CN114181315B - 一种内体逃逸肽及其应用 - Google Patents
一种内体逃逸肽及其应用 Download PDFInfo
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Abstract
本发明提供了一种内体逃逸肽,包含内体逃逸肽的载体,包含载体的融合蛋白,编码内体逃逸肽、载体或融合蛋白的核酸。本发明还提供了内体逃逸肽、载体或融合蛋白在基因编辑或者肿瘤治疗领域的应用。本发明还提供了一种基因编辑的方法。本发明提供的内体逃逸肽,仅在酸性条件下发挥作用,做到从内体中顺利逃逸,并且避免抗体在内吞过程中的降解,更加减少药物蛋白在内体中的滞留。
Description
技术领域
本发明涉及药物递送技术领域,具体涉及一种内体逃逸肽、载体以及融合蛋白,并将其用于基因编辑或肿瘤治疗领域的组织特异性大分子药物的递送。
背景技术
随着从分子生物学时代的开始,越来越多的疾病靶点被发现,大分子的蛋白质药物如抗体药物,结构更加复杂多样,与靶点结合的亲和力高、特异性好。
然而众所周知的是,大分子很难穿过具有选择透过性的哺乳动物细胞磷脂双分子层,所以蛋白质药物一般作用的是胞外靶点。大分子药物需要依靠专门的递送载体帮助其穿过细胞膜,到达胞内作用靶点。
细胞穿透肽可以携带核酸和蛋白质进入胞内。CPP是一类小于20个氨基酸的多肽,正电荷氨基酸例如精氨酸、赖氨酸占有较高比例,有一些CPP具有α-螺旋的二级结构,通过其带有的正电荷和疏水性的氨基酸,与细胞膜相互作用,经由内吞途径、转导易位或者在膜上打孔直接进入细胞。
但是因为CPP与膜直接相互作用,缺乏细胞特异性;而且经由内吞途径进入胞内会存在溶酶体滞留的问题,影响大分子递送的效率。
在临床上,我们常常希望可以将药物特异性递送到病变部位,减少对正常组织的毒性,同时提高了药物的有效作用量。现阶段开发的特异性递送载体并不多,某些病毒载体对组织有偏好性感染,某些毒素的亚基可以特异性识别细胞表面受体,还有一些和抗体组装的递送载体因为特异性和安全性更高,是当前研究的热点。
抗体作为靶向药物的代表,常常被用于细胞的特异性识别,抗体可以和小分子结合,帮助小分子的特异性给药,例如近年来兴起的抗体药物偶联技术ADC(Antibody DrugConjugates)。抗体也可以和蛋白质融合,通过细胞穿透肽与抗体的融合表达,可以增加CPP细胞特异性。但是因为CPP是强正电荷的短肽,细胞周围充满了很多负电荷基质,CPP其实大部分都留在了负电荷的基质中,没有达到目的细胞。
所以,如何降低细胞毒性和免疫原性、如何进行精准的组织和细胞特异性递送,是决定药物安全性的大前提。如何有效的促进溶酶体的溶酶体逃逸,促使足够量的目的蛋白达到作用部位,很大程度上影响了整个系统的递送效率。如何延长药物的半衰期,减少在基质中的粘连,降低在溶酶体中的驻留,这三个过程最终决定了可以实际作用的药物量。
对大分子药物的胞内递送是一个技术难题,但是可以利用整个过程依托的生物学机制,来合理设计载药系统,规避可能会遇到的问题,达到更多的递送效率。技术的革新无疑会带来基础科学的进步,尤其在基因编辑的时代下,开发出高效的递送工具十分必要。
专利CN107129521A公开了一种具有透过细胞膜或体组织屏障功能的肽及其应用。具体的,公开了一种穿膜肽,即CC12多肽,其具体序列为EMFTPPSMIERL。该穿膜肽可以携带功能性分子,用于治疗眼部疾病。
专利CN108138150A公开了一种细胞透性改善的帕金重组蛋白及其用途,所述重组蛋白中包含疏水性的CPP,即高级大分子转导域启动,该重组蛋白可以解决血脑屏障透性、组织透性和生物传递功能。
专利CN109453187A公开了一种具有双重酶敏感特性的抗体核酸药物偶联物及其制备方法和应用。
专利CN105727304A公开了一种核酸偶联物、其制备方法及其应用,该核酸偶联物包含穿膜肽、柔性链段及核酸药物。该穿膜肽可以携带核酸药物进入细胞,并发挥生物活性,提供其生物利用度。
因此,现有技术中仅仅公开了若干种穿膜肽,并且可以用于携带核酸或者蛋白进入细胞,但是并没有公开采用组氨酸和谷氨酸的组合进行屏蔽CPP的正电荷,并且还没有一种可以仅在酸性条件下敏感的内体逃逸肽。
发明内容
本发明的目的是实现组织特异性的细胞内的大分子(优选为蛋白)递送。因此,本申请提供了一种内体逃逸肽,其包含屏蔽CPP正电荷的(HE)n和CPP,该内体逃逸肽在中性条件下呈电中性,结构无序且没有功能,但是在内吞过程中随着酸性条件的增大,使其具有膜活性,达到从内体中逃逸的作用。本申请还提供了一种载体,该载体包含内体逃逸肽和靶向细胞的分子,该载体可以携带大分子例如蛋白,通过靶向细胞的分子(优选为抗体)定位至特定的细胞(需要进行基因编辑的细胞或者肿瘤细胞),然后内体逃逸肽可以携带蛋白进入细胞的内体中,随着内体中酸性的增大,使得内体逃逸肽呈现强正电性,并且被内体中聚集的酶切割(HE)n部分,然后从内体例如内涵体或溶酶体中逃逸。本发明还提供了一种融合蛋白,其包含载体和药物蛋白,其可以用于治疗各种相关疾病。本发明还提供了一种融合蛋白,其包含载体和序列特异性核酸酶,其可以用于基因编辑中序列特异性核酸酶的递送。本发明还提供了一种编码上述内体逃逸肽、载体或融合蛋白的核酸。本发明还提供了一种包含上述核酸的表达载体。本发明还提供了一种包含上述核酸、上述表达载体、上述包含内体逃逸肽的载体或上述融合蛋白的细胞。本发明还提供了一种基因编辑的方法,其包含采用本发明所述的内体逃逸肽或载体递送基因编辑所需的序列特异性核酸酶。
具体的,
本发明的第一方面,提供了一种内体逃逸肽(Endosome escapepeptide,EEP),所述的内体逃逸肽包含组氨酸H、谷氨酸E和CPP。
其中,CPP为细胞穿膜肽。
优选的,所述的内体逃逸肽包含n个HE,其中n选自1至20中的自然数。优选的,所述的n选自8至15中的自然数。进一步优选的,所述的n为11。
在本发明的一个具体实施方式中,所述的n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
优选的,所述的CPP为阳离子型细胞穿膜肽。进一步优选为低分子量鱼精蛋白(LMWP)、人类免疫缺陷病毒HIV的转录反式激活因子(TAT)、Penetratin穿透肽、单纯性疱疹病毒的结构蛋白(VP22)、人体降钙素(hCT(9-32))、黄蜂毒素加兰肽(Transportan)、SynB抗菌肽、血管内皮细胞钙粘连蛋白(Pvec)、MAP(Model Amphipathic Peptides)寡聚精氨酸(R12)、莱科毒素(M-lycotoxin)、鱼类抗菌肽(Chrysophsin)、蝉新型抗菌肽(Cryptonin)、细胞穿透肽1(Pep-1)、HIV-1/gp41组合肽(MPG)、转孔蛋白10(F(SG)4TP10)、细胞穿透肽2(F(SG)4Pen2)或核定位信号序列(NLSs)等。
其中,具体序列如下:
优选的,所述的EEP为质子浓度响应型的短肽,利用组氨酸和谷氨酸屏蔽CPP中正电性强的精氨酸和赖氨酸,在中性pH条件下呈电中性,结构无序且没有功能,但是在内吞过程中的酸性条件下大量吸收质子,呈强正电性,具有膜活性,可破坏内涵体/溶酶体膜导致内涵体/溶酶体内部的蛋白药物的释放。
在本发明的一个具体实施方式中,所述的CPP为低分子量鱼精蛋白,其氨基酸序列包含与SEQ ID NO:1具有80%以上的同源性或者包含SEQ ID NO:1。
优选的,所述的内体逃逸肽还包含酶切位点,所述的酶切位点连接(HE)n与CPP。所述的n选自1至20中的自然数。所述的酶切位点优选为组织蛋白酶B(Cathepsin B)识别位点。
在本发明的一个具体实施方式中,所述的组织蛋白酶B识别位点包含VGFA的氨基酸序列。
采用组织蛋白酶B识别位点链接(HE)n与CPP结构,可以使得内体逃逸肽在进入内涵体或溶酶体的早期即实现逃逸。
优选的,所述的内体逃逸肽包含(HE)n-酶切位点-CPP,其中,n选自1至20中的自然数。进一步优选的,所述的内体逃逸肽包含(HE)11-VGFA-低分子量鱼精蛋白或低分子量鱼精蛋白-VGFA-(HE)11。更进一步优选的,所述的内体逃逸肽包含与SEQ ID NO:2或3具有80%以上的同源性或者包含SEQ ID NO:2或3。
