CN111760026A - FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用 - Google Patents
FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用 Download PDFInfo
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Abstract
本发明公开了FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用。本发明是基于本发明发明人发现FGF‑7能诱导血小板活化因子PAF的产生所得到的研究成果。本发明发明人发现，PAF产生后能诱导促炎因子的水平上升，继而引发炎症反应，将抑制FGF‑7与FGFR2结合的分子作为FGF7的竞争性拮抗剂，结合FGF7特异受体FGFR2b，阻断FGFR2b激活为磷酸化FGFR2b，能有效抑制过度的炎症反应从而治疗ARDS症状，而且可以改善肺部纤维化。
Description
技术领域
本发明属于医药生物领域，特别涉及FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用。
背景技术
急性呼吸窘迫综合征(ARDS)是由肺内原因和/或肺外原因引起的，以顽固性低氧血症为显著特征的临床综合征，因高病死率而倍受关注。其发病机理涉及不受控制的病人自身免疫防御反应，并导致炎症、内皮损伤、增强凝结、减少的纤溶和纤维增殖，是一种由各种病原导致的临床综合病症。1994年，对ARDS的美国-欧洲共识会议委员会推荐了该疾病的定义；标准包括：(1)急性发作，(2)胸腔X线片上双侧浸润，(3)肺动脉楔压≤18mm Hg或者缺乏左心房高血压的临床证据，和(4)Pao2/Fio2比率≤300(定义为ALI)或者Pao2/Fio2比率≤200(定义ARDS为ALI的更严重形式)(Cepkova和Matthay，J.Intensive Care Med.，21：119-143，2006)。弥漫性肺泡损伤是ARDS的特征。该疾病有三个交迭的阶段：渗出阶段(最开始的4-7天)，增殖阶段(≥7-14或21天)和纤维化阶段(≥14或21天)(MacLaren和Stringge，Pharmacotherapy，27：860-873，2007)。
在急性阶段存在显著的中性粒细胞的聚集。中性粒细胞在从感染人群中获得的肺水肿液和肺泡灌洗液中占优势。肺泡巨噬细胞分泌细胞因子例如白细胞介素IL-1、IL-6、IL-10、IL-8和肿瘤坏死因子(TNF)-α，这些细胞因子会刺激中性粒细胞趋化性和激活中性粒细胞。然后中性粒细胞释放氧化剂、蛋白酶(包括中性粒细胞弹性蛋白酶)、白三烯和其他促炎性细胞介质(Ware和Mattray，New England J.Med.342：1334-1349)。这些介质以复杂的方式相互作用从而损伤和炎症化肺泡毛细血管界面，导致一系列的炎症反应及其他症状。
目前已有的ARDS治疗方案主要通过抑制免疫(糖皮质激素)、支持治疗(通氧)等方法进行缓解和治疗。糖皮质激素可以避免免疫系统的过度反应对机体造成进一步的破坏，但是它也有着巨大的副作用，包括且不限于加重感染、骨质疏松、心血管系统与消化系统并发症。从另一方面讲，支持疗法只是在维持病人的生命，而不能治疗疾病，对于病人生存率的提升效果十分有限。
由于没有弄清该病的发生和发展起因，一直以来未能开发出应对ARDS的针对性治疗方法，因而研发创新性的治疗药物迫在眉睫。
发明内容
本发明的目的在于克服现有技术的缺点与不足，提供FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用。
本发明的目的通过下述技术方案实现：FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，是基于本发明发明人发现FGF-7能诱导血小板活化因子PAF的产生所得到的研究成果。
所述的PAF介导的疾病包括急性呼吸窘迫综合征(ARDS)以及肺水肿等急性炎症性疾病、肺纤维化疾病、动脉硬化等心血管疾病、各种与PAF相关的肿瘤、放化疗导致的PAF介导的肿瘤转移和复发、以及神经退行疾病如阿尔兹海默症(Alzheimer's Disease，AD)、帕金森氏病(Parkinson Disease，PD)。
所述的急性呼吸窘迫综合征优选为细菌感染和/或包括新冠肺炎在内的病毒性感染引起的肺损伤、肺水肿以及急性呼吸窘迫综合征。
所述的病毒优选为新型冠状病毒；进一步优选为SARS-CoV、MERS-CoV、2019-nCoV。
所述的肺纤维化为特发性肺纤维化和炎症导致的肺纤维化。
所述的FGFR2b抑制分子包括抑制FGF-7表达的分子、抑制FGFR2b激活为磷酸化FGFR2b的分子和竞争性抑制FGF-7与FGFR2b结合的分子。
所述的分子包括但不限于siRNA、寡肽、多肽等。
所述的竞争性抑制FGF-7与FGFR2b结合的分子优选选自申请号为2019102390870、发明名称为“用于治疗脱发的短肽、药物及其应用”的国家发明专利申请中记载的短肽；优选为分别以EWVRTD、ELSGRA、QDVDS、或VFSTTGV为中心，在两端分别增加、删除或突变0～2个氨基酸得到的短肽；最优选为EWVRTD、WVRTD、RHEWSRTD、ELSGRA、HTVELSGRAK、QDVDS、VFSTTGV、FGSVFSTTGV。
