of the PB2 subunit is combined.
- PA C can form a structure similar to a "faucet", and the "faucet” between the upper and lower jaws just forms a hydrophobic groove.
- the PB1 subunit is inserted into the "top and bottom” through its first 25 amino acid polypeptides at the amino terminus to be combined with the faucet. Therefore, the “up and down” of the PA C “faucet” has become a potential drug target. In general, interactions between proteins require larger surface areas and more amino acid site contacts to achieve a tight junction.
- a compound capable of inhibiting the interaction of influenza virus polymerase subunit PA and PB1 which is represented by formula (I), formula (II) or formula (III).
- the compound, the structural formula of the compound represented by the formula (I) is as follows:
- the compound represented by the above formula (I) is named PAC-3, and the compound represented by the above formula (II) is named PAC-3-A-1, and the above formula (III) is shown.
- the compound is named PAC-3-A-2, and the compounds of the formula (I), formula (II) and formula (III) of the present invention all belong to influenza A viruses including H1N1, H3N2, H5N1, H7N7, H7N9. Subtypes such as H9N2 provide broad-spectrum antiviral effects.
- BALB/c mice received PAC-3-A-1 nasal administration after infection with a lethal dose of H1N1 influenza virus, which significantly improved survival and reduced viral load in lung tissue.
- the present invention provides the use of a compound as described above for the preparation of a medicament against influenza virus.
- influenza virus is an influenza A virus.
- the invention has the beneficial effects that the present invention provides a compound which is a compound represented by formula (I), formula (II) or formula (III), which is capable of inhibiting influenza virus polymerase subunits PA interacts with PB1 and functions as an anti-influenza virus.
- FIG. 1 is a graph showing the in vitro antiviral effect of the compounds PAC-3 and PAC-3-A-1 of the present invention in Example 1 of the present invention;
- Example 2 is a diagram showing the antiviral effect of the compound PAC-3-A-1 of the present invention in Example 1 of the present invention
- Figure 3 is a diagram showing the antiviral mechanism of the compound PAC-3-A-1 of the present invention in Example 1 of the present invention.
- Canine kidney cells (MDCK) and human embryonic kidney cells (HEK-293T) contain 10% heat-inactivated fetal bovine serum (FBS), 50 units/ml penicillin and 50 ⁇ g/ml streptomycin (P/S). Culture in DMEM medium. MDCK was cultured in MEM containing 1 ⁇ g/ml of TPCK trypsin but not fetal calf serum after viral infection.
- FBS heat-inactivated fetal bovine serum
- P/S streptomycin
- a total of 8 strains/6 subtypes of influenza virus strains namely A/HK/415742/09 (H1N1), A/Hong Kong/1/1968 (H3N2), A/Shenzhen/406H/2006 (H5N1), A/ Hong Kong/156/97 (H5N1), A/Vietnam/1194/2004 (H5N1), A/Netherlands/219/2003 (H7N7), A/Anhui/1/2013 (H7N9) and A/HK/1073/1999 (H9N2) was propagated in MDCK cells and used in this study.
- a mouse lethal influenza virus strain A/HK/415742Md/09 (H1N1) obtained in multiple passages in BALB/c mice was an animal experiment that was propagated in chicken embryos and used in this study. of.
- the titer of the virus was determined by a plaque assay and dispensed and stored at -80 degrees Celsius. All tests related to live virus are performed in Biosafety Level 2 or Level 3 facilities.
- the peptide involved in the experiment was purchased from Hefei Saimanuo Biotechnology Co., Ltd. (Anhui, China).
- the selectivity index is calculated by dividing the cytotoxic concentration (CC50) by 50% by the viral inhibitory concentration (IC50). The higher the index, the better the clinical application prospects of the drug. .
- CC50 cytotoxic concentration
- IC50 viral inhibitory concentration
- MDCK cells were cultured in MEM medium containing 20 ⁇ M of the compound of the present invention and 1 ⁇ g/ml of TPCK trypsin after inoculation of influenza H1N1 virus having a multiplicity of infection (MOI) of 0.002. After 0, 6, 21, 25, 32, 47 and 54 hours after infection, the viral supernatant was collected and the virus titer was determined using the plaque assay.
- MOI multiplicity of infection
- the antiviral effects of the compounds of the invention against multiple subtypes of influenza viruses were also tested. Briefly, MDCK cells were washed with PBS 1 hour after inoculation of 0.002 MOI of influenza virus, and the medium was replaced with fresh compounds containing different concentrations (20, 5, 1.25, 0.31 micromoles) of the present invention. MEM medium. After 24 hours of virus inoculation, the cell supernatant was collected and the titer of the virus was determined by reverse transcription-real-time fluorescence quantitative polymerase chain reaction (RT-qPCR).
