CN115028683B - 五肽化合物及其在制备治疗肝纤维化疾病药物中的应用 - Google Patents
五肽化合物及其在制备治疗肝纤维化疾病药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种五肽化合物及其在制备治疗肝纤维化疾病药物中的应用,所述五肽化合物的氨基酸序列为X‑甘氨酸‑精氨酸‑苯丙氨酸‑Y,其中X、Y分别代表N端和C端的氨基酸;所述X代表半胱氨酸、天冬氨酸、苯丙氨酸、色氨酸中任意一种,Y代表甘氨酸;或者所述X代表组氨酸,Y代表苯丙氨酸、亮氨酸、苏氨酸酸、色氨酸中任意一种。本发明五肽化合物对HSC‑T6细胞增殖的抑制作用显著,且IC50值均低于100μM,且表现出明显的剂量依赖性,有望开发成新型的治疗肝纤维化疾病的药物。
Description
技术领域
本发明属于医药技术领域,具体涉及一类五肽化合物,以及该类五肽化合物在制备治疗肝纤维化疾病药物中的应用。
背景技术
肝纤维化是一种由多种因素长期互相作用所形成的慢性疾病,在世界范围内具有较高的发病率,是目前全球公共卫生领域亟待解决的重要课题。大量既往研究广泛证实了早期肝纤维化的可逆性,人们对肝纤维化的发生原因、形成机制、涉及的细胞及信号通路等各方面也都有了精准的把握,充分意识到肝纤维化形成过程的复杂性、多靶点性等特点;近年来,越来越多的多肽类化合物被用于开发治疗肝纤维化疾病;大量的研究和临床经验表明多肽类化合物治疗肝纤维化疾病有副作用小,易通过血脑屏障,吸收率高等优点,因此开发治疗肝纤维化疾病的多肽类药物是大势所趋。
发明内容
本发明的目的是提供一类对HSC-T6具有显著抑制活性的五肽化合物,以及该类五肽化合物的新用途。
本发明所述五肽化合物的氨基酸序列为X-甘氨酸-精氨酸-苯丙氨酸-Y(简写为XGRFY),其中X代表半胱氨酸、天冬氨酸、苯丙氨酸、色氨酸中任意一种,Y代表甘氨酸;或者X代表组氨酸,Y代表苯丙氨酸、亮氨酸、苏氨酸酸、色氨酸中任意一种。
进一步的,所述五肽化合物的氨基酸序列中,优选所有的氨基酸构型为L型构型。
进一步的,所述五肽化合物优选以醋酸盐的形态存在。
本发明五肽化合物采用固相法合成,以Fmoc保护的氨基酸为原料,2-CTC Resin(取代度为1.0mmol/g)为固相载体,DIC/HOBt为缩合剂,合成五肽化合物,最后从树脂上裂解下来,并用高效液相纯化,最终每个五肽化合物的纯度均在95%以上。
本发明五肽化合物对HSC-T6的增值抑制作用显著,可用于制备治疗肝纤维化疾病药物。
本发明的有益效果如下:
研究表明HSC细胞(肝星状细胞)是形成肝纤维化的主要细胞,通过抑制HSC细胞的增殖和促进HSC细胞的凋亡可以达到抗肝纤维化的作用,研究发现大鼠肝星状细胞(HSC-T6)几乎具备了活性星状细胞的所有特性,因此本发明以HSC-T6为模型,用高通量筛选的方法筛选大量的三肽,发现甘氨酸-精氨酸-苯丙氨酸(GRF)这三肽片段能够明显的抑制HSC-T6的增殖,因此本发明以GRF片段为核心片段,对其C端和N端分别加入一个特定的氨基酸组合进行修饰,不仅可以增加其活性,还可以改变其亲脂性,从而影响药物药代动力学和药效学。实验结果表明,本发明五肽化合物的IC50值均低于100μM,对HSC-T6的抑制活性显著,且表现出明显的剂量依赖性,有望开发成新型的治疗肝纤维化疾病的药物。
附图说明
图1是CGRFG的MS图。
图2是DGRFG的MS图。
图3是FGRFG的MS图。
图4是WGRFG的MS图。
图5是HGRFF的MS图。
图6是HGRFL的MS图。
图7是HGRFT的MS图。
图8是HGRFW的MS图。
具体实施方式
下面结合附图和实施例对本发明进一步详细说明,但本发明的保护范围不仅限于这些实施例。
实施例1
合成CGRFG