所述的抑制FGFR2b激活为磷酸化FGFR2b的分子优选选自申请号为201310714120.3、发明名称为“FGFR2b胞外段的基因序列、多肽及其应用”的国家发明专利记载的短肽。
本发明相对于现有技术具有如下的优点及效果：
(1)本发明发明人首次发现FGF7能诱导血小板活化因子PAF的产生。
(2)本发明发明人还发现，PAF产生后能诱导促炎因子的水平上升，继而引发炎症反应，将抑制FGF-7与FGFR2结合的分子作为FGF7的竞争性拮抗剂，结合FGF7特异受体FGFR2b，阻断FGFR2b激活为磷酸化FGFR2b，能有效抑制过度的炎症反应从而治疗ARDS症状，而且有利于改善肺部纤维化。
(3)本发明所用的生长因子拮抗剂PI9(EWVRTD)是6个氨基酸的短肽，通过在胞外阻止FGF7与膜上受体结合而发挥作用，具有无需进入胞内和半衰期短的特点；同时FGF7具有唯一结合受体FGFR2b，因而靶点明确，药理作用非常专一，易于评价其毒副作用。因此本发明在制备ARDS药物中具有广阔的应用前景。
附图说明
图1为通过脂质组学的方法检测并分析得到组间差异脂类PAF得到的结果图；每一组柱子从左到右分别表示A组、B组、C组和D组，A组为空白组，B组为PI9组，C组为FGF7组，D组FGF7+PI9组。
图2为通过PAF诱导皮脂腺细胞表达的IL-6、IL-8相对表达水平结果图。
图3为在LPS诱导建立的ARDS小鼠模型中的细胞因子检测结果图。
图4为博来霉素诱导的SD大鼠肺纤维化模型的肺组织照片图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
下述实施例中所使用的试验技术方法如无特殊说明，均为常规分子生物学技术方法，本领域的科研人员能够按常规分子生物学技术方法操作实现其结果；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
本发明所用的PBS是0.1mol/L、pH 7.4的PBS，组成如下：NaCl 16.00g、KCl 0.40g、KH2PO4 0.40g、Na2HPO4·12H2O 5.80g，用水定容到1L。
实施例1
本实施例1提供一种短肽及其药物制剂，通过对FGFR胞外段(SEQ NO ID.52)截取5-12个氨基酸，通过0-2个点突变得到的序列。所述的由FGFR胞外段截取5-12个氨基酸，是根据FGFR胞外段的三维结构截取的空间上相邻的氨基酸。具体地，设计得到的氨基酸分别以EWVRTD(PI9，SEQ NO ID.9)、ELSGRA(PI15，SEQ NO ID.15)、QDVDS(PI29，SEQ NO ID.29)、VFSTTGV(PI47，SEQ NO ID.47)为中心，在两端分别增加或删除氨基酸序列，短肽命名为PI1～PI51。
其中，FGFR胞外段氨基酸序列(自氨基端至羧基端)如下(SEQ NO ID.52)：
APYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPGREKEITASPDYLEIAIYCIGVFLIACMVVTVIL。
短肽命名、氨基酸序列及序列号如表1所示。
表1
短肽需加入一定的赋形剂(Excipients)，并以冻干粉的形式保存。具体制备一定浓度的短肽溶液，例如短肽溶液中短肽的浓度可以为10～1000μg/ml，优选为100μg/ml，在上述制备的短肽溶液中加入3％(m/v)蔗糖、1％(m/v)乳糖、6％(m/v)山梨醇作为赋形剂，置于4℃保存4-5h，使保护剂充分溶解并在短肽溶液中分布均匀，在预冻温度为-20℃的条件下预冻12-14h，预冻。
实施例2
本实施例2通过脂质组学研究发现FGF7调控Platlet Activating Factor(PAF)表达。
1.1制备处理样本
培养SZ95人皮脂腺细胞，当细胞长至七成满的时候，用胰酶消化细胞5min，弃去胰酶，加入SEB-1完全培养基(SEB-1皮脂腺细胞培养基+10％胎牛血清，美国Zenbio公司)终止胰酶的消化作用，将细胞吹打下来，混匀，形成细胞悬液，计数，如下表所示对细胞进行分组，每组3个重复，将原代皮脂腺细胞铺板至10cm培养皿中，每孔加入3.7×105个细胞，加入10mL SEB-1完全培养基，贴壁培养，48h换一次培养液，当细胞长至七成满时，加入无血清培养基(即SEB-1培养基)饥饿12h，弃去培养基，如表2所示处理细胞，A组不加任何药物的培养基，B组加入4μg/mLPI9(溶剂为培养基)，C组加入10ng/mL FGF-7(FGF-7购自美国R&D公司；溶剂为培养基)，D组加入4μg/mL PI9+10ng/mL FGF7(溶剂为培养基)，每孔各加入10ml含药培养基，培养48h。吸弃培养基，胰酶消化收集细胞，进行下一步处理。
12例细胞样本三组，分组情况如下表，采用正负两种离子模式进行LC-MS检测，针对检测结果，进行组间比对，此次报告提供3次比对数据。
表2 12例细胞样本分组情况
1.2试剂与耗材
表3 LC-MS实验使用的试剂
| 乙腈(Acetonitrile) | Thermo Fisher |
| 甲醇(Methanol) | Thermo Fisher |
| 甲酸(Formic acid) | Sigma |
| 甲酸铵 | CNW |
| 超纯水(Ultrapure water) | Millipore |
| 二氯甲烷(Chloroform) | Merck(Darmstadt,Germany) |
1.3实验方法
1.3.1样本预处理
1.加入800μL甲醇，超声30min，离心取上清，N2吹干；