其中,V为缬氨酸,G为甘氨酸,F为苯丙氨酸,A为丙氨酸。
SEQ ID NO:2的具体序列为HEHEHEHEHEHEHEHEHEHEHEVGFAGSVSRRRRRRGGRRRR。
SEQ ID NO:3的具体序列为GSVSRRRRRRGGRRRRVGFAHEHEHEHEHEHEHEHEHEHEHE。
本发明的第二方面,提供了一种CPP的改造的方法,在CPP的氨基酸序列中引入组氨酸H和/或谷氨酸E,使得改造后的CPP具有从内体中逃逸的功能。
优选的,所述的CPP选自低分子量鱼精蛋白、人类免疫缺陷病毒HIV的转录反式激活因子、Penetratin穿透肽、单纯性疱疹病毒的结构蛋白、人体降钙素、黄蜂毒素加兰肽、SynB抗菌肽、血管内皮细胞钙粘连蛋白、MAP寡聚精氨酸、莱科毒素、鱼类抗菌肽、蝉新型抗菌肽、细胞穿透肽1、HIV-1/gp41组合肽、转孔蛋白10、细胞穿透肽2或核定位信号序列。
优选的,在CPP中引入(HE)n结构,使得改造后的CPP呈电中性。其中,n选自1到20之间的自然数。
本发明的第三方面,提供了一种内体逃逸肽的构建的方法,在CPP的氨基酸序列中引入组氨酸H和/或谷氨酸E,使得改造后的CPP具有从内体中逃逸的功能。
优选的,所述的CPP选自低分子量鱼精蛋白、人类免疫缺陷病毒HIV的转录反式激活因子、Penetratin穿透肽、单纯性疱疹病毒的结构蛋白、人体降钙素、黄蜂毒素加兰肽、SynB抗菌肽、血管内皮细胞钙粘连蛋白、MAP寡聚精氨酸、莱科毒素、鱼类抗菌肽、蝉新型抗菌肽、细胞穿透肽1、HIV-1/gp41组合肽、转孔蛋白10、细胞穿透肽2或核定位信号序列。
优选的,在CPP中引入(HE)n结构,使得改造后的CPP呈电中性。其中,n选自1到20之间的自然数。
本发明的第四方面,提供了一种载体,所述的载体包含本发明所述的内体逃逸肽和靶向细胞的分子。
优选的,所述的载体的结构为靶向细胞的分子-(HE)n-酶切位点-CPP。
优选的,所述的靶向细胞的分子可以为抗体、生长因子、激素或细胞因子。其中,所述的生长因子选自转化生长因子、表皮生长因子、胰岛素样生长因子、成纤维细胞生长因子、调蛋白、血小板衍生生长因子、血管内皮生长因子或缺氧诱导因子中的一种或两种以上的组合。所述的激素选自人绒毛膜促进性腺素、促性腺素释放激素、雄激素、雌激素、促甲状腺激素、促卵泡激素、黄体生成素、促乳素、生长激素、促肾上腺皮质激素、抗利尿激素、催产素、促甲状腺激素释放激素、生长激素释放激素、促肾上腺皮质激素释放激素、促生长素抑制素、褪黑激素、甲状腺素、降钙素、甲状旁腺激素、糖皮质激素类、电解质代谢皮质激素、肾上腺素、去甲肾上腺素、孕酮、胰岛素、胰高血糖素、促红细胞生成素、胃泌素、促胰液素、胆囊收缩素、瘦激素或血小板生成素中的一种或两种以上的组合。所述的细胞因子选自IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、粒细胞-集落刺激因子、巨噬细胞-集落刺激因子、粒细胞-巨噬细胞集落刺激因子、白血病抑制因子、红细胞生成素、LT-β、CD40配体、CD27配体、IFN-γ、IFN-α、IFN-β、Fas配体、CD30配体、4-1BBL、TGF-β、IL1α、IL1β、MIF或IGIF中的一种或两种以上的组合。所述的抗体选自全长抗体、嵌合抗体、Fab、Fab’、F(ab’)2、单结构域抗体(DAB)、Fv、scFv、双抗体、三抗体中的一种或两种以上的组合。
在本发明的一个具体实施方式中,所述的靶向细胞的分子为抗体。优选的,所述的抗体选自Her2的抗体、PD-1的抗体、PD-L1的抗体、CXCR4的抗体、CD19的抗体、CD20的抗体、CD22的抗体、CD30的抗体、PSMA的抗体、PGGFR的抗体或VEGFR的抗体中的一种或两种以上的组合。
在本发明的一个具体实施方式中,所述的载体的氨基酸序列如SEQ ID NO:24所示。
优选的,所述靶向的细胞满足以下条件即可:
(a)抗原在靶细胞上大量且唯一地表达;(b)抗原脱落较少,由于分泌的受体可以结合循环中的抗体,因此限制了在靶细胞的暴露数量;(c)可以高效的介导内吞,根据前人的研究,转铁蛋白受体(TfR)、人表皮生长因子受体2(Her2)和CD30等可以被用作靶受体。
优选的,靶向的细胞选自过表达Her2、PD-1、PD-L1、CXCR4、CD19、CD20、CD22、CD30、PSMA、PGGFR或VEGFR的细胞。
在本发明的一个具体实施方式中,所述的载体的结构为抗体-(HE)n-酶切位点-CPP。
本发明的第五方面,提供了一种编码本发明所述的内体逃逸肽或载体的核酸。
本发明的第六方面,提供了一种本发明所述的内体逃逸肽、所述的载体或所述的核酸的用途,所述的用途包括携带功能性分子透过细胞膜或体组织屏障,或者用于与功能性分子连接制备能够透过细胞膜或体组织屏障的复合物。
优选的,所述的功能性分子选自序列特异性核酸酶或药物蛋白。
优选的,所述的序列特异性核酸酶选自Cas9、miniCas9、Cpf1或Cre。
优选的,所述的药物蛋白选自MyoD(成肌分化蛋白)、CEBPα(增强子结合蛋白)、BID(B细胞淋巴瘤2同源相互作用结构域死亡激动剂)、tBID(截断的B细胞淋巴瘤2同源相互作用结构域死亡激动剂)、Caspase3(半胱天冬酶3)、Cleavaged Caspase3(激活型半胱天冬酶3)、Caspase8(半胱天冬酶8)、PAPR1(多聚腺苷二磷酸核糖聚合酶1)、CleavagedPAPR1、Bax(剪切的多聚腺苷二磷酸核糖聚合酶1)、P53(人体抑癌基因53)、GSDMA(消皮素A)、GSDMB(消皮素B)、GSDMC(消皮素C)、GSDMD(消皮素D)、GSDME(消皮素E)、Granzyme A(颗粒酶A)或Granzyme B(颗粒酶B)中的一种或两种以上的组合。
优选的,所述的功能性分子还可以是显影剂、脂质体、纳米制剂、荧光示踪剂或病毒载体等。
优选的,所述的功能性分子可以是功能性核酸片段、具有分子包装载物功能的制剂或病毒载体。
进一步优选的,所述的功能性核酸片段包括但不限于质粒、DNA、miRNA、反义核酸、寡核苷酸或siRNA。
进一步优选的,所述的具有分子包装载物功能的制剂包括但不限于脂质体、多聚体、树突状分子或纳米包装制剂。
进一步优选的,所述的病毒载体可以为逆转录病毒载体、慢病毒载体或腺病毒载体。
优选的,所述的体组织屏障是眼屏障。
在本发明的一个具体实施方式中,所述的眼屏障可以是眼组织屏障、泪液屏障或血眼屏障。
优选的,所述的内体逃逸肽或载体与功能性分子的连接可以是共价连接或非共价连接。只要能够保留内体逃逸肽或载体穿模的功能以及保证功能性分子的功能,任何连接方式均可以。其中,共价连接例如以共价键的形式将两个分子进行连接。非共价连接例如偶联、吸附或结合等。
本发明的第七方面,提供了一种融合蛋白,所述的融合蛋白包含本发明所述的内体逃逸肽或所述的载体。
优选的,所述的融合蛋白包含序列特异性核酸酶。进一步优选的,所述的序列特异性核酸酶选自Cas9、miniCas9、Cpf1或Cre。
在本发明的一个具体实施方式中,所述的序列特异性核酸酶的氨基酸序列如SEQID NO:26所示。
优选的,所述的产品包含凋亡诱导分子或细胞毒剂。其中,所述的凋亡诱导分子选自粒酶(例如粒酶A、粒酶B、粒酶C、粒酶D、粒酶E、粒酶F、粒酶G、粒酶H、粒酶I、粒酶J、粒酶K、粒酶L、粒酶M或粒酶N)、Bc1-2家族成员(例如Bax、Bak、Bc1-Xs、Bad、BID、Bik、Hrk或Bok)、细胞色素C或胱冬梅(例如胱冬梅-1、胱冬梅-2、胱冬梅-3、胱冬梅-4、胱冬梅-5、胱冬梅-6、胱冬梅-7、胱冬梅-8、胱冬梅-9、胱冬梅-10、胱冬梅-11、胱冬梅-12、胱冬梅-13或胱冬梅-14)。所述的细胞毒剂选自TNF-α、白树毒素、灵菌红素、核糖体抑制蛋白(RIP)、假单胞菌外毒素、艰难梭菌毒素B、幽门螺杆菌VacA、小肠结肠炎耶尔森菌YopT、紫色杆菌素、二亚乙基三胺五乙酸、伊罗夫文、白喉毒素、丝林霉素、蓖麻毒蛋白、肉毒杆菌毒素、霍乱毒素或皂草毒蛋白6。