选用取代度为1.0mmol/g的2-CTC Resin为固相载体,称取10g 2-CTC Resin于反应柱中,加入80mL DCM溶胀树脂10min,抽滤。将2-CTC Resin 1.1倍摩尔当量的Fmoc-Gly-OH与4倍摩尔当量的DIEA,用80mL DCM溶解制成反应液加入反应柱中,通入N2吹拂搅拌,反应1.5h,再加入10mL无水甲醇封闭30min,抽滤除去反应液后,依次用IPA、DMF各洗涤两次,每次3min,将树脂肽上所附着的氨基酸反应液洗涤干净,即得Fmoc-Gly-2-CTC树脂肽。随后加入体积分数为20%的PIP/DMF溶液,通入N2吹拂搅拌,反应30min,脱去а-氨基的Fmoc保护基,抽滤除去反应液后,依次用IPA、DMF各洗涤两次,每次3min。并用玻璃棒蘸取树脂肽于试管中,加入2mL 0.05g/mL茚三酮的乙醇溶液(Kaiser显色法),于95℃水浴锅中恒温2min,肉眼观察进行检测,显示树脂为阳性(黑色)。
脱保护反应完全后,开始进行下一个氨基酸的连接。以80mL DMF完全溶解2-CTCResin 2倍摩尔当量的Fmoc-Phe-OH、2.5倍摩尔当量的DIC和2.5倍摩尔当量的HOBt制成反应液,在反应柱中加入反应液,并通入N2吹拂搅拌,反应1.5h。同样的,以Kaiser显色法检测反应是否完全,待反应完全后,抽滤除去反应液,依次用IPA、DMF各洗涤两次,每次3min。随后,重复脱保护-缩合-脱保护的操作步骤,按照半胱氨酸-甘氨酸-精氨酸-苯丙氨酸-甘氨酸(简称CGRFG)的氨基酸序列依次连接Fmoc-Arg(pbf)-OH、Fmoc-Gly-OH、Fmoc-Cys(trt)-OH。肽链合成完成且脱去Fmoc保护基后,用IPA、DMF各洗涤两次,每次3min,再用无水甲醇洗涤3次,每次3min,常温下抽滤干燥,即得到CGRFG树脂肽。
将上述固相合成得到的CGRFG树脂肽置于250mL烧杯中,在搅拌下加入100mL切割液,反应2h,切割树脂和各侧链保护基,切割液体积比组成为TFA:TIS:PhSCH3:H2O=88:4:5:3。抽滤,并用DCM洗涤树脂3次,40℃下旋蒸滤液进行浓缩,浓缩液用甲基叔丁基醚进行析出,充分搅拌后,3500r/min离心10min,常温下挥干甲基叔丁基醚,即得固体粉末状CGRFG粗品。
取3~5g CGRFG粗品于100mL烧杯中,用50mL纯水超声溶解,0.45μm滤膜过滤后色谱分离纯化。色谱条件:LC3000半制备液相色谱仪,反相柱层析填料色谱柱(50mm×350mm,30~50μm);流动相:A相为0.1%的三氟乙酸水溶液,B相为0.1%的三氟乙酸甲醇溶液,流速:30mL/min,100%A相上样,1%B 10min,1%B~7.5%B 50min,洗掉杂质后7.5%B恒流洗出并收集产物。进样量:30mL,检测波长215nm,LC3000工作站进行洗脱过程监测,收样瓶收集主产物峰,分析后合并纯度高于95%的流出液,旋转蒸发浓缩后,冷冻干燥机冷冻72h,即得CGRFG纯品冻干粉。
取CGRFG纯品冻干粉以超纯水制样,浓度不超过50ppm,0.22μm滤膜过滤,采用Waters Acquity超高效液-质联用色谱仪进行质谱鉴定。色谱条件:Acquity UPLC C18色谱柱(2.1mm×50mm,1.7μm);流动相:A相为0.1%的甲酸水溶液,B相为0.1%的甲酸乙腈溶液,按照质谱检测方法的程序,运行程序1%~31%,流速:0.3mL/min,时间15min,进样量:2μL。质谱检测:scan 100-1100,锥孔电压15-20V,Waters Laboratory Informatics控制软件监测检测过程并显示和处理数据,结果见图1。
上述实施例1中的Fmoc-Cys(trt)-OH分别用等摩尔量的Fmoc-Asp(otbu)-OH、Fmoc-Phe-OH、Fmoc-Trp-OH替换,其他步骤与实施例1相同,可相应获得天冬氨酸-甘氨酸-精氨酸-苯丙氨酸-甘氨酸(DGRFG)、苯丙氨酸-甘氨酸-精氨酸-苯丙氨酸-甘氨酸(FGRFG)、色氨酸-甘氨酸-精氨酸-苯丙氨酸-甘氨酸(WGRFG)粗品,再各自用表1中相应的纯化条件进行纯化得到相应的纯品。所得纯品的表征结果见图2~4。
表1五肽化合物纯化的洗脱程序
五肽序列 | 洗脱程序 |
DGRFG | 1%B 10min,1%B~14%B 35min,14%B恒流 |