2.加入1.5mL二氯甲烷/甲醇(2：1，V/V)溶液及500μL水，涡旋振荡1min,静止后离心(3000rpm，15min)
3.取下层有机相至新玻璃管里；
4.在高速真空浓缩离心机挥干，用异丙醇/甲醇(1：1，V/V)复溶，转移到进样瓶中，-20℃下保存备用。
1.3.2 LC-MS分析
1.仪器分析平台：LC-MS(Thermo,Ultimate 3000LC,Orbitrap Elite)
2.色谱柱：C18色谱柱(Kinetex C18(100×2.1mm,1.9μm))
3.色谱分离条件为：柱温为45℃；流速0.4mL/min；
流动相组成A：乙腈：水(60:40，V/V)，溶液含10mmol/L甲酸铵；B：乙腈：异丙醇(10:90，V/V)，溶液含10mmol/L甲酸铵和0.1％甲酸；
进样量为4μL，自动进样器温度4℃。
4.流动相梯度洗脱程序见表4。
表4流动相洗脱程序
1.3.3数据分析
使用Lipid Search软件(Thermo公司)对LC/MS检测数据进行提取和预处理，并在Excel 2010中对数据进行归一化及后期编辑，将所得数据矩阵导入SIMCA-P 13.0(Umetrics AB，Umea，Sweden)软件进行多元统计分析。
1.3.4结果分析
差异脂质PAF包含多种形式，通过对不同形式的PAF进行测试，差异脂质PAF相对含量结果如图1所示。可见，FGF-7能诱导PAF的表达，PI9和FGF-7结合使用，能抑制FGF-7诱导的的PAF表达。在FGF7调控脂质合成代谢组学研究中，PAF是其中的一类差异脂质，PAF作为强促炎介质与炎症反应相关。
实施例3
用20μM的PAF(上海玉博生物科技有限公司)去诱导SZ95人皮脂腺细胞，然后用ELISA法检测不同时间PAF诱导促炎细胞因子表达的作用。检测步骤如下：
①样品收集：吸取细胞培养液转移至EP管中，在预冷的冷冻离心机中4℃、12000rpm离心5min钟，取上清，分装于EP管中，每支EP管400μL，保存于-20℃冰箱，临用时取出放置室温融化；
②根据北京四正柏生物科技有限公司的IL-6ELISA检测试剂盒与IL-8ELISA检测试剂盒说明书将4℃保存的试剂盒与实验样品拿到室温条件下放置30min，平衡至室温；
③将待测样品加入相应的酶标孔中，每孔100μL，用封板胶纸封住反应孔，37℃恒温箱中孵育90min；
④洗板4次：取出酶标板，甩弃样品，加入350μL的洗涤液，静置30s，甩弃洗涤液，重复洗涤4次，在吸水纸上拍干；
⑤加入生物素化抗体工作液100μL/孔，封板纸封住反应孔，37℃恒温箱孵育60min；重复步骤④洗板；
⑥加入酶结合物工作液，100μL/孔，用封板纸封住反应孔，37℃恒温箱中孵育30min，重复步骤④；
⑦加入显色液100μL/孔，37℃避光孵育15min，取出酶标板，加入100μL/孔终止液，轻轻振荡混匀，5min内测量OD450值。
结果分析显示，促炎细胞因子表达结果如图2所示，PAF诱导皮脂腺细胞表达IL-6、IL-8随时间增加而增加，诱导16h后IL-6与IL-8达到最大值，相比对照组IL-6升高4.1倍，IL-8升高3.4倍。诱导24h、48h后二者的表达有所下降。
实施例4
通过建立LPS诱导的急性呼吸窘迫症(Acute respiratory distress sydrome,ARDS)小鼠模型，进行小鼠肺部灌洗液细胞计数和肺部灌洗液细胞因子的检测。
4.1使用来自上海灵畅实验动物有限公司的BALB/c小鼠进行实验，分组信息如表5所示。
表5分组及给药方案
4.1.1 LPS溶液制备：LPS溶解于PBS中，使LPS溶液最终浓度为1.0mg/mL。
4.1.2 -0.5小时第一次口服给药地塞米松。
4.1.3 0小时将G2-G5组动物以及6小时将G6-G7动物LPS诱导急性肺损伤，使用特殊的雾化气雾针经气管给予造模剂LPS 50微升。G1接受同等体积的LPS的溶媒处理。气管注射前，动物接受2-5％的异氟烷吸入麻醉。
4.1.4按照表5进行给药。
4.1.5动物接受LPS造模后24小时，所有动物接受25mg/kg的舒泰腹腔注射麻醉，进行气管插管，用0.5mL的PBS(包含0.04M EDTA-K2)对肺进行第一次灌洗。另取0.5mL的PBS(包含0.04M EDTA-K2)对肺进行第二次灌洗。将两次灌洗的灌洗液(bronchoalveolarlavage fluid，BALF)置于冰上。
离心并用PBS重悬，获得细胞。稀释细胞液至浓度约为107细胞/毫升，移取100μL细胞液到血细胞分离器中，800rpm离心5分钟。将玻片在空气中风干，放在甲醇溶液中适当固定，然后使用Wright-Giemsa染色液染色，从而区分出嗜酸细胞，中性白细胞，巨噬细胞和淋巴细胞。在光学显微镜下计数。
4.1.6并将所有上清保存在超低温冰箱中，转移给体外实验室进行总蛋白测定和TNF-α、IL-1β、IL-6、FGF7和PAF的检测，均为复孔上样。
将实验小鼠分为G1-7组，其中G1为正常组，G2为模型-溶媒组，G3为模型-地塞米松组，G4为模型-0小时给药组(100μg/只小鼠),G5为模型-0小时给药组(150μg/只小鼠),G6为模型-6小时给药组(100μg/只小鼠),G7为模型-6小时给药组(150μg/只小鼠)，对肺部灌洗液中细胞因子的检测结果如图3所示，从细胞因子的检测结果中可以看出，模型组-溶媒组TNF-α、IL-6、IL-1β、FGF7和BALF蛋白的含量显著高于正常组。模型-地塞米松组可显著性抑制BALF上清中的TNF-α、IL-6、IL-1β和FGF7，模型-给药组100μg/只老鼠剂量组造模后6小时和12小时各给予一次给药，造模后24小时可显著性抑制BALF上清中的PAF，可见细胞因子的表达被FGF-7短肽抑制剂抑制的程度具有时效性。
