CN117500821A - 具有细胞内递送功能的Bio PROTAC蛋白和包含该蛋白的药物组合物 - Google Patents
具有细胞内递送功能的Bio PROTAC蛋白和包含该蛋白的药物组合物 Download PDFInfo
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- C07K—PEPTIDES
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Abstract
本发明涉及具有细胞内递送功能的蛋白降解靶向嵌合体(PROTAC)蛋白和包含该蛋白的药物组合物。根据本发明的PROTAC蛋白具有比通过常规方法制备的PROTAC更高的溶解性,并且当应用于细胞时有效地降解内在疾病蛋白,因此在治疗癌症或炎性疾病中是有效的。
Description
技术领域
本发明涉及具有细胞内递送功能的蛋白降解靶向嵌合体(PROTAC)蛋白和包含该蛋白的药物组合物。
背景技术
蛋白降解靶向嵌合体(PROTAC)是双头分子,其结合到致病蛋白,诱导蛋白酶体降解该蛋白,导致选择性蛋白降解。PROTAC由两个蛋白结合分子组成,一个用于结合E3泛素连接酶,另一个用于结合靶蛋白。通过与两种蛋白结合,PROTAC将靶蛋白递送至E3连接酶,并引起靶蛋白的标记,即泛素化,以随后被蛋白酶体降解。
泛素化包括三个步骤:由泛素激活酶(E1)、泛素缀合酶(E2)和泛素连接酶(E3)进行的激活、缀合和连接。作为这种顺序级联的结果,泛素与靶蛋白共价连接。泛素化的蛋白质最终被蛋白酶体降解。
PROTAC技术首次报道于2001年(Sakamoto et al.,Proceedings of theNational Academy of Sciences of the United States of America.98:8554,2001)。从那时起,该技术已被用于各种药物设计:pVHL、MDM2、beta-TrCP1、cereblon和c-IAP1。PROTAC药物主要由小分子化合物开发而来。衍生自沙利度胺家族的各种类型的小分子化合物具有能够在结构上同时结合靶蛋白和E3连接酶的优点。这些已知的PROTAC药物是非常有用的,但是需要措施来解决对小分子化合物的低溶解度、由于低的细胞内渗透导致内在蛋白质降解效率降低和安全性的担忧,并且需要克服这些问题的PROTAC药物。
因此,本发明人没有使用小分子化合物,而是付出了巨大的努力来开发具有高的靶蛋白降解效率和细胞内递送功能的PROTAC蛋白,并确定通过由5个甘氨酸组成的接头连接到von Hippel-Lindau(VHL)蛋白序列可以构建靶蛋白结合序列,所述von Hippel-Lindau(VHL)蛋白序列作为底物识别单元能够将E3连接酶转移到靶蛋白,所述E3连接酶是癌症、炎性疾病和感染中的重要靶标,并且可以使用接头将抗体或细胞穿透肽连接到该嵌合蛋白的末端,因此可以通过细胞内递送实际上降解基础疾病的靶蛋白,从而完成本发明。
在背景技术部分中描述的上述信息仅用于加深对本发明的背景技术的理解,并且其不包括形成本发明所属领域的普通技术人员已知的现有技术的信息。
发明内容
本发明的一个目的是提供具有高的靶蛋白降解效率和细胞内递送功能的PROTAC蛋白。
本发明的另一个目的是提供编码PROTAC蛋白的核酸。
本发明的再另一个目的是提供包括PROTAC蛋白或编码该蛋白的核酸作为活性成分的药物组合物。
本发明的又另一个目的是提供一种预防或治疗疾病的方法,该方法包括给予PROTAC蛋白或编码该蛋白的核酸。
本发明的再另一个目的是提供PROTAC蛋白或编码该蛋白的核酸用于预防或治疗疾病的用途。
本发明的还另一个目的是提供PROTAC蛋白或编码其的核酸在制备用于预防或治疗疾病的药物中的用途。
为了实现上述目的,本发明提供了具有以下化学式1或化学式2的结构的PROTAC蛋白:
[化学式1]
PEP-[L1-(TB-L2-UR)n]m;
[化学式2]
在化学式1或化学式2中,
(i)PEP是抗体或抗体片段,或细胞穿透肽,
(ii)L1和L2是接头,L1和L2可以彼此相同或不同,并且L1与TB或L2结合,
(iii)TB是与靶蛋白结合的结合剂或缀合物,
(iv)UR是与泛素连接酶结合的配体,和
(iv)n和m各自独立地为1至10的整数。
此外,本发明提供编码PROTAC蛋白的核酸。
此外,本发明提供包括PROTAC蛋白或编码该蛋白的核酸作为活性成分的药物组合物。
此外,本发明提供一种预防或治疗疾病的方法,该方法包括给予PROTAC蛋白或编码该蛋白的核酸。
此外,本发明提供PROTAC蛋白或编码该蛋白的核酸用于预防或治疗疾病的用途。