FGRFG | 5%B~15%B 30min,15%B~22%B 20min,22%B恒流 |
WGRFG | 5%B 10min,5%B~15%B 20min,15%B~21%B 30min,21%B恒流 |
实施例2
合成HGRFF
选用取代度为1.0mmol/g的2-CTC Resin为固相载体,称取10g 2-CTC Resin于反应柱中,加入80mL DCM溶胀树脂10min,抽滤。将2-CTC Resin 1.1倍摩尔当量的Fmoc-Phe-OH与4倍摩尔当量的DIEA,用80mL DCM溶解制成反应液加入反应柱中,通入N2吹拂搅拌,反应1.5h,再加入10mL无水甲醇封闭30min,抽滤除去反应液后,依次用IPA、DMF各洗涤两次,每次3min,将树脂肽上所附着的氨基酸反应液洗涤干净,即得Fmoc-Phe-2-CTC树脂肽。随后加入体积分数为20%的PIP/DMF溶液,通入N2吹拂搅拌,反应30min,脱去а-氨基的Fmoc保护基,抽滤除去反应液后,依次用IPA、DMF各洗涤两次,每次3min。并用玻璃棒蘸取树脂肽于试管中,加入2mL0.05g/mL茚三酮的乙醇溶液(Kaiser显色法),于95℃水浴锅中恒温2min,肉眼观察进行检测,显示树脂为阳性(黑色)。
脱保护反应完全后,开始进行下一个氨基酸的连接。以80mL DMF完全溶解2-CTCResin 2倍摩尔当量的Fmoc-Phe-OH、2.5倍摩尔当量的DIC和2.5倍摩尔当量的HOBt制成反应液,在反应柱中加入反应液,并通入N2吹拂搅拌,反应1.5h。同样的,以Kaiser显色法检测反应是否完全,待反应完全后,抽滤除去反应液,依次用IPA、DMF各洗涤两次,每次3min。随后,重复脱保护-缩合-脱保护的操作步骤,按照组氨酸-甘氨酸-精氨酸-苯丙氨酸-苯丙氨酸(简称HGRFF)的氨基酸序列依次连接Fmoc-Arg(pbf)-OH、Fmoc-Gly-OH、Fmoc-His(trt)-OH。肽链合成完成且脱去Fmoc保护基后,用IPA、DMF各洗涤两次,每次3min,再用无水甲醇洗涤3次,每次3min,常温下抽滤干燥,即得到HGRFF树脂肽。
将上述固相合成得到的HGRFF树脂肽置于250mL烧杯中,在搅拌下加入100mL切割液,反应2h,切割树脂和各侧链保护基,切割液体积比组成为TFA:TIS:PhSCH3:H2O=88:4:5:3。抽滤,并用DCM洗涤树脂3次,40℃下旋蒸滤液进行浓缩,浓缩液用甲基叔丁基醚进行析出,充分搅拌后,3500r/min离心10min,常温下挥干甲基叔丁基醚,即得固体粉末状HGRFF粗品。
取3~5g HGRFF粗品于100mL烧杯中,用50mL纯水超声溶解,0.45μm滤膜过滤后色谱分离纯化。色谱条件:LC3000半制备液相色谱仪,反相柱层析填料色谱柱(50mm×350mm,30~50μm);流动相:A相为0.1%的三氟乙酸水溶液,B相为0.1%的三氟乙酸甲醇溶液,流速:30mL/min,100%A相上样,1%B 10min,1%B~7.5%B 50min,洗掉杂质后7.5%B恒流洗出并收集产物。进样量:30mL,检测波长215nm,LC3000工作站进行洗脱过程监测,收样瓶收集主产物峰,分析后合并纯度高于95%的流出液,旋转蒸发浓缩后,冷冻干燥机冷冻72h,即得HGRFF纯品冻干粉。
取HGRFF纯品冻干粉以超纯水制样,浓度不超过50ppm,0.22μm滤膜过滤,采用Waters Acquity超高效液-质联用色谱仪进行质谱鉴定。色谱条件:Acquity UPLC C18色谱柱(2.1mm×50mm,1.7μm);流动相:A相为0.1%的甲酸水溶液,B相为0.1%的甲酸乙腈溶液,按照质谱检测方法的程序,运行程序1%~31%,流速:0.3mL/min,时间15min,进样量:2μL。质谱检测:scan 100-1100,锥孔电压15-20V,Waters Laboratory Informatics控制软件监测检测过程并显示和处理数据,结果见图5。