肺部灌洗液细胞计数结果如表6所示，给药组中性粒细胞(neu)的平均数量多于地塞米松组，说明PI9对中性粒细胞的抑制作用比地塞米松弱，而地塞米松对炎症反应的抑制过强，可能会影响机体对抗外来病原体。
表6肺部灌洗液细胞计数
实施例5
使用实施例1中所述的短肽PI1-PI51(浓度为100μg/ml)，通过建立LPS诱导的急性呼吸窘迫症(Acute respiratory distress sydrome,ARDS)小鼠模型(见实施例4)进行的PI1-PI51对ARDS的肺部灌洗液中PAF表达的影响的研究(按实施例4操作)。
表7
注：以正常对照组为基准，相对值即抑制率
从表7可见，与阴性对照组无效的相比，与EWVRTD(PI9，SEQ NO ID.9)、ELSGRA(PI15，SEQ NO ID.15)、QDVDS(PI29，SEQ NO ID.29)、VFSTTGV(PI47，SEQ NO ID.47)相似性大的短肽具有较好的抑制PAF表达的效果。
实施例6
通过建立博来霉素诱导的肺纤维化大鼠(购自广东省动物实验中心)模型进行的PI9对肺纤维化的抑制作用的研究。
I.构建博来霉素诱导的SD大鼠肺纤维化模型
所有大鼠术前禁食、禁水12h，称重，腹腔注射10％水合氯醛麻醉大鼠，麻醉剂剂量为3ml/Kg；颈部备皮，将备皮后的大鼠四脚和头部和门牙固定于操作台，用碘伏局部消毒后再用酒精擦拭；用眼科剪在支气管上部作长约0.5cm左右的竖切口；用眼科镊子和直镊逐层分离肌肉，暴露出气管，确认甲状软骨的位置；抬高鼠头一端，使之与桌面成30°以上夹角，然后在直视下用注射器针刺入气管环状软骨，刺入时有落空感，将博莱霉素溶液缓慢注入；竖立鼠板，保持大鼠直立，左右交替旋转2min，使药液均匀分布于两肺；缝合肌肉和皮肤层后碘伏局部消毒，腹腔注射剂量为80000IU/只的青霉素溶液，预防术后感染。
II.实验分组和给药方案
分组：
正常对照组：建模时气管内注射250μl生理盐水；
BLM组：建模时气管内注射5mg/Kg博来霉素溶液；
BLM+PI9组：建模时气管内注射5mg/Kg博来霉素溶液，建模7天后给药。
给药方式：
建模第7天开始给药，连续给药14天。
正常对照组：腹腔注射400μl生理盐水；
BLM组：腹腔注射400μl生理盐水；
BLM+PI9给药组：腹腔注射P-8多肽，100μg/只/天。
各种大鼠肺组织结果如图4所示，观察博来霉素诱导的SD大鼠肺纤维化模型，治疗组大鼠肺组织苏木精-伊红染色(Hematoxylin-eosin staining,HE)与模型组相比，肺结构较完整，胶原蛋白和FGF-2明显减少，结果都表明PI9对肺纤维化有明显的抑制作用。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
序列表
<110> 暨南大学
<120> FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用
<160> 52
<170> SIPOSequenceListing 1.0
<210> 1
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI1
<400> 1
Ala Arg His Glu Trp Val Arg Thr Asp Gly
1 5 10
<210> 2
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI2
<400> 2
His Glu Trp Ser Arg Thr
1 5
<210> 3
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI3
<400> 3
Arg His Glu Trp Ser Arg Thr
1 5
<210> 4
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI4
<400> 4
Arg His Glu Trp Val Arg Thr Asp Gly
1 5
<210> 5
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI5
<400> 5
Ala Arg His Glu Trp Val Arg Thr Asp Gly
1 5 10
<210> 6
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI6
<400> 6
Ala Arg His Glu Trp Val Thr Thr Asp Gly Gly
1 5 10
<210> 7
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI7
<400> 7
Ala Arg His Glu Trp Val Arg Thr Asp Gly Gly Ser
1 5 10
<210> 8
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI8
<400> 8
Trp Val Arg Thr Asp
1 5
<210> 9
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI9
<400> 9
Glu Trp Val Arg Thr Asp
1 5