其中,Bc1-2家族通过控制线粒体膜的通透性来调控凋亡。促进凋亡的Bc1-2家族成员Bad,tBID,Bax和Bim定位在细胞质中,在接受到上级的凋亡信号后转移到线粒体膜上,膜通透性增加,细胞色素C被大量释放,激活下游的信号Caspase-9和Caspase-3。细胞凋亡是一种受到调节的程序性死亡机制,表现为细胞核的浓缩、起皱、膜发泡以及DNA的片段化。凋亡途径涉及多个信号因子,激活和抑制相互拮抗,共同调控细胞的命运。
优选的,所述的融合蛋白包含药物蛋白,优选的,所述的药物蛋白选自MyoD(成肌分化蛋白)、CEBP α(增强子结合蛋白)、BID(B细胞淋巴瘤2同源相互作用结构域死亡激动剂)、tBID(截断的B细胞淋巴瘤2同源相互作用结构域死亡激动剂)、Caspase3(半胱天冬酶3)、Cleavaged Caspase3(激活型半胱天冬酶3)、Caspase8(半胱天冬酶8)、PAPR1(多聚腺苷二磷酸核糖聚合酶1)、CleavagedPAPR1、Bax(剪切的多聚腺苷二磷酸核糖聚合酶1)、P53(人体抑癌基因53)、GSDMA(消皮素A)、GSDMB(消皮素B)、GSDMC(消皮素C)、GSDMD(消皮素D)、GSDME(消皮素E)、Granzyme A(颗粒酶A)或Granzyme B(颗粒酶B)中的一种或两种以上的组合。
在本发明的一个具体实施方式中,所述的药物蛋白为BID、Caspase3、Caspase8或Bax。
在本发明的一个具体实施方式中,所述的药物蛋白的氨基酸序列如SEQ ID NO:25所示。
其中,Caspase3是一个有效的促凋亡蛋白,属于Caspase家族。Caspase-3是细胞凋亡过程中最主要的终末剪切酶,也是CTL细胞杀伤机制的重要组成部分。这类天冬氨酸蛋白水解酶家族,通过自身的半胱氨酸活性位点,识别底物蛋白上的特定天冬氨酸残基,进行亲核进攻,进而启动靶蛋白的水解程序。Caspase-3最主要的底物是多聚(ADP-核糖)聚合酶(poly(ADP-ribose)polymerase,PARP),该酶与DNA自检查和修复有关。在细胞凋亡启动时,116kD的PARP在Asp216-Gly217之间被Caspase-3剪切成31kD和85kD的两个片段,使PARP中与DNA结合的两个锌指结构与羧基端的催化区域分离,不能发挥正常功能。结果使受PARP负调控影响的Ca2+/Mg2+依赖性核酸内切酶的活性增高,裂解核小体间的DNA,触发细胞凋亡途径。Pro-caspase-3含有277个氨基酸残基,分子量约32kD。Pro-caspase-3在活化过程中从Asp28~Ser29和Asp175~Ser176两处被剪切,形成P17(29~175)和P10(182~277)两个片段,两种亚基再组成活性形式的Caspase-3。
在本发明的一个具体实施方式中,所述的融合蛋白包含下列各组中任一项:
A)靶向细胞的分子和内体逃逸肽;
B)靶向细胞的分子、内体逃逸肽和药物蛋白;
C)靶向细胞的分子、内体逃逸肽和序列特异性核酸酶;
D)内体逃逸肽和药物蛋白;或,
E)内体逃逸肽和序列特异性核酸酶。
在本发明的一个具体实施方式中,所述的融合蛋白包含下列各组中任一项:
a)抗体和内体逃逸肽;
b)抗体、内体逃逸肽和药物蛋白;
c)抗体、内体逃逸肽和序列特异性核酸酶;
d)内体逃逸肽和药物蛋白;或,
e)内体逃逸肽和序列特异性核酸酶。
优选的,所述的抗体选自Her2的抗体、PD-1的抗体、PD-L1的抗体、CXCR4的抗体、CD19的抗体、CD20的抗体、CD22的抗体、CD30的抗体、PSMA的抗体、PGGFR的抗体或VEGFR的抗体中的一种或两种以上的组合。
优选的,所述的内体逃逸肽与药物蛋白之间、内体逃逸肽与序列特异性核酸酶、或者内体逃逸肽与靶向细胞的分子之间的连接可以是共价连接或非共价连接。只要能够保留内体逃逸肽穿模的功能、靶向细胞的分子以及保证药物蛋白或序列特异性核酸酶的功能,任何连接方式均可以。其中,共价连接例如以共价键的形式将两个分子进行连接。非共价连接例如偶联、吸附或结合等。
当融合抗体经过内吞进入内涵体以后,避免抗体被内涵体和溶酶体中富集的多种水解酶降解,而且考虑到携带抗体逃逸更加臃肿,系统可能会经由Fc片段的循环回到膜上,故在进入内涵体或溶酶体的早期即去除内体逃逸肽与Herceptin的连接,更有效的逃逸至细胞质。
在本发明的一个具体实施方式中,所述的融合蛋白为Herceptin-(HE)11-VGFA-LMWP-BID,其氨基酸序列如SEQ ID NO:4。
在本发明的一个具体实施方式中,所述的融合蛋白为Herceptin-(HE)11-VGFA-LMWP-Cre,其氨基酸序列如SEQ ID NO:6。
本发明的第八方面,提供了一种编码本发明所述的融合蛋白的核酸。
优选的,所述的融合蛋白为Herceptin-(HE)11-VGFA-LMWP-BID,其核苷酸序列如SEQ ID NO:5。
优选的,所述的融合蛋白为Herceptin-(HE)11-VGFA-LMWP-Cre,其核苷酸序列如SEQ ID NO:7。
本发明的第九方面,提供了一种表达载体,所述的表达载体包含编码本发明所述的内体逃逸肽的核酸、编码本发明所述的载体的核酸或编码本发明所述融合蛋白的核酸。
本发明的第十方面,提供了一种包含本发明所述的内体逃逸肽、所述的载体、所述的核酸、所述的融合蛋白或所述的核酸的细胞。
优选的,所述的细胞可以为原核细胞(如细菌细胞)、低等真核细胞(如酵母细胞)、高等真核细胞(植物细胞)等等,优选为大肠杆菌、链霉菌属、农杆菌、酵母或植物细胞等等。
本发明的第十一方面,提供了一种包含本发明所述的内体逃逸肽、所述的载体、所述的核酸、所述的融合蛋白、所述的核酸或所述的细胞在基因编辑或者在制备治疗疾病的药物中的应用。
优选的,所述的疾病选自乳腺癌、白血病、胃癌、肺癌、肝癌、直肠癌、前列腺癌、转移性黑色素瘤、非小细胞肺癌、肾细胞癌、膀胱癌、尿路上皮癌或杜氏肌营养不良。
本发明的第十二方面,提供了一种基因编辑的方法,所述的方法包括采用本发明所述的内体逃逸肽或所述的载体向待编辑细胞递送序列特异性核酸酶。
优选的,所述的序列特异性核酸酶选自Cas9、miniCas9、Cpf1或Cre。
本发明的第十三方面,提供了一种治疗疾病的方法,所述的方法包括采用本发明所述的内体逃逸肽或载体向个体递送药物蛋白。
优选的,所述的药物蛋白选自MyoD、CEBPα、BID、tBID、Caspase3、CleavagedCaspase3、Caspase8、PAPR1、CleavagedPAPR1、Bax、P53、GSDMA、GSDMB、GSDMC、GSDMD、GSDME、Granzyme A或Granzyme B中的一种或两种以上的组合。
优选的,所述的疾病选自乳腺癌、白血病、胃癌、肺癌、肝癌、直肠癌、前列腺癌、转移性黑色素瘤、非小细胞肺癌、肾细胞癌、膀胱癌、尿路上皮癌或杜氏肌营养不良。
优选的,所述的疾病为肿瘤。
在本发明的一个具体实施方式中,所述的疾病为乳腺癌。
优选的,所述的治疗疾病的方法还包含其他协同治疗手段,优选为化疗、手术、放疗、基因治疗、激素治疗、免疫治疗中的一种或两种以上的组合。
本发明的第十四方面,提供了一种试剂盒,所述的试剂盒包含本发明所述的内体逃逸肽、载体、融合蛋白、核酸、包含核酸的表达载体、细胞或组织等等。
本发明所述的“内体”是膜包裹的囊泡结构,有初级内体(early endosome)和次级内体(late endosome)之分,初级内体通常位于细胞质的外侧,次级内体常位于细胞质的内侧,靠近细胞核。优选为内涵体或溶酶体。
本发明所述的“逃逸”为内体中的物质从内体中出来。优选的,可以是破坏内体结构后从内体中释放。
本发明所述的“治疗”表示在疾病已开始发展后减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性,但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除。
本发明所述的“功能性分子”是指对于体内病症具有识别或诊断、预防或治疗功效的物质,或者可用于携带对于体内病症具有识别或诊断、预防或治疗的物质的载体物质,或者基因编辑所需的核酸特异性核酸酶。
本发明所述的“表达载体”可以为现有技术中任何可以携带核酸并在宿主体内稳定复制和表达的载体。其包含复制起点、启动子、标记基因和翻译控制元件。优选可以为细菌质粒、噬菌体、酵母质粒、植物细胞病毒、哺乳动物病毒等等。