此外,本发明提供PROTAC蛋白或编码其的核酸在制备用于预防或治疗疾病的药物中的用途。
附图说明
图1示意性地显示了具有细胞穿透活性的PROTAC蛋白的表达载体。
图2显示了在导入细胞的质粒上表达的PROTAC蛋白的蛋白质印迹的结果。
图3显示了在导入细胞的质粒上表达的PROTAC蛋白对癌细胞生存力影响的结果
图4显示了蛋白质印迹的结果,证实了在导入细胞的质粒上表达的PROTAC蛋白对活性KRAS表达的抑制。
图5显示了蛋白质印迹的结果,证实了在将编码PROTAC蛋白的mRNA导入细胞后,细胞中PROTAC蛋白的表达和抑制活性KRAS的表达。
本发明的详细描述和优选实施方案
除非另有定义,否则本文所用的所有技术和科学术语与本发明所属领域的技术人员通常理解的含义相同。通常,本文使用的术语和下面描述的实验方法是本领域公知的,并且是典型的。
本发明基于以下发现:当泛素途径蛋白和靶蛋白接近于与泛素途径蛋白和靶蛋白结合的嵌合构建体时,泛素途径蛋白泛素化任何靶蛋白。
本发明主要旨在克服常规PROTAC技术的局限性,即当应用于细胞时,PROTAC具有低溶解度或不能有效地降解内在疾病蛋白。
一方面,本发明涉及具有以下化学式1或化学式2的结构的PROTAC蛋白:
[化学式1]
PEP-[L1-(TB-L2-UR)n]m;
[化学式2]
在化学式1或化学式2中,
(i)PEP是抗体或抗体片段,或细胞穿透肽,
(ii)L1和L2是接头,L1和L2可以彼此相同或不同,并且L1与TB或L2结合,
(iii)TB是与靶蛋白结合的结合剂或缀合物,
(iv)UR是与泛素连接酶结合的配体,和
(iv)n和m各自独立地为1至10的整数。
如本文所用,术语“PROTAC”是蛋白降解靶向嵌合体的缩写,是指由两个活性结构域和接头组成的双功能小分子,并且能够去除特定的不需要的蛋白质。在本说明书中,“PROTAC蛋白”可以与“bio PROTAC蛋白”和“嵌合蛋白”互换使用。
根据本发明的PROTAC蛋白能够诱导所选的靶蛋白的泛素化,并且被设计为通过接头连接以包括靶蛋白结合位点和泛素连接酶结合位点。
在本发明中,PROTAC蛋白在一端包括泛素连接酶结合配体,在另一端包括靶蛋白结合位点,并且在与靶蛋白结合的蛋白的末端或在连接泛素连接酶结合配体和靶蛋白结合位点的接头中包括细胞穿透域。因此,当PROTAC蛋白被引入细胞中时,其位于靶蛋白附近,使其可以诱导蛋白的降解,并且根据n和m的数值以高浓度存在于细胞中,从到诱导有效的靶蛋白降解。
在本发明中,PROTAC蛋白可以由SEQ ID NO:1至6的氨基酸序列表示,但不限于此。
SEQ ID NO:1:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTFSMNWVRQAPGKGLEWVSYISRTSKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGRFFDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGEAPKLLIYSASVLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVMIPMTFGQGTKVEIKGSGGGGSMPRRAENWDEAEVGAEEAGVEEYGPEEDGGEESGAEESGPEESGPEELGAEEEMEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLNFDGEPQPYPTLPPGTGRRIHSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDIVRSLYEDLEDHPNVQKDLERLTQERIAHQRMGDENLYFQGGSGGSGGSHHHHHHHH
SEQ ID NO:2:
MAWVWTLLFLMAAAQSIQAVSRRRRRRGGRRRRGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFSTFSMNWVRQAPGKGLEWVSYISRTSKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGRFFDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGEAPKLLIYSASVLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVMIPMTFGQGTKVEIKGSGGGGSMPRRAENWDEAEVGAEEAGVEEYGPEEDGGEESGAEESGPEESGPEELGAEEEMEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLNFDGEPQPYPTLPPGTGRRIHSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDIVRSLYEDLEDHPNVQKDLERLTQERIAHQRMGDENLYFQGGSGGSGGSHHHHHHHH