<210> 10
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI10
<400> 10
His Glu Trp Ser Arg Thr
1 5
<210> 11
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI11
<400> 11
Arg His Glu Trp Ser Arg Thr Asp Gly
1 5
<210> 12
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI12
<400> 12
Arg His Glu Trp Ser Arg Thr Asp
1 5
<210> 13
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI13
<400> 13
Glu Leu Ser Gly Arg Ala Lys
1 5
<210> 14
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI14
<400> 14
Thr Lys Glu Leu Ser Gly Arg Ala
1 5
<210> 15
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI15
<400> 15
Glu Leu Ser Gly Arg Ala
1 5
<210> 16
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI16
<400> 16
His Thr Val Glu Leu Ser Gly Arg Ala Lys
1 5 10
<210> 17
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI17
<400> 17
His Thr Lys Glu Leu Ser Gly Arg Ala Lys Leu
1 5 10
<210> 18
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI18
<400> 18
Thr Val Glu Leu Ser Gly Arg Ala Lys
1 5
<210> 19
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI19
<400> 19
His Thr Lys Glu Leu Ser Gly Arg Ala
1 5
<210> 20
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI20
<400> 20
Val Glu Leu Ser Gly Arg Ala Lys
1 5
<210> 21
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI21
<400> 21
Glu Leu Ser Gly Arg
1 5
<210> 22
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI22
<400> 22
Lys Glu Leu Ser Gly Arg Ala
1 5
<210> 23
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI23
<400> 23
His Thr Lys Glu Leu Ser Gly Arg Ala Lys Leu Ile
1 5 10
<210> 24
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI24
<400> 24
Glu His Ser Gly Arg
1 5
<210> 25
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI25
<400> 25
Lys Glu His Ser Gly Arg
1 5
<210> 26
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI26
<400> 26
Leu Ser Gly Arg Ala
1 5
<210> 27
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI27
<400> 27
Pro Leu Arg Gln Asp Val Asp Ser
1 5
<210> 28
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI28
<400> 28
Pro Leu Arg Gln Asp Val Asp
1 5
<210> 29
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI29
<400> 29
Gln Asp Val Asp Ser
1 5
<210> 30
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI30
<400> 30
Pro Leu Arg Gln Asp Val Asp Ser Arg Ser Thr His
1 5 10
<210> 31
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI31