本发明所述的“宿主细胞”可以为原核细胞(如细菌细胞)、低等真核细胞(如酵母细胞)、高等真核细胞(植物细胞)等等,优选为大肠杆菌、链霉菌属、农杆菌、酵母或植物细胞等等。
本发明所述的“包含”在本申请中用于描述蛋白质或核酸的序列时,所述蛋白质或核酸可以是由所述序列组成,或者在所述蛋白质或核酸的一端或两端可以具有额外的氨基酸或核苷酸,但仍然具有本发明所述的活性。
本发明所述“同源性”,是指在使用蛋白序列或核苷酸序列的方面,本领域技术人员可以根据实际工作需要对序列进行调整,使使用序列与现有技术获得的序列相比,具有(包括但不限于)1%,2%,3%,4%,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%,36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%,50%,51%,52%,53%,54%,55%,56%,57%,58%,59%,60%,70%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%,99.1%,99.2%,99.3%,99.4%,99.5%,99.6%,99.7%,99.8%,99.9%的同源性。
本申请提供的基于“抗体介导内吞-溶酶体逃逸”的特异性大分子药物胞内递送体系,其药物递送过程如下:
第一步,经过体内循环,通过抗体在特异性表达其对应受体的组织和细胞上吸附结合;第二步,经由受体介导的内吞途径进入到细胞内部;第三步,EEP在逐渐酸化的内涵体中吸收质子,获得极大的正电性或者具有α-螺旋的结构;第四步,内涵体去稳定化,切除抗体及HE结构,并具有膜扰动能力的EEP携带药物逃逸出内涵体和溶酶体,将药物递送至细胞质内。其中,本申请提供的内体逃逸肽仅在内体(例如内涵体或溶酶体)的酸性环境下有效的pH敏感性EEP。在中性环境下,无序也无功能。
该胞内递送体系通过抗体靶向特定细胞实现组织特异性,其只靶向受体特异性高表达的细胞,故避免了药物对正常细胞的毒性,必然会提高药物的有效作用浓度。而且也极大的延长了药物的半衰期,在体内可以存留几个月之久。同时为防止抗体在内吞过程中的降解,以及药物蛋白在溶酶体中的滞留,采用本申请所述的内体逃逸肽与抗体共同携带药物蛋白或者序列特异性核酸酶,使得被递送物质顺利作用到细胞质或者其他亚细胞器定位的靶点。利用抗体的特异性靶向和EEP的内涵体去稳定化的组合使得整个药物递送系统更加安全,建立了一个具有组织特异性的细胞内高效药物递送策略。
附图说明
以下,结合附图来详细说明本发明的实施例,其中:
图1:从血液循环和细胞基质到内吞途径中内体逃逸肽的构象变化。皮下注射后,在血液循环和细胞基质中的EEP,被负电荷序列HE屏蔽掉了本身的正电荷,此时整个系统成电中性。而经过内吞途径进入到内涵体以后,在早期的弱酸性环境中,组氨酸和谷氨酸大量吸收质子,与EEP的电荷作用减弱;同时在早期内涵体中大量富集的组织蛋白酶B会识别两个短肽间的酶切位点,促进二者的分离,使得EEP尽快恢复正电性,重新具有穿膜活性。
图2:采用内体逃逸肽或载体进行细胞内蛋白递送在基因编辑领域应用的结果。其中,图2a显示了携带Cargo(Cre)的EEP在内涵体或溶酶体中被酶切割,Cre与HE、抗体分离,从内涵体或溶酶体中逃逸,进入细胞核,识别loxp位点后发生基因重组,原本表达红色荧光蛋白的细胞就会表达绿色荧光蛋白,T-EEP-Cre即为Herceptin-(HE)11-VGFA-LMWP-Cre;图2b显示了eGFP(增强型绿色荧光蛋白)、DsRed(红色荧光蛋白)、Merge(左图既有红色荧光也有绿色荧光,右图只有红色荧光出现)、BF为对照组,各组在468或SK-Br3细胞系中的编辑情况,其中左图为Herceptin-(HE)11-VGFA-LMWP-Cre,右图为Herceptin-Cre作为对照。
图3:采用内体逃逸肽或载体进行细胞内药物蛋白的递送在肿瘤治疗领域的应用的结果。其中,图3a显示了融合蛋白BID处理乳腺癌(MDA-MB-435、NC-N87和468)细胞24h后肿瘤细胞的凋亡情况,T-EEP-BID为按照实施例3的方法制备的融合蛋白BID,T-EEP、T-BID作为对照,分别为抗体与内体逃逸肽的融合、抗体直接携带BID。图3b显示了Annexin V-FITC/PI双染细胞凋亡检测试剂盒检测结果。图3c显示了采用不同浓度药物处理更多的细胞系,分别为MDA-MB-435、NC-N87、BT474、SK-Br3及468,随着浓度的逐渐增大检测肿瘤细胞的存活率。图3d显示了采用WB检测细胞凋亡通路中几个关键蛋白的表达变化。
图4:在小鼠乳腺癌模型中评估融合蛋白BID在肿瘤治疗的效果。其中,各组分别为注射融合蛋白BID(T-EEP-BID)、抗体携带BID组(T-BID)、抗体与内体逃逸肽组(T-EEP)及注射等体积PBS组作为对照。图4a显示了小鼠尾静脉注射融合蛋白BID后,肿瘤组织的观察结果。图4b显示注射融合蛋白BID后随着时间的变化肿瘤体积的变化结果。图4c显示注射融合蛋白BID后随着时间的变化肿瘤质量的变化结果。图4d显示肿瘤组织的石蜡切片染色实验,获得TUNEL图像观察融合蛋白BID对肿瘤细胞的杀伤作用。图4e显示HE染色观察融合蛋白BID对肿瘤细胞的杀伤作用。图4f显示注射融合蛋白BID后随着时间的变化小鼠体重的变化结果。图4g显示分别评估血清各项指标,确定融合蛋白BID对小鼠心脏、肝脏和肾脏的影响。图4h显示HE染色观察融合蛋白BID的处理组和对照组对小鼠心脏、肝脏、脾、肺、肾的影响,其中T-HE-BID为T-EEP-BID,PBS为对照组。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:内体逃逸肽
内体逃逸肽由(HE)n、酶切位点和CPP组成,该内体逃逸肽是在中性条件下没有膜活性,但是酸性条件下重新具有膜扰动能力可以在膜上打孔的环境影响型EEP。本实施例以低分子量鱼精蛋白(LMWP)为CPP,以Cathepsin B的识别位点为酶切位点,进行阐述内体逃逸肽的制备。
首先,确定HE的个数。HE用于屏蔽CPP的正电性,使得在正常环境下,内体逃逸肽呈现电中性,减少其在细胞基质中的粘连,经计算确定,HE的个数(11个)与电荷抵消数的关系如表1所示。当然,本领域技术人员应当知晓,如果CPP换成低分子量鱼精蛋白以外的其他类型,需要重新确定HE的个数。
表1引入11个HE后随着pH值的不同EEP电荷的变化情况
其中,Δ为本实施例中pH的最大差值对应的电荷差值。
本实施例以HE个数为11为例制备内体逃逸肽,即内体逃逸肽的氨基酸序列如SEQID NO:2或3所示。通过PCR制备出内体逃逸肽的核酸序列,克隆在表达载体pFuse上。然后转染至细胞中表达、纯化,获得内体逃逸肽。
本实施例制备的内体逃逸肽结构及从血液循环和细胞基质到内吞途径中内体逃逸肽的构象变化参见图1。
实施例2:载体
载体包含靶向细胞的分子和内体逃逸肽。本实施例以抗体作为靶向细胞的分子,进行阐述载体的制备。具体的,抗体为Herceptin,内体逃逸肽为SEQ ID NO:2。步骤如下:
(1)克隆载体的构建
Herceptin-(HE)n-VGFA-LMWP克隆载体包含Herceptin、(HE)n、VGFA和LMWP四个元件,在每个元件的基因两端设计同源重组序列,其中(HE)n重复序列与LMWP的序列设计在同一个基因片段上。将上述基因片段均交由金斯瑞公司合成,通过同源重组的方法克隆一步克隆在表达载体pFuse上。
(2)表达纯化
将质粒用293fectin瞬时转染到专用于分泌表达哺乳动物蛋白的293F细胞系中,第2天和第4天将细胞离心,收取上清。纯化获得载体。
实施例3:融合蛋白
融合蛋白包含靶向细胞的分子、内体逃逸肽以及药物蛋白或序列特异性核酸酶。本实施例分别以包含药物蛋白(例如BID、Bax或Caspase-3)或者序列特异性核酸酶(例如Cre)为例,制备融合蛋白。
(1)克隆载体的构建
抗体-内体逃逸肽-药物蛋白或者抗体-内体逃逸肽-序列特异性核酸酶的克隆载体,在每个元件的基因两端设计同源重组序列,其中(HE)n重复序列与待选CPP的序列设计在同一个基因片段上。将上述基因片段均交由金斯瑞公司合成,通过同源重组的方法克隆一步克隆在表达载体pFuse上。