SEQ ID NO:3:
MAWVWTLLFLMAAAQSIQAEVQLLESGGGLVQPGGSLRLSCAASGFTFSTFSMNWVRQAPGKGLEWVSYISRTSKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGRFFDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGEAPKLLIYSASVLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVMIPMTFGQGTKVEIKGSGGGGSMPRRAENWDEAEVGAEEAGVEEYGPEEDGGEESGAEESGPEESGPEELGAEEEMEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLNFDGEPQPYPTLPPGTGRRIHSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDIVRSLYEDLEDHPNVQKDLERLTQERIAHQRMGDGGGGSVSRRRRRRGGRRRRENLYFQGGSGGSGGSHHHHHHHH
SEQ ID NO:4:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTFSMNWVRQAPGKGLEWVSYISRTSKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGRFFDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGEAPKLLIYSASVLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVMIPMTFGQGTKVEIKGSGGGGSMENRWQVMIVWQVDRMRIRTWKSLVKHHMYVSGKARGWFYRHHYESPHPRISSEVHIPLGDARLVITTYWGLHTGERDWHLGQGVSIEWRKKRYSTQVDPELADQLIHLYYFDCFSDSAIRKALLGHIVSPRCEYQAGHNKVGSLQYLALAALITPKKIKPPLPSVTKLTEDRWNKPQKTKGHRGSHTMNGHENLYFQGGSGGSGGSHHHHHHHH
SEQ ID NO:5:
MAWVWTLLFLMAAAQSIQAVSRRRRRRGGRRRRGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFSTFSMNWVRQAPGKGLEWVSYISRTSKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGRFFDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGEAPKLLIYSASVLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVMIPMTFGQGTKVEIKGSGGGGSMENRWQVMIVWQVDRMRIRTWKSLVKHHMYVSGKARGWFYRHHYESPHPRISSEVHIPLGDARLVITTYWGLHTGERDWHLGQGVSIEWRKKRYSTQVDPELADQLIHLYYFDCFSDSAIRKALLGHIVSPRCEYQAGHNKVGSLQYLALAALITPKKIKPPLPSVTKLTEDRWNKPQKTKGHRGSHTMNGHENLYFQGGSGGSGGSHHHHHHHH
SEQ ID NO:6:
MAWVWTLLFLMAAAQSIQAEVQLLESGGGLVQPGGSLRLSCAASGFTFSTFSMNWVRQAPGKGLEWVSYISRTSKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGRFFDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGEAPKLLIYSASVLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVMIPMTFGQGTKVEIKGSGGGGSMENRWQVMIVWQVDRMRIRTWKSLVKHHMYVSGKARGWFYRHHYESPHPRISSEVHIPLGDARLVITTYWGLHTGERDWHLGQGVSIEWRKKRYSTQVDPELADQLIHLYYFDCFSDSAIRKALLGHIVSPRCEYQAGHNKVGSLQYLALAALITPKKIKPPLPSVTKLTEDRWNKPQKTKGHRGSHTMNGHGGGGSVSRRRRRRGGRRRRENLYFQGGSGGSGGSHHHHHHHH
与靶蛋白结合的结合剂或缀合物,在本发明中称为TB,可以选自文库。TB被设计为通过接头与泛素途径蛋白结合位点(例如VHL蛋白)偶联。泛素途径蛋白识别E3泛素连接酶。
在本发明中,PROTAC蛋白的靶蛋白可以包括但不限于突变的RAS超家族、激酶、转录因子和磷酸酶。
在本发明中,RAS超家族可以选自由KRAS、HRAS和NRAS组成的组。
在本发明中,TB可以选自由以下组成的组:突变的RAS超家族抑制剂、激酶抑制剂、磷酸酶抑制剂、热激蛋白90(HSP90)抑制剂、MDM2(小鼠双微体2同系物)抑制剂、HDAC(组蛋白脱乙酰酶)抑制剂、人赖氨酸甲基转移酶抑制剂、血管生成抑制剂、免疫抑制化合物、靶向人BET(含溴结构域和外端结构域)含溴结构域蛋白的化合物、靶向芳基烃受体(AHR)的化合物、靶向EGF(上皮生长因子)受体激酶的化合物、靶向FKBP(FK506结合蛋白)的化合物、靶向雄激素受体(AR)的化合物、靶向雌激素受体(ER)的化合物、靶向甲状腺激素受体的化合物、靶向HIV蛋白酶的化合物、靶向HIV整合酶的化合物、靶向HCV蛋白酶的化合物、靶向酰基蛋白硫酯酶-l的化合物(APT1)的化合物和靶向酰基蛋白硫酯酶-2(APT2)的化合物,但不限于此。
在本发明中,TB可以是包含选自SEQ ID NO:7至SEQ ID NO:14的任一氨基酸的多肽,但并不限于此。
SEQ ID NO:7:LTPHKHHKHLHA
SEQ ID NO:8:WPGKHHNHYLRS
SEQ ID NO:9:HDGYWWHSMTMW
SEQ ID NO:10:LIHPMTVKHVHL
SEQ ID NO:11:GSHWHFPKHQQQ
SEQ ID NO:12:GSHWHFPKHQQH
SEQ ID NO:13:WPGKHHHHYLRR
SEQ ID NO:14:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTFSMNWVRQAPGKGLEWVSYISRTSKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGRFFDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGEAPKLLIYSASVLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVMIPMTFGQGTKVEIK
在本发明中,UR是与泛素连接酶结合的配体,可以是与E3连接酶结合的配体,选自由以下组成的组:XIAP(X-连锁凋亡抑制蛋白)、VHL(von Hippel-Lindau)蛋白、IAPs(凋亡抑制蛋白)、cereblon和MDM2(小鼠双微体2同系物),但不限于此。
在本发明中,PEP可以是抗体或抗体片段,或细胞穿透肽。
在本发明中,细胞穿透肽是具有特异性穿透目标疾病细胞的能力的肽,并且可用的细胞穿透肽序列的实例示于下表1中,但不限于此。
[表1]
癌细胞穿透肽序列
(*:o定义为1-5,决定间隔物的长度)
在本发明中,抗体可以与选自由以下组成的组的至少一种多肽结合:EGFR、DLL3、EDAR、CLL1、BMPR1B、E16、STEAP1、0772P、MPF、NaPi2b、Sema 5b、PSCAhlg、ETBR、MSG783、STEAP2、TrpM4、CRIPTO、CD21、CD79b、FcRH2、B7-H4、HER2、NCA、MDP、IL20Rct、brevican、EphB2R、ASLG659、PSCA、GEDA、BAFF-R、CD22、CD79a、CXCRS、HLA-DOB、P2X5、CD72、LY64、FcRH1、IRTA2、TENB2、PMEL17、TMEFF1、GDNF-Ra1、Ly6E、TMEM46、Ly6G6D、LGR5、RET、LY6K、GPR19、GPR54、ASPHD1、酪氨酸酶、TMEM118、GPR172A、MUC16和CD33,但本发明不限于此。