<400> 31
Pro Leu Arg Gln His Val Asp Ser Arg Ser Thr
1 5 10
<210> 32
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI32
<400> 32
Arg Gln Asp Val Asp Ser Arg
1 5
<210> 33
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI33
<400> 33
Leu Gly Gln Asp Val Asp Ser
1 5
<210> 34
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI34
<400> 34
Pro Leu Arg Gln Asp Val
1 5
<210> 35
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI35
<400> 35
Arg Gln Asp Val Asp Ser
1 5
<210> 36
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI36
<400> 36
Leu Gly Gln Asp Val Asp
1 5
<210> 37
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI37
<400> 37
Pro Leu Arg Gln Asp Val Asp Ser Arg Ser
1 5 10
<210> 38
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI38
<400> 38
Leu Gly Gln Asp Val Asp Ser Arg
1 5
<210> 39
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI39
<400> 39
Pro Leu Arg Gln Asp Val Asp Ser Arg
1 5
<210> 40
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI40
<400> 40
Phe Gly Ser Val Phe Ser Thr Thr Gly
1 5
<210> 41
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI41
<400> 41
Gly Ser Val Phe Ser Thr Thr Gly Val
1 5
<210> 42
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI42
<400> 42
Ser Val Phe Ser Thr Thr Gly Val
1 5
<210> 43
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI43
<400> 43
Phe Gly Ser Val Phe Ser Thr
1 5
<210> 44
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI44
<400> 44
Phe Gly Ser Val Phe Ser Thr Thr Gly Val Ile Ser Arg
1 5 10
<210> 45
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI45
<400> 45
Ser Val Phe Ser Thr Thr Gly
1 5
<210> 46
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI46
<400> 46
Val Phe Ser Thr Thr Ile
1 5
<210> 47
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI47
<400> 47
Val Phe Ser Thr Thr Gly Val
1 5
<210> 48
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI48
<400> 48
Phe Gly Ser Val Phe Ser Thr Thr Gly Val Ile Ser
1 5 10
<210> 49
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI49
<400> 49
Phe Gly Ser Val Phe Ser Thr Thr
1 5
<210> 50
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI50
<400> 50
Phe Gly Ser Val Phe Ser Thr Thr Gly Val
1 5 10
<210> 51
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PI51
<400> 51
Phe Gly Ser Val Phe Ser Thr Cys Gly Val Ile
1 5 10
<211> 246
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FGFR胞外段氨基酸序列