(2)融合蛋白的表达纯化。
将质粒用293fectin瞬时转染到专用于分泌表达哺乳动物蛋白的293F细胞系中,第2天和第4天将细胞离心,收取上清。通过protein G结合,利用pH=2.8的甘氨酸(100mM)洗脱,得到纯化后的融合蛋白(结构分别为Herceptin-(HE)11-VGFA-LMWP-Cre、Herceptin-(HE)11-VGFA-LMWP-BID、Herceptin-(HE)11-VGFA-LMWP-tBID、Herceptin-(HE)11-VGFA-LMWP-Bax和Herceptin-(HE)11-VGFA-LMWP-Caspase-3),加甘油冻存于-80。
后续实施例以乳腺癌高表达HER2的细胞系为模型,验证本申请提供的内体逃逸肽、载体或融合蛋白的功能。利用Herceptin介导的特异性定位,通过Her2内吞途径携带目的蛋白进入细胞内的内涵体和溶酶体,二者中富集的Cathepsin B将Herceptin和EEP-Cargo分离开来。从内涵体到溶酶体,载药系统所处的环境中氢离子浓度逐渐升高,H+响应型的EEP吸收质子,从电荷中性变成强正电性,重新具有穿膜逃逸的特性,携带药物蛋白Cargo到胞质中,根据靶点进行下一步亚细胞定位。
实施例4:基因编辑领域的应用
1、实验步骤
(1)构建在基因组上稳定插入loxp-RFP-loxp-GFP序列的乳腺癌细胞系SK-Br3、BT474、468,以测试内体逃逸肽或载体的递送系统的能力。其中,SK-Br3、BT474为高表达HER2的乳腺癌细胞系,468为无HER2表达细胞系。具体步骤如下:
配置含有不同浓度的嘌呤霉素(Puromycin)培养基,每两天换一次液,一周后利用0.1%的阿尔玛蓝(Alarma Blue)检测细胞活性,得到不同细胞在嘌呤霉素筛选压力下的致死曲线。利用将所有细胞杀死的最低浓度抗生素作为稳转细胞系的筛选压力。将包含loxp-RFP-loxp-GFP序列的质粒包装在慢病毒载体中,待病毒成熟后,用其感染SK-Br3、BT474、468三个细胞系。然后在其对应的筛选压力下,进行为期一周的筛选,得到在基因组上稳定插入loxp-RFP-loxp-GFP的稳转细胞系。
(2)本实施例所用融合蛋白抗体-内体逃逸肽-Cre
抗体为Herceptin,内体逃逸肽如SEQ ID NO:2所示,抗体-内体逃逸肽-Cre(即实施例3制备获得的Herceptin-(HE)11-VGFA-LMWP-Cre)的氨基酸序列如SEQ ID NO:6所示,其核酸序列如SEQ ID NO:7所示。
(3)通过动态细胞观测仪(incucyte)观察loxp-RFP-loxp-GFP稳转细胞系的GFP表达情况。
在96孔板上铺稳定表达loxp-RFP-loxp-GFP的Her2高表达细胞系SK-br3和Her2无表达细胞系468,待细胞聚合度达到80%时加入纯化好的融合蛋白,37℃孵育4小时后,继续培养24小时,在长时间动态细胞观测仪incucyte中拍摄,观察loxp-RFP-loxp-GFP稳转细胞系的GFP表达情况。
2、实验结果
如果Cre重组酶已经进入细胞核,识别loxp位点,就会发生基因重组,原本表达红色荧光蛋白的细胞就会表达绿色荧光蛋白(参见图2a)。Herceptin的可变区识别Her2受体,融合蛋白通过内吞进入内涵体和溶酶体当中。随着内吞的进行,内涵体成熟过程中H离子增多,在逐渐酸化的过程中,HE和LMWP之间被酶切位点被识别切割,二者分离,LMWP恢复膜活性,携带Cre逃逸到细胞质中,经由NLS核定位信号,将Cre进一步定位到细胞核中,识别loxP位点,切割中间的RFP序列,红色荧光不再表达,GFP表达。
SK-Br3是Her2高表达的细胞系,当用Herceptin-(HE)11-VGFA-LMWP-Cre处理36小时后,很多细胞由红色变为绿色,但是没有Her2受体的468细胞,因为不能被Herceptin-(HE)11-VGFA-LMWP-Cre识别,依然只表达红色荧光。Herceptin和Cre共孵育的细胞也只表达红色荧光,因为内吞进去的Cre蛋白滞留在内涵体中无法逃逸。Herceptin-(HE)11-VGFA-LMWP-Cre的药物处理浓度影响发生重组的细胞数目,100nM的药物可以使得30%的细胞发生loxP位点的重组(参见图2b)。
实施例5:肿瘤治疗领域的应用
本实施例以BID/Bax/Caspase-3作为杀伤肿瘤细胞的大分子药物,采用实施例1制备的内体逃逸肽或者实施例2制备的载体递送至肿瘤细胞内部,通过分析肿瘤细胞凋亡的速度和比例,在体外水平表征递药系统(内体逃逸肽或载体)的作用,并且在皮下注射融合蛋白到乳腺癌小鼠中,通过测量小鼠的生存时间与肿瘤大小,测试药物在小鼠体内的特异性递送效果,进一步评价在肿瘤治疗领域的应用前景。
本实施例所用融合蛋白为实施例3制备的Herceptin-(HE)11-VGFA-LMWP-BID(简称融合蛋白BID),其氨基酸序列如SEQ ID NO:4所示,核苷酸序列如SEQ ID NO:5所示。
1、体外检测
1)在96孔板上铺Her2高表达细胞系MDA-MB-435、NC-N87,和Her2无表达细胞系468,待细胞聚合度达到80%时加入纯化好的融合蛋白,37℃孵育4小时后,继续培养24小时,在长时间动态细胞观测仪incucyte中拍摄,利用Annexin V-FITC/PI双染细胞凋亡检测试剂盒检测凋亡情况。
BID是凋亡通路中的一个关键蛋白,会被caspase8切割为tBID,增加线粒体的通透性,导致细胞色素C的释放,激活caspase3切割DNA,最终诱导细胞凋亡。如果把BID蛋白递送到细胞质内,就有可能激活凋亡通路。本实施例选择Her2过表达的乳腺癌细胞系MDA-MB-435、NC-N87,用100nM融合蛋白BID处理细胞4天,从图3a、b中可以看出,细胞会发生明显的凋亡。但是Herceptin-HE-LMWP(T-EEP)和Herceptin-BID(T-BID)并不会导致细胞的凋亡。同样的结果在Her2高表达的细胞系NC-N87上也可以观察到,但是没有Her2受体的乳腺癌细胞系468生长良好。
2)采用不同浓度药物处理更多的细胞系,分别为MDA-MB-435、NC-N87、BT474、SK-Br3及468,随着浓度的逐渐增大检测肿瘤细胞的存活率。同时,采用WB检测细胞凋亡通路中几个关键蛋白的表达变化。
从图3c可以看出,融合蛋白BID在100nM的浓度都可以对有Her2表达的细胞进行有效的杀伤,其中对BT474和MDA-MB-435效果最为明显。药物的IC50在10nM左右,提高药物浓度至100nM以上,并不能诱导更多的细胞发生凋亡,可能是因为Her2在细胞外的饱和结合浓度是50-100nM。
从图3d可以看出,通过WB检测细胞凋亡通路中几个关键蛋白的表达变化,最下游的PARP1和Caspase3已经被切割活化,BID被切割为tBID,融合表达在抗体重链C端的大部分LMWP-BID被切割,即BID的大量增多激活了凋亡通路。
2、体内检测
将SK-Bt3、BT474、468细胞注射至小鼠体内,构建乳腺癌小鼠模型;将实施例3制备的融合蛋白BID、融合蛋白Bax和融合蛋白Caspase3分别静脉注射至小鼠体内,每两天对小鼠进行称重,并记录小鼠的存活时间,一个月后取出肿瘤进行体积测量,比较各个融合蛋白的体内作用效果。结果如图4所示。具体如下:
1)在接种肿瘤后的第6天,通过尾静脉注射融合蛋白BID,每周两次,第21天处死小鼠,剥离肿瘤组织,结果如图4a、b、c显示,接受实施例3制备的融合蛋白BID治疗的小鼠肿瘤体积明显小于其他组,而注射Herceptin-EEP和Herceptin-BID的小鼠肿瘤体积小于PBS对照组。主要是因为Herceptin对乳腺癌细胞的抑制作用。但是每个给药组之间,小鼠的体重没有明显的差异(参见图4f),说明在这21天中,药物没有对小鼠的生长造成明显的影响。
2)从肿瘤组织的石蜡切片染色来看,融合蛋白BID明显诱导肿瘤细胞凋亡,TUNEL的图像中有很多绿色荧光,HE染色的图像也可以看到明显的细胞间隙。而对照组的TUNEL并没有很多绿色荧光,HE染色的结果也是致密的细胞排列,说明融合蛋白BID是通过诱导肿瘤细胞凋亡来达到治疗肿瘤的目的(参见图4d、e)。