- RT-qPCR reverse transcription-real-time fluorescence quantitative polymerase chain reaction
- mice 6-8 week old BALB/c female mice were used as experimental animals. All experiments followed the standard operating procedures for biosafety level 2 animal facilities and were approved by the University of Hong Kong Animal Ethics Committee. After anesthesia, a total of 56 mice (14/group) were inoculated intranasally with a 60% lethal dose (LD60) of influenza H1N1 strain A/HK/415742Md/09. The drug was administered by the nasal route 6 hours after virus inoculation, 2 times a day for 3 days. The first group of mice received 20 microliters of 2.5 mg/ml PAC-3-A-1 (i.e., 2.5 mg/kg body weight). The second group of mice received 20 microliters of 2.5 mg/ml PAC-3 via the nasal cavity.
- LD60 60% lethal dose
- a third group of mice received 20 microliters of 2.5 mg/ml zanamivir as a positive control via the nasal cavity.
- the last group of mice was injected intranasally with 20 microliters of PBS as a negative control.
- Animal vital signs were monitored for a total of 21 days or until death.
- lung tissues were randomly collected from each group of mice and sacrificed. Half of the lung tissue was milled and the supernatant was taken. The virus titer was determined by plaque method and RT-qPCR, and the other half of the lung tissue was immediately fixed in 10% formalin for histopathological analysis.
- PAC-3-A-1 To determine which stage of the viral life cycle was interfered with by PAC-3-A-1, MDCK cells were first inoculated with 2 MOI of influenza H1N1 virus. Thereafter, PAC-3-A-1 (20 micromolar) was added to the medium when the virus entered the cells (-1 h) or 1 h after infection, respectively. For the former (ie -1h), the virus and cells were incubated with PAC-3-A-1 for 1 hour and replaced with fresh compound-free medium; for the latter, PAC-3-A-1 was always present in culture. Base. Six hours after the virus was seeded, the virus titer in the cells and supernatant was measured by RT-qPCR.
- RNA in the cells was extracted using a tissue RNA extraction kit (purchased from QIAGEN) for RT-qPCR analysis at 3 hours and 6 hours after infection, respectively.
- zanamivir 100 micromolar was used as a positive control for virus release inhibitors.
- the selectivity index of the compound PAC-3 was calculated by dividing the half cytotoxic concentration (ie, CC50) obtained by the MTT assay by the semi-inhibitory virus concentration (EC50). Meanwhile, in Table 1, we also list the half inhibitory protein binding concentration (i.e., IC50) of the compound PAC-3 in the ELISA assay.
- PAC-3 shows a high selectivity index.
- Table 2 two analogs of PAC-3 (i.e., PAC-3-A-1 and PAC-3-A-2) were identified to possess an antiviral effect and a high selectivity index.
- PAC-3 and PAC-3-A-1 provide a broad spectrum of anti-influenza A virus effects
- the inventors compared the performance of PAC-3 and PAC-3-A-1 in a multi-cycle viral growth assay. As shown in Figure 1A, both compounds showed significant antiviral effects. For the H1N1 subtype influenza virus, the use of 20 micromolar compounds can reduce the virus titer in the supernatant of infected cells by more than 1000 times.
- PAC-3-A-1 was able to inhibit replication of all tested influenza strains in a dose-dependent manner.
- PAC-3 and PAC-3-A-1 can inhibit virus growth in vivo
- mice were first infected with an LD60 H1N1 virus, and after 6 hours, they received PAC-3-A-1 or PAC-3 by nasal drip. Medical treatment. As shown in Figure 2A, mice that received 2.5 mg/kg body weight of PAC-3-A-1 or a positive control (ie, zanamivir) were all alive, and mice receiving PAC-3 treatment survived 80. %, while mice treated with PBS only survived 20%.
- Figure 2B shows the change in body weight of mice after receiving virus inoculation and drug treatment. The mice treated with PAC-3-A-1 and the positive control drug showed little change in body weight.