上述实施例2中的第一个Fmoc-Phe-OH分别用等摩尔量的Fmoc-Leu-OH、Fmoc-Thr(otbu)-OH、Fmoc-Trp-OH替换,其他步骤与实施例2相同,可相应获得组氨酸-甘氨酸-精氨酸-苯丙氨酸-亮氨酸(HGRFL)、组氨酸-甘氨酸-精氨酸-苯丙氨酸-苏氨酸(HGRFT)、组氨酸-甘氨酸-精氨酸-苯丙氨酸-色氨酸(HGRFW)粗品,再各自用表2中相应的纯化条件进行纯化得到相应的纯品。所得纯品的表征结果见图6~8。
表2五肽化合物纯化的洗脱程序
五肽序列 | 洗脱程序 |
HGRFL | 5%B 10min,5%B~15%B 50min,15%B~21%B 30min,21%B恒流 |
HGRFT | 5%B 10min,5%B~15%B 50min,15%B恒流 |
HGRFW | 15%B 10min,15%B~25%B 30min,25%B~33%B 40min,15%B恒流 |
实施例3
本发明五肽化合物对HSC-T6的增殖的抑制作用
1、细胞培养
(1)细胞复苏
紫外线消毒超净工作台及实验物品0.5h,培养基等试剂于室温下复温,工作台台面以75%的酒精擦拭消毒,关闭紫外灯后开无菌风,点燃酒精灯,在酒精灯外焰周围的无菌环境中操作。快速从液氮罐中取出冻存的HSC-T6细胞,核对记录中的细胞类型、细胞代数以及冻存日期,于37℃水浴锅中解冻细胞,持续轻晃细胞冻存管加速融化,同时应注意防止冻存管封口接触水浴锅中的液体而造成细胞污染。在超净工作台无菌环境中,用移液器将解冻的细胞移至9mL 10%FBS High-DMEM培养基的15mL离心管中,吹打至混匀,常温下800rpm离心5min,弃去上清液,在离心管中加入1mL培养基使细胞重悬,吹打至均匀后,移至1mL10%FBS High-DMEM培养基的25cm2培养瓶中,于5%CO2、95%饱和湿度的培养箱中培养,24h内换液一次。
(2)细胞传代
借助倒置光学显微镜观察细胞的状态,当培养瓶底部铺满80%以上的细胞时,即可以进行传代操作。无菌环境移除培养瓶中的培养基,PBS洗液洗涤细胞3次,每次3mL,然后加入3mL 0.25%的胰蛋白酶,并使其均匀铺满培养瓶,放入孵箱中消化2min左右。显微镜下观察到细胞变圆且大片脱落时,证明已经消化完全,加入4mL 10%FBS High-DMEM培养基以及胰蛋白酶终止反应,并缓慢吹打反应液至贴壁的细胞完全剥落。随后将细胞悬液转移至15mL无菌离心管中,室温下800rpm离心5min,弃去上清液,加入2mL 10%FBS High-DMEM培养基使细胞重悬,离心管中反复吹打形成单细胞悬液,以便于进一步的传代或接种。
(3)细胞冻存
细胞冻存与细胞传代的步骤相同,消化后离心并弃去上清液,于离心管中加入1mLDMSO:FBS:DMEM=1:2:7(v/v/v)的细胞冻存液,反复吹打至混合均匀,随后移至细胞冻存管中并以封口膜密闭封存,标记细胞的种类、冻存日期等信息,在-20℃冰箱中静置2h后,-80℃冰箱中静置过夜,即可在液氮罐中保存。
2、实验分组及MTT法检测
实验分组:设置对照组(Control组):HSC-T6细胞+High-DMEM培养基;5ng/mL TGF-β1组:HSC-T6细胞+High-DMEM培养基+5ng/mL TGF-β1;3.125μM浓度组:HSC-T6细胞+High-DMEM培养基+5ng/mL TGF-β1+3.125μM的XGRFY;6.25μM浓度组:HSC-T6细胞+High-DMEM培养基+5ng/mL TGF-β1+6.25μM的XGRFY;12.5μM浓度组:HSC-T6细胞+High-DMEM培养基+5ng/mLTGF-β1+12.5μM的XGRFY;25μM浓度组:HSC-T6细胞+High-DMEM培养基+5ng/mL TGF-β1+25μM的XGRFY;50μM浓度组::HSC-T6细胞+High-DMEM培养基+5ng/mL TGF-β1+50μM的XGRFY;100μM浓度组::HSC-T6细胞+High-DMEM培养基+5ng/mL TGF-β1+100μM的XGRFY。