3)从图4g、h中我们可以看出,从表征几个器官的血清各项指标来看,融合蛋白BID的处理并没有给心脏,肝脏和肾脏带来损伤。HE染色也显示融合蛋白BID的处理组和对照组的小鼠各大器官都没有明显病理变化。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
序列表
<110> 清华大学
<120> 一种内体逃逸肽及其应用
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ttcctgtaca gcaagctgac cgtggacaag agccgctggc agcagggcaa cgtgttcagc 600
tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagagcct gagcctgagc 660
cccggcaagg gcggtagcca cgagcacgaa cacgagcacg agcacgaaca cgagcacgag 720
cacgaacacg aacacgaaca cgagggcggt agccgccgcg ttggtttcgc gggcggtagc 780
ggtagcgtta gccgtcgtcg tcgtcgtcgt ggcggtcgtc gtcgtcgtgg cagcggtggt 840
atgagcaatt tactgaccgt acaccaaaat ttgcctgcat tgccggtcga tgcaacgagt 900
gatgaggttc gcaagaacct gatggacatg ttcagggatc gccaggcgtt ttctgagcat 960
acctggaaaa tgcttctgtc cgtttgccgg tcgtgggcgg catggtgcaa gttgaataac 1020
cggaaatggt ttcccgcaga acctgaagat gttcgcgatt atcttctata tcttcaggcg 1080
cgcggtctgg cagtaaaaac tatccagcaa catttgggcc agctaaacat gcttcatcgt 1140
cggtccgggc tgccacgacc aagtgacagc aatgctgttt cactggttat gcggcgtatc 1200
cgaaaagaaa acgttgatgc cggtgaacgt gcaaaacagg ctctagcgtt cgaacgcact 1260
gatttcgacc aggttcgttc actcatggaa aatagcgatc gctgccagga tatacgtaat 1320
ctggcatttc tggggattgc ttataacacc ctgttacgta tagccgaaat tgccaggatc 1380
agggttaaag atatctcacg tactgacggt gggagaatgt taatccatat tggcagaacg 1440
aaaacgctgg ttagcaccgc aggtgtagag aaggcactta gcctgggggt aactaaactg 1500
gtcgagcgat ggatttccgt ctctggtgta gctgatgatc cgaataacta cctgttttgc 1560
cgggtcagaa aaaatggtgt tgccgcgcca tctgccacca gccagctatc aactcgcgcc 1620
ctggaaggga tttttgaagc aactcatcga ttgatttacg gcgctaagga tgactctggt 1680
cagagatacc tggcctggtc tggacacagt gcccgtgtcg gagccgcgcg agatatggcc 1740
cgcgctggag tttcaatacc ggagatcatg caagctggtg gctggaccaa tgtaaatatt 1800
gtcatgaact atatccgtaa cctggatagt gaaacagggg caatggtgcg cctgctggaa 1860
gatggcgacg gcggatcccc caagaagaag aggaaggtg 1899
<210> 8
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg
1 5 10
<210> 9
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Ile Trp Leu Thr Ala Leu Lys Phe Leu Gly Lys His Ala Ala Lys His
1 5 10 15
Leu Ala Lys Gln Gln Leu Ser Lys Leu
20 25
<210> 10
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Phe Ile Gly Leu Leu Ile Ser Ala Gly Lys Ala Ile His Asp Leu Ile
1 5 10 15
Arg Arg Arg His
20
<210> 11
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Gly Leu Leu Asn Gly Leu Ala Leu Arg Leu Gly Lys Arg Ala Leu Lys
1 5 10 15
Lys Ile Ile Lys Arg Leu Cys Arg
20
<210> 12
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg
1 5 10
<210> 13
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Lys Glu Thr Trp Trp Glu Thr Trp Trp Thr Glu Trp Ser Gln Pro Lys
1 5 10 15
Lys Lys Arg Lys Val
20
<210> 14
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Gly Ala Leu Phe Leu Gly Trp Leu Gly Ala Ala Gly Ser Thr Met Gly
1 5 10 15
Ala Pro Lys Lys Lys Arg Lys Val
20
<210> 15
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Phe Ser Gly Ser Gly Ser Gly Ser Gly Ala Gly Tyr Leu Leu Gly Arg
1 5 10 15
Ile Asn Leu Arg Ala Leu Ala Ala Leu Ala Arg Arg Ile Leu Gly Cys
20 25 30
<210> 16
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Phe Ser Gly Ser Gly Ser Gly Ser Gly Arg Gln Ile Lys Ile Trp Phe
1 5 10 15
Gln Asn Arg Arg Met Lys Trp Lys Lys Gly Cys
20 25
<210> 17
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Arg Gln Ile Lys Ile Trp Phe Gln Asn Arg Arg Met Lys Trp Lys Lys
1 5 10 15
<210> 18
<211> 34
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Asp Ala Ala Thr Ala Thr Arg Gly Arg Ser Ala Ala Ser Arg Pro Thr