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Abstract
本发明提供了一种化合物，所述化合物为式(I)、式(II)或式(III)所示的化合物，所述化合物均能够抑制流感病毒聚合酶亚基PA与PB1相互作用，具有抗流感病毒的功能。
Description
本发明涉及一种化合物，具体涉及一种能够抑制流感病毒聚合酶亚基PA与PB1相互作用的化合物。
流感通过常规的季节性流行和在全球范围的大流行在人群中造成相当的发病率和一定的死亡率。由于流感病毒可以通过基因突变抑或在不同亚型间基因重组来逃避疫苗的作用以及对抗药物的抗病毒效果。因此，目前亟需新的药物靶点和创新性的治疗策略来推进抗流感病毒的疗法。
相关实施例揭示，高度保守的流感病毒蛋白与蛋白间相互作用是抗流感病毒药物开发的潜在目标。流感病毒RNA聚合酶(RdRp)包含了PB1、PB2和PA三个亚基，并负责病毒基因组的转录和复制。在进入宿主的细胞核发挥功能之前，这三个亚基彼此间通过非共价键形成三元复合体。其中主要的蛋白-蛋白相互作用是通过PB1亚基的氨基端结构域(PB1N)和PA亚基的羧基端结构域(PAC)结合以及PB1亚基的羧基端结构域(PB1C)和PB2亚基的氨基端结构域(PB2N)结合构成。PAC与PB1N的共结晶结构已被成功解析。初略地说，PAC可以形成一个类似于“龙头”的结构，而“龙头”的上下颚之间恰好形成了一个疏水性的凹槽。于是，PB1亚基通过其氨基端的首25个氨基酸多肽，插入“上下颚”得以和龙头结合在一起。因此，PAC“龙头”的“上下颚”成为了潜在的药物靶点。通常来说，蛋白质之间的相互作用需要较大的表面积和较多的氨基酸位点接触以实现紧密的连接。不同的是，在PAC与PB1N复合体的相互作用中，只需要少数的氨基酸位点参与其中以贡献大部分结合所需的自由能，这使得小分子化合物抑制剂的成药成为可能。另外，相关实施例已经表明替换PAC或者PB1N结构域中参与蛋白相互作用的关键氨基酸位点将显著抑制整个RNA聚合酶的活性。所以，由PAC-PB1N结构域筛选而来的抗病毒药物所诱导产生耐药毒株的可能性会大大降低。
发明内容
本发明的目的在于克服现有技术存在的不足之处而提供了一种化合物，所述化合物能够抑制流感病毒聚合酶亚基PA与PB1相互作用，本发明还提供了所述化合物的用途。
为实现上述目的，所采取的技术方案：一种能够抑制流感病毒聚合酶亚基PA与PB1相互作用的化合物，所述化合物为式(I)、式(II)或式(III)所示的化合物，所述式(I)所示的化合物的结构式如下：
所述式(II)所示的化合物的结构式如下：
所述式(III)所示的化合物的结构式如下：
将上述所述式(I)所示的化合物命名为PAC-3，将上述所述式(II)所示的化合物命名为PAC-3-A-1，将上述所述式(III)所示的化合物命名为PAC-3-A-2，本发明所述式(I)、式(II)和式(III)所示的化合物均对甲型流感病毒包括H1N1、H3N2、H5N1、H7N7、H7N9和H9N2等亚型提供广谱抗病毒作用。BALB/c小鼠在感染致命剂量的H1N1流感病毒后接受PAC-3-A-1鼻腔给药，能够显著提高存活率并减少肺组织中的病毒量。
本发明提供了上述所述的化合物在制备抗流感病毒的药物中的用途。
优选地，所述流感病毒为甲型流感病毒。
本发明的有益效果在于：本发明提供了一种化合物，所述化合物为式(I)、式(II)或式(III)所示的化合物，所述化合物均能够抑制流感病毒聚合酶亚基PA与PB1相互作用，具有抗流感病毒的功能。
图1为本发明实施例1中本发明所述化合物PAC-3和PAC-3-A-1的体外抗病毒效果图；
图2为本发明实施例1中本发明所述化合物PAC-3-A-1的体内抗病毒效果图；
图3为本发明实施例1中本发明所述化合物PAC-3-A-1的抗病毒机制相关图。
为更好的说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
实施例1
1、材料和方法
1.1细胞、病毒