<400> 52
Ala Pro Tyr Trp Thr Asn Thr Glu Lys Met Glu Lys Arg Leu His Ala
1 5 10 15
Val Pro Ala Ala Asn Thr Val Lys Phe Arg Cys Pro Ala Gly Gly Asn
20 25 30
Pro Met Pro Thr Met Arg Trp Leu Lys Asn Gly Lys Glu Phe Lys Gln
35 40 45
Glu His Arg Ile Gly Gly Tyr Lys Val Arg Asn Gln His Trp Ser Leu
50 55 60
Ile Met Glu Ser Val Val Pro Ser Asp Lys Gly Asn Tyr Thr Cys Val
65 70 75 80
Val Glu Asn Glu Tyr Gly Ser Ile Asn His Thr Tyr His Leu Asp Val
85 90 95
Val Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala Gly Leu Pro Ala
100 105 110
Asn Ala Ser Thr Val Val Gly Gly Asp Val Glu Phe Val Cys Lys Val
115 120 125
Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Ile Lys His Val Glu Lys
130 135 140
Asn Gly Ser Lys Tyr Gly Pro Asp Gly Leu Pro Tyr Leu Lys Val Leu
145 150 155 160
Lys His Ser Gly Ile Asn Ser Ser Asn Ala Glu Val Leu Ala Leu Phe
165 170 175
Asn Val Thr Glu Ala Asp Ala Gly Glu Tyr Ile Cys Lys Val Ser Asn
180 185 190
Tyr Ile Gly Gln Ala Asn Gln Ser Ala Trp Leu Thr Val Leu Pro Lys
195 200 205
Gln Gln Ala Pro Gly Arg Glu Lys Glu Ile Thr Ala Ser Pro Asp Tyr
210 215 220
Leu Glu Ile Ala Ile Tyr Cys Ile Gly Val Phe Leu Ile Ala Cys Met
225 230 235 240
Val Val Thr Val Ile Leu
245
Claims (10)
1.FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用。
2.根据权利要求1所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的PAF介导的疾病包括急性呼吸窘迫综合征、肺水肿、肺纤维化疾病、动脉硬化心血管疾病、各种与PAF相关的肿瘤、放化疗导致的PAF介导的肿瘤转移和复发、以及神经退行疾病如阿尔兹海默症、帕金森氏症。
3.根据权利要求1所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的急性呼吸窘迫综合征为病毒性感染和细菌性感染引起的急性呼吸窘迫综合征。
4.根据权利要求3所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的病毒为冠状病毒。
5.根据权利要求4所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的冠状病毒为SARS-CoV、MERS-CoV或2019-n CoV。
6.根据权利要求2所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的肺纤维化为特发性肺纤维化和炎症导致的肺纤维化。
7.根据权利要求1～6任一项所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的FGFR2b抑制分子包括抑制FGF-7表达的分子、抑制FGFR2b激活为磷酸化FGFR2b的分子和竞争性抑制FGF-7与FGFR2b结合的分子。
8.根据权利要求7所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的分子包括但不限于siRNA、寡肽、多肽。
9.根据权利要求7所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的竞争性抑制FGF-7与FGFR2b结合的分子选自申请号为2019102390870、发明名称为“用于治疗脱发的短肽、药物及其应用”的国家发明专利申请中记载的短肽；进一步为分别以EWVRTD、ELSGRA、QDVDS、或VFSTTGV为中心，在两端分别增加、删除或突变0～2个氨基酸得到的短肽；进一步为EWVRTD、WVRTD、RHEWSRTD、ELSGRA、HTVELSGRAK、QDVDS、VFSTTGV或FGSVFSTTGV。