1 5 10 15
Glu Arg Pro Arg Ala Pro Ala Arg Ser Ala Ser Arg Pro Arg Arg Pro
20 25 30
Val Asp
<210> 19
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Leu Gly Thr Tyr Thr Gln Asp Phe Asn Lys Phe His Thr Phe Pro Gln
1 5 10 15
Thr Ala Ile Gly Val Gly Ala Pro
20
<210> 20
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Gly Trp Thr Leu Asn Ser Ala Gly Tyr Leu Leu Gly Lys Ile Asn Leu
1 5 10 15
Lys Ala Leu Ala Ala Leu Ala Lys Lys Ile Leu
20 25
<210> 21
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Arg Gly Gly Arg Leu Ser Tyr Ser Arg Arg Arg Phe Ser Thr Ser Thr
1 5 10 15
Gly Arg
<210> 22
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Leu Leu Ile Ile Leu Arg Arg Arg Ile Arg Lys Gln Ala His Ala His
1 5 10 15
Ser Lys
<210> 23
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Lys Leu Ala Leu Lys Leu Ala Leu Lys Ala Leu Lys Ala Ala Leu Lys
1 5 10 15
Leu Ala
<210> 24
<211> 276
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
1 5 10 15
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
20 25 30
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
35 40 45
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
50 55 60
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
65 70 75 80
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
85 90 95
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
100 105 110
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Val Leu Pro
115 120 125
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Leu Cys Leu
130 135 140
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
145 150 155 160
Gly Gln Pro Glu Asn Asn Tyr Leu Thr Trp Pro Pro Val Leu Asp Ser
165 170 175
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
180 185 190
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
195 200 205
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
210 215 220
Gly Ser His Glu His Glu His Glu His Glu His Glu His Glu His Glu
225 230 235 240
His Glu His Glu His Glu His Glu Gly Gly Ser Arg Arg Val Gly Phe
245 250 255
Ala Gly Gly Ser Gly Ser Val Ser Arg Arg Arg Arg Arg Arg Gly Gly
260 265 270
Arg Arg Arg Arg
275
<210> 25
<211> 196
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Gly Met Asp Cys Glu Val Asn Asn Gly Ser Ser Leu Arg Asp Glu Cys
1 5 10 15
Ile Thr Asn Leu Leu Val Phe Gly Phe Leu Gln Ser Cys Ser Asp Asn
20 25 30
Ser Phe Arg Arg Glu Leu Asp Ala Leu Gly His Glu Leu Pro Val Leu
35 40 45
Ala Pro Gln Trp Glu Gly Tyr Asp Glu Leu Gln Thr Asp Gly Asn Arg
50 55 60
Ser Ser His Ser Arg Leu Gly Arg Ile Glu Ala Asp Ser Glu Ser Gln
65 70 75 80
Glu Asp Ile Ile Arg Asn Ile Ala Arg His Leu Ala Gln Val Gly Asp
85 90 95
Ser Met Asp Arg Ser Ile Pro Pro Gly Leu Val Asn Gly Leu Ala Leu
100 105 110
Gln Leu Arg Asn Thr Ser Arg Ser Glu Glu Asp Arg Asn Arg Asp Leu
115 120 125
Ala Thr Ala Leu Glu Gln Leu Leu Gln Ala Tyr Pro Arg Asp Met Glu
130 135 140
Lys Glu Lys Thr Met Leu Val Leu Ala Leu Leu Leu Ala Lys Lys Val
145 150 155 160
Ala Ser His Thr Pro Ser Leu Leu Arg Asp Val Phe His Thr Thr Val
165 170 175
Asn Phe Ile Asn Gln Asn Leu Arg Thr Tyr Val Arg Ser Leu Ala Arg
180 185 190
Asn Gly Met Asp
195
<210> 26
<211> 354
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Gly Met Ser Asn Leu Leu Thr Val His Gln Asn Leu Pro Ala Leu Pro
1 5 10 15
Val Asp Ala Thr Ser Asp Glu Val Arg Lys Asn Leu Met Asp Met Phe
20 25 30
Arg Asp Arg Gln Ala Phe Ser Glu His Thr Trp Lys Met Leu Leu Ser
35 40 45
Val Cys Arg Ser Trp Ala Ala Trp Cys Lys Leu Asn Asn Arg Lys Trp
50 55 60