实验步骤:HSC-T6细胞进行传代培养,当细胞铺满培养瓶底80%以上时,加入3mL0.25%的胰蛋白酶放入二氧化碳培养箱中消化2min,接着加入新鲜的High-DMEM培养基防止过度消化,然后离心收集细胞,在新鲜培养基中将细胞吹打至单细胞混悬液,将细胞接种至96孔培养板中,每孔加入180μL 10%FBS High-DMEM培养基和20μL细胞悬液,37℃、5%CO2、95%饱和湿度培养24h,显微镜下观察细胞是否贴壁,细胞贴壁后,吸去上清液,此时更换无血清High-DMEM培养基继续培养12h,吸取上清液,按照实验分组的设计,Control组为不含药物的正常细胞,TGF-β1刺激组和XGRFY药物处理组分别加入含5ng/mL的TGF-β1的培养基培养2h,各个药物处理组分别再加入3.125μM、6.25μM、12.5μM、25μM、50μM、100μM的XGRFY的High-DMEM培养基。
MTT法显色:每个组分别设4个复孔,将完成加药的96孔板放置恒温培养箱中培养48h,吸取上清液,每孔加入0.5mg/mL的MTT溶液100μL,37℃,5%的CO2,95%的饱和湿度继续培养4h后,吸取旧的培养液,然后每孔加入150μL的分析纯DMSO,在37℃下于恒温水平摇床振荡10min,用酶联免疫检测仪在490nm波长处测定吸光值(OD)。
3、数据分析
利用SPSS 20.0软件进行数据分析,每个化合物在不同浓度下的吸光值用 表示,应用单因素方差分析,P<0.05表示差异具有显著意义。根据下述公式计算细胞生长抑制率:
抑制率=(1-药物组OD值/对照组OD值)×100%
抑制率>0即化合物对细胞的增殖具有抑制作用,抑制率<0则化合物对细胞的增殖具有促进作用,根据抑制率和样品浓度,用SPSS 20.0计算IC50值,结果见表3和表4。
表3本发明五肽化合物对HSC-T6增殖的抑制作用(n=3)
注:表中*P<0.05与control组相比,#P<0.05与TGF-β1组相比。
表4本发明五肽化合物对HSC-T6细胞增殖的抑制作用的IC50值
五肽序列 | IC50(μM) | 五肽序列 | IC50(μM) |
CGRFG | 68.93 | HGRFF | 82.904 |
DGRFG | 32.903 | HGRFL | 37.611 |
FGRFG | 31.944 | HGRFT | 92.294 |
WGRFG | 29.727 | HGRFW | 23.619 |
由表3和表4可见,CGRFG、DGRFG、FGRFG、WGRFG、HGRFF、HGRFL、HGRFT、HGRFW的IC50值均低于100μM,对HSC-T6的抑制活性显著,且表现出明显的剂量依赖性。其中WGRFG(IC50值29.727μM)、HGRFW(IC50值23.619μM)这两个五肽的活性最好,能有效抑制HSC-T6的增殖,值得进行进一步的动物药理活性评价。
序列表
<110> 陕西慧康生物科技有限责任公司
<120> 五肽化合物及其在制备治疗肝纤维化疾病药物中的应用
<140> 2022106596253
<141> 2022-06-13
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Cys Gly Arg Phe Gly 5
Claims (2)
1.一种治疗肝纤维化疾病的五肽,其特征在于:所述五肽的氨基酸序列为X-甘氨酸-精氨酸-苯丙氨酸-Y,其中X、Y 分别代表N端和C端的氨基酸;所述X代表半胱氨酸,Y代表甘氨酸;所述五肽的氨基酸序列中,所有的氨基酸构型为L型构型。
2.权利要求1所述的五肽在制备治疗肝纤维化疾病药物中的应用。
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CN105713095A (zh) * | 2016-03-14 | 2016-06-29 | 南京安吉生物科技有限公司 | 一种多功能融合多肽及其制备方法和应用 |
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