10.根据权利要求7所述的FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用，其特征在于：所述的抑制FGFR2b激活为磷酸化FGFR2b的分子选自申请号为201310714120.3、发明名称为“FGFR2b胞外段的基因序列、多肽及其应用”的国家发明专利记载的短肽。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010783944.6A CN111760026A (zh) | 2020-08-06 | 2020-08-06 | FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用 |
| PCT/CN2020/136500 WO2022027898A1 (zh) | 2020-08-06 | 2020-12-15 | FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用 |
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| CN202010783944.6A CN111760026A (zh) | 2020-08-06 | 2020-08-06 | FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用 |
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| WO2022027898A1 (zh) * | 2020-08-06 | 2022-02-10 | 汪炬 | FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用 |
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| CN103757036A (zh) * | 2007-10-03 | 2014-04-30 | 维莱尼姆公司 | 木聚糖酶、编码它们的核酸以及其制备和应用方法 |
| CN108368174A (zh) * | 2015-11-23 | 2018-08-03 | 戊瑞治疗有限公司 | 用于癌症治疗的单独fgfr2抑制剂或与免疫刺激剂的组合 |
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| AU2001279313B2 (en) * | 2000-08-04 | 2007-03-01 | Ampio Pharmaceuticals, Inc. | Method of using diketopiperazines and composition containing them |
| DE102007026877A1 (de) * | 2007-06-08 | 2008-12-11 | Bayer Schering Pharma Aktiengesellschaft | Verwendung des Fibroblastenwachstumsfaktors 7 (Fgf7) und des Rezeptors Fgfr2b als Biomarker |
| US9771560B2 (en) * | 2012-03-14 | 2017-09-26 | Children's Medical Center Corporation | High-throughput image-based chemical screening in zebrafish blastomere cell culture |
| CN103757026B (zh) * | 2013-12-20 | 2017-04-05 | 广州圣露生物技术有限公司 | FGFR2b胞外段的基因序列、多肽及其应用 |
| EP4650004A2 (en) * | 2017-05-16 | 2025-11-19 | Five Prime Therapeutics, Inc. | Anti-fgfr2 antibodies in combination with chemotherapy agents in cancer treatment |
| CN107213254A (zh) * | 2017-06-15 | 2017-09-29 | 中山大学 | 复方血栓通制剂在制备治疗paf介导疾病药物中的用途 |
| CN110404051A (zh) * | 2019-03-27 | 2019-11-05 | 汪炬 | 用于治疗脱发的短肽、药物及其应用 |
| CN111760026A (zh) * | 2020-08-06 | 2020-10-13 | 汪炬 | FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用 |
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- 2020-08-06 CN CN202010783944.6A patent/CN111760026A/zh active Pending
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| WO2022027898A1 (zh) * | 2020-08-06 | 2022-02-10 | 汪炬 | FGFR2b抑制分子在制备治疗PAF介导的疾病药物中的应用 |
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