犬肾细胞(MDCK)和人胚肾细胞(HEK-293T)在包含有10％热灭活胎牛血清(FBS)，50单位/毫升青霉素和50微克/毫升链霉素(P/S)的DMEM培养基中培养。MDCK在病毒感染后，在含有1微克/毫升的TPCK胰蛋白酶但不合有胎牛血清的MEM中培养。总共8株/6种亚型的流感病毒株，即A/HK/415742/09(H1N1)、A/Hong Kong/1/1968(H3N2)、A/Shenzhen/406H/2006(H5N1)、A/Hong Kong/156/97(H5N1)、A/Vietnam/1194/2004(H5N1)、A/Netherlands/219/2003(H7N7)、A/Anhui/1/2013(H7N9)和A/HK/1073/1999(H9N2)分别在MDCK细胞中增殖并在本研究中使用。此外，还有一株在BALB/c小鼠体内多次传代获得的小鼠致死性流感病毒株A/HK/415742Md/09(H1N1)，是在鸡胚中增殖并应用于本次研究的动物实验的。病毒的滴度通过空斑试验(plaque assay)测定后，分装并保存在-80摄氏度。所有与活病毒相关试验是在生物安全2级或3级设施中进行的。该实验所涉及的多肽购自合肥赛曼诺生物科技有限公司(中国安徽)。
1.2选择性指数
选择性指数(selectivity index)是通过50％的细胞毒性浓度(CC50)除以50％的病毒抑制浓度(IC50)计算而来的，该指标数值越高则指示该药物有越好的临床应用前景。我们通过MTT法测定了本发明所述化合物的CC50，再通过空斑减数试验确定IC50值，最终得到了本发明所述化合物的选择性指数。
1.3多周期病毒生长试验
MDCK细胞在接种了感染复数(MOI)为0.002的流感H1N1病毒后，在含有20微摩的本发明所述化合物以及1微克/毫升TPCK胰蛋白酶的MEM培养基中培养。感染后0、6、21、25、32、47和54小时后，收集病毒上清液并使用空斑法测定病毒滴度。
1.4交叉保护力试验
本发明所述化合物针对多个亚型的流感病毒，包括甲型H1N1、H3N2、H5N1、H7N7、H7N9和H9N2的抗病毒效果也进行了测试。简单地说，MDCK细胞在接种0.002个MOI的流感病毒后1小时，用PBS洗净，并将培养基置换成新鲜的含有不同浓度(20、5、1.25、0.31微摩)本发明所述化合物的MEM培养基。病毒接种24小时候后，收集细胞上清液，并采用反转录-实时荧光定量聚合酶链式反应(RT-qPCR)技术测定病毒的滴度。
1.5本发明所述化合物体内抗病毒疗效评估
本实验采用6-8周龄的BALB/c雌性小鼠作为实验动物。所有实验遵循生物安全2级动物设施标准作业程序并得到香港大学动物伦理委员会的批准。麻醉后，共56只小鼠(14只/组)经鼻腔接种60％致死量(LD60)的流感H1N1病毒株A/HK/415742Md/09。药物在病毒接种6小时后由鼻腔途径给药，每日2次，共3天。第一组的小鼠接受20微升2.5毫克/毫升的PAC-3-A-1(即2.5毫克/千克体重)。第二组的小鼠经鼻腔接受20微升2.5毫克/毫升的PAC-3。第三组的小鼠经鼻腔接受20微升2.5毫克/毫升的扎那米韦作为阳性对照。最后一组小鼠经鼻腔注射以20微升PBS作为阴性对照。动物的生命体征总共监测21天或直至死亡。在病毒接种后的第4天，随机从每组小鼠中选取四只处死后收集肺部组织。一半的肺组织碾磨后取上清采用空斑法和RT-qPCR法测定病毒滴度，另一半肺组织立即被固定在10％福尔马林中进行的组织病理学分析。
1.6抗病毒机理的研究
为了确定病毒生命周期中的哪个阶段被PAC-3-A-1干扰，MDCK细胞首先接种2个MOI的流感H1N1病毒。此后，PAC-3-A-1(20微摩)分别在病毒进入细胞时(-1h)或在感染后1h后添加入培养基。对于前者(即-1h)，病毒、细胞与PAC-3-A-1共孵育1小时后替换以新鲜的不含化合物的培养基；对于后者，PAC-3-A-1一直存在于培养基中。病毒接种细胞6小时后，利用RT-qPCR技术检测细胞内及上清液中的病毒滴度。此外，我们还检测了病毒在RNA复制和转录水平上的变化，即细胞内mRNA及病毒基因组RNA(vRNA)的数量。简单地说，MDCK在接种2个MOI的流感病毒后，添加20微摩的PAC-3-A-1。分别在感染后3小时和6小时，采用组织RNA提取试剂盒(购自QIAGEN)提取细胞内总RNA用于RT-qPCR分析。在实验中，扎那米韦(100微摩)被用于病毒释放抑制剂的阳性对照。
2、结果