Phe Pro Ala Glu Pro Glu Asp Val Arg Asp Tyr Leu Leu Tyr Leu Gln
65 70 75 80
Ala Arg Gly Leu Ala Val Lys Thr Ile Gln Gln His Leu Gly Gln Leu
85 90 95
Asn Met Leu His Arg Arg Ser Gly Leu Pro Arg Pro Ser Asp Ser Asn
100 105 110
Ala Val Ser Leu Val Met Arg Arg Ile Arg Lys Glu Asn Val Asp Ala
115 120 125
Gly Glu Arg Ala Lys Gln Ala Leu Ala Phe Glu Arg Thr Asp Phe Asp
130 135 140
Gln Val Arg Ser Leu Met Glu Asn Ser Asp Arg Cys Gln Asp Ile Arg
145 150 155 160
Asn Leu Ala Phe Leu Gly Ile Ala Tyr Asn Thr Leu Leu Arg Ile Ala
165 170 175
Glu Ile Ala Arg Ile Arg Val Lys Asp Ile Ser Arg Thr Asp Gly Gly
180 185 190
Arg Met Leu Ile His Ile Gly Arg Thr Lys Thr Leu Val Ser Thr Ala
195 200 205
Gly Val Glu Lys Ala Leu Ser Leu Gly Val Thr Lys Leu Val Glu Arg
210 215 220
Trp Ile Ser Val Ser Gly Val Ala Asp Asp Pro Asn Asn Tyr Leu Phe
225 230 235 240
Cys Arg Val Arg Lys Asn Gly Val Ala Ala Pro Ser Ala Thr Ser Gln
245 250 255
Leu Ser Thr Arg Ala Leu Glu Gly Ile Phe Glu Ala Thr His Arg Leu
260 265 270
Ile Tyr Gly Ala Lys Asp Asp Ser Gly Gln Arg Tyr Leu Ala Trp Ser
275 280 285
Gly His Ser Ala Arg Val Gly Ala Ala Arg Asp Met Ala Arg Ala Gly
290 295 300
Val Ser Ile Pro Glu Ile Met Gln Ala Gly Gly Trp Thr Asn Val Asn
305 310 315 320
Ile Val Met Asn Tyr Ile Arg Asn Leu Asp Ser Glu Thr Gly Ala Met
325 330 335
Val Arg Leu Leu Glu Asp Gly Asp Gly Gly Ser Pro Lys Lys Lys Arg
340 345 350
Lys Val
Claims (24)
1.一种内体逃逸肽,其特征在于,所述的内体逃逸肽包含由组氨酸H、谷氨酸E组成的(HE)n序列和CPP,所述的CPP为低分子量鱼精蛋白,其氨基酸序列为SEQ ID NO:1;
所述的内体逃逸肽还包含酶切位点,所述的酶切位点连接(HE)n与CPP,其中,n选自8至15中的自然数;
所述的酶切位点为组织蛋白酶B识别位点。
2.根据权利要求1所述的内体逃逸肽,其特征在于,所述的n为11。
3.根据权利要求1所述的内体逃逸肽,其特征在于,所述的组织蛋白酶B识别位点的氨基酸序列为VGFA。
4.根据权利要求1所述的内体逃逸肽,其特征在于,所述的内体逃逸肽为(HE)11-VGFA-低分子量鱼精蛋白或低分子量鱼精蛋白-VGFA-(HE)11。
5.根据权利要求1所述的内体逃逸肽,其特征在于,所述的内体逃逸肽的序列为SEQ IDNO:2或3。
6.一种CPP的改造或者内体逃逸肽的构建的方法,其特征在于,在CPP中引入(HE)n结构,使得改造后的CPP呈电中性,其中,n选自8至15中的自然数;
所述的CPP为低分子量鱼精蛋白,其氨基酸序列为SEQ ID NO:1;
所述的内体逃逸肽还包含酶切位点,所述的酶切位点连接(HE)n与CPP;
所述的酶切位点为组织蛋白酶B识别位点。
7.一种载体,其特征在于,所述的载体包含权利要求1-5任一所述的内体逃逸肽和靶向细胞的分子。
8.根据权利要求7所述的载体,其特征在于,所述的靶向细胞的分子为抗体。
9.根据权利要求8所述的载体,其特征在于,所述的抗体选自Her2的抗体、PD-1的抗体、PD-L1的抗体、CXCR4的抗体、CD19的抗体、CD20的抗体、CD22的抗体、CD30的抗体、PSMA的抗体、PGGFR的抗体或VEGFR的抗体中的一种或两种以上的组合。
10.根据权利要求7所述的载体,其特征在于,靶向的细胞选自过表达Her2、PD-1、PD-L1、CXCR4、CD19、CD20、CD22、CD30、PSMA、PGGFR或VEGFR的细胞。
11.一种编码权利要求1-5任一所述的内体逃逸肽或权利要求7-10任一所述的载体的核酸。
12.一种权利要求1-5任一所述的内体逃逸肽、权利要求7-10任一所述的载体或权利要求11所述的核酸的用途,其特征在于,所述的用途包括携带功能性分子透过细胞膜,或者用于与功能性分子连接制备能够透过细胞膜的复合物;
所述的用途不涉及疾病的诊断和治疗方法。
13.根据权利要求12所述的用途,其特征在于,所述的功能性分子选自序列特异性核酸酶或药物蛋白。
14.一种融合蛋白,其特征在于,所述的融合蛋白包含权利要求1-5任一所述的内体逃逸肽或权利要求7-10任一所述的载体。
15.根据权利要求14所述的融合蛋白,其特征在于,所述的融合蛋白包含序列特异性核酸酶;或者,所述的融合蛋白包含药物蛋白。
16.根据权利要求15所述的融合蛋白,其特征在于,所述的序列特异性核酸酶选自Cas9、miniCas9、Cpf1或Cre。
17.根据权利要求15所述的融合蛋白,其特征在于,所述的药物蛋白选自MyoD、CEBPα、BID、tBID、Caspase3、Cleavaged Caspase3、Caspase8、PAPR1、CleavagedPAPR1、Bax、P53、GSDMA、GSDMB、GSDMC、GSDMD、GSDME、Granzyme A或Granzyme B中的一种或两种以上的组合。
18.根据权利要求14所述的融合蛋白,其特征在于,所述的融合蛋白包含下列各组中任一项:
A)靶向细胞的分子和权利要求1-5任一所述的内体逃逸肽;B)靶向细胞的分子、权利要求1-5任一所述的内体逃逸肽和药物蛋白;或,C)靶向细胞的分子、权利要求1-5任一所述的内体逃逸肽和序列特异性核酸酶。
19.一种编码权利要求14-18任一所述的融合蛋白的核酸。
20.一种包含权利要求1-5任一所述的内体逃逸肽、权利要求7-10任一所述的载体、权利要求11所述的核酸、权利要求14-18任一所述的融合蛋白或权利要求19所述的核酸的细胞。
21.一种包含权利要求1-5任一所述的内体逃逸肽、权利要求7-10任一所述的载体、权利要求11所述的核酸、权利要求14-18任一所述的融合蛋白、权利要求19所述的核酸或权利要求20所述的细胞在基因编辑或者在制备治疗疾病的药物中的应用;
所述的基因编辑不涉及疾病的诊断和治疗方法。
22.根据权利要求21所述的应用,其特征在于,所述的疾病选自乳腺癌、白血病、胃癌、肺癌、肝癌、直肠癌、前列腺癌、转移性黑色素瘤、非小细胞肺癌、肾细胞癌、膀胱癌、尿路上皮癌或杜氏肌营养不良。
23.一种基因编辑的方法,其特征在于,所述的方法包括采用权利要求1-5任一所述的内体逃逸肽或权利要求7-10任一所述的载体向待编辑细胞递送序列特异性核酸酶;所述的方法不涉及疾病的诊断和治疗方法。
24.根据权利要求23所述的方法,其特征在于,所述的序列特异性核酸酶选自Cas9、miniCas9、Cpf1或Cre。
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