我们接着测定了化合物PAC-3的选择性指数(selectivity index)(表1)并筛选了化合物PAC-3的类似物以期得到水溶性好，抗病毒效果更佳的小分子化合物。选择性指数由MTT试验所得出的半数细胞毒性浓度(即CC50)除以半抑制病毒浓度(EC50)计算获得。同时，在表1中，我们也罗列了化合物PAC-3在ELISA试验中的半数抑制蛋白结合浓度(即IC50)。
表1 PAC-3的选择性指数
由于PAC-3显示出很高的选择性指数。通过PAC-3的母核结构，我们预测并筛选了PAC-3的类似物。如表2所示，有两种PAC-3的类似物(即PAC-3-A-1和PAC-3-A-2)被鉴定拥有抗病毒效果和较高的选择性指数。
表2 PAC-3-A-1和PAC-3-A-2的选择性指数
2.1 PAC-3和PAC-3-A-1能够提供广谱的抗甲型流感病毒作用
首先，发明人比较了PAC-3和PAC-3-A-1在多周期病毒生长试验中的表现。如图1A所示，两种化合物均显示了明显的抗病毒作用。针对H1N1亚型流感病毒，使用20微摩的化合物能够使受感染细胞上清液中的病毒滴度减少1000倍以上。我们进一步评估了PAC-3-A-1对H1N1、H3N2、H5N1、H7N7、H7N9及H9N2亚型的毒株在细胞水平的抗病毒效果。如图1B所示，PAC-3-A-1能够以剂量依赖的方式抑制所有测试的流感毒株的复制。然而，不同亚型的病毒对PAC-3-A-1表现出不同的敏感性。显然，本发明所述化合物PAC-3-A-1可以至少在体外提供广谱的抗病毒作用。表3显示了本发明所述化合物PAC-3-A-1针对不同亚型流感病毒的半数抑制浓度。
表3 PAC-3-A-1的半数效应浓度(EC50)
2.2 PAC-3和PAC-3-A-1能够在体内抑制病毒生长
为了评估PAC-3-A-1在体内的抗病毒效果，试验小鼠先经过1个LD60的H1N1病毒感染，6小时之后再通过滴鼻方式接受PAC-3-A-1抑或是PAC-3的药物治疗。如图2A所示，接受到2.5毫克/千克体重的PAC-3-A-1或阳性对照(即扎那米韦)滴鼻治疗的小鼠全部存活，接受PAC-3治疗的小鼠存活80％，而只接受PBS治疗的小鼠有只存活20％。图2B显示了小鼠在接受病毒接种及药物治疗后体重的变化趋势，接受PAC-3-A-1以及阳性对照药物治疗的小鼠体重几乎没有变化。在感染过后的第4天，每个组中随机挑选4只小鼠取肺并通过空斑试验和RT-qPCR测定肺组织中的病毒含量。如图2C结果表明，PAC-3-A-1的治疗能够显著减少肺组织中的病毒量。此外，如图2D所示的组织病理学检查进一步表明，经过PAC-3-A-1治疗的小鼠，肺组织间质炎性细胞浸润及肺泡损伤亦得到改善。我们的结果表明PAC-3-A-1能有效抑制流感病毒在体内的复制。
2.3 PAC-3-A-1的抗病毒机制验证
为了验证PAC-3-A-1的抗病毒机制，我们首先确定病毒生命周期的哪个阶段被PAC-3-A-1干扰。结果表明，当PAC-3-A-1在病毒进入细胞的过程中(即-1小时)添加，之后移除，并没有观察到抗病毒效果(图3A)。相反，在病毒完成进入细胞的过程后再将PAC-3-A-1添加到培养基时，发现细胞内和上清中的病毒含量都减少了。实验结果提示PAC-3-A-1不能阻止病毒感染细胞抑或是病毒从细胞释放，而是阻碍病毒复制的过程。进一步的研究表明PAC-3-A-1抑制了病毒基因组的复制(图3B)。紧接着，我们构建了流感病毒的微型复制子系统，证明了在PAC-3-A-1的存在下，正常细胞的生存状态没有受到太多影响，而RNA聚合酶的活力显著下降(图3C)。我们推测，这是由RNA聚合酶无法正常组装所造成的。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (3)
- 一种能够抑制流感病毒聚合酶亚基PA与PB1相互作用的化合物，其特征在于，所述化合物为式(I)、式(II)或式(III)所示的化合物，所述式(I)所示的化合物的结构式如下：
所述式(II)所示的化合物的结构式如下：
所述式(III)所示的化合物的结构式如下：
- 如权利要求1所述的化合物在制备抗流感病毒的药物中的用途。
- 根据权利要求2所述的用途，其特征在于，所述流感病毒为甲型流感病毒。
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