在本发明中,抗体可以是单克隆抗体或其变体,并且单克隆抗体可以选自由以下组成的组:曲司珠单抗、西妥昔单抗、利妥昔单抗、维布妥昔单抗(brentuximab)、吉妥珠单抗(gemtuzumab)、伊组单抗(inotuzumab)、沙西妥珠单抗(sacituzumab)、阿仑珠单抗和尼妥组单抗(nimotuzumab)。
在另一方面,本发明涉及编码PROTAC蛋白的核酸。
在本发明中,核酸可以是DNA、mRNA、质粒DNA等,并且编码PROTAC蛋白质的基因,诸如质粒DNA或由其衍生的mRNA,可以通过穿透细胞的纳米载体递送到细胞中,从而表现出相同的靶蛋白降解功效。
在本发明中,所述核酸可以与各种载体一起使用,所述载体诸如脂质纳米颗粒(LNP)、脂质体等,已知它们可以有效地将寡核苷酸递送到细胞中,但是本发明不限于此。
在另一个方面,本发明涉及包含PROTAC蛋白或编码PROTAC蛋白的核酸的药物组合物。
本发明涉及靶蛋白的降解,因此提供了与本发明PROTAC蛋白相关的多种药物组合物
在本发明中,药物组合物可以用于治疗或预防癌症或炎性疾病,特别是选自由以下组成的组的疾病:癌症、哮喘、自身免疫性疾病、类风湿性关节炎、多发性硬化症、睫状体疾病(ciliary disease)、腭裂、糖尿病、心脏病、高血压、炎性肠病、精神发育迟缓、情绪障碍、肥胖症、屈光不正、不育症、恩格尔曼综合症(Engelman syndrome)、卡纳万氏病(Canavan disease)、慢性消化系统疾病、恰克-马利-杜斯氏症、囊性纤维化、迪谢内肌营养不良、血色素沉积症、血友病、克兰费尔特综合征(Klinefelter syndrome)、神经纤维瘤病、苯丙酮尿症、常染色体显性多囊性肿瘤(PKD1或PKD2)、普拉德-威利综合征(Prader-Willisyndrome)、镰状细胞贫血、泰-萨克斯病(Tay-Sachs disease)、特纳综合征(Turnersyndrome)、HIV感染疾病和HCV感染疾病。
在本发明中,癌症可以选自由以下组成的组:鳞状细胞癌,基底细胞癌,腺癌,肝细胞癌,肾细胞癌,膀胱癌,肠癌,乳腺癌,宫颈癌,子宫癌,结肠癌,食道癌,头部癌,肾癌,肝癌,肺癌,卵巢癌,胰腺癌,前列腺癌,胃癌,白血病,良性和恶性淋巴瘤,特别地伯基特淋巴瘤和非霍奇金淋巴瘤,良性和恶性黑色素瘤,骨髓增生性疾病,肉瘤(包括尤因肉瘤、血管肉瘤、卡波西肉瘤、脂肉瘤、肌瘤、神经上皮肉瘤、滑膜肉瘤、神经肉瘤、星形细胞瘤、少突胶质细胞瘤、室管膜瘤、胶质母细胞瘤、神经母细胞瘤、神经节细胞瘤、神经节细胞胶质瘤、髓母细胞瘤、松果体细胞瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和神经鞘瘤),睾丸癌,甲状腺癌,癌肉瘤,霍奇金病,维尔姆斯瘤和畸胎癌。
在本发明中,炎性疾病可以选自由关节炎、自身免疫性疾病、帕金森病、痴呆、肝炎和病毒感染组成的组。
本发明的药物组合物可以通过口服、肠胃外、吸入喷雾、局部、直肠、鼻或植入储器途径给药,并且可以在口服或肠胃外给药时使用纳米颗粒或脂质体作为载体给药。
在本发明的一个实施方案中,PROTAC蛋白的单次剂量可以为1ng/kg至100mg/kg,优选5ng/kg至50mg/kg,并且可以每天一次或每周1-3次给药。然而,给药的剂量和间隔不限于此。
在再另一方面,本发明涉及预防或治疗疾病的方法,该方法包括给予PROTAC蛋白或编码PROTAC蛋白的核酸。
在再另一方面,本发明涉及PROTAC蛋白或编码该蛋白的核酸用于预防或治疗疾病的用途。
本发明的还另一个目的是提供PROTAC蛋白或编码PROTAC蛋白的核酸在制备用于预防或治疗疾病的药物中的用途。
在本发明中,疾病可以是癌症或炎性疾病,但不限于此。
在本发明中,所述方法和用途包括根据本发明的PROTAC蛋白或编码其的核酸,并且涉及包括PROTAC蛋白或编码其的核酸的药物组合物,因此省略对PROTAC蛋白质或编码其地核酸和药物组合物的多余描述。
通过以下实施例可以更好地理解本发明。这些实施例仅用于说明本发明,而不应理解为限制本发明的范围,这对本领域的普通技术人员来说是显而易见的。
实施例1:在动物细胞(哺乳动物细胞)中表达具有细胞穿透活性的PROTAC蛋白
如下所述,本发明人设计了降解靶蛋白的PROTAC蛋白的表达载体。将靶向人KRAS的第12位甘氨酸突变为半胱氨酸的活化蛋白(KRASG12C)的单克隆抗体、与E3连接酶结合的VHL蛋白和包括与核糖体结合并帮助转录的kozak序列的cDNA插入pcDNA3.4载体中,克隆并通过DNA测序鉴定。向得到的质粒DNA序列中加入信号肽、接头和PEP序列。信号肽位于N端,通过不同长度的接头连接的靶向突变型人KRAS G12C的单克隆抗体、VHL和PEP被克隆到不同的位置。用如此构建的质粒(图1)转染CHO-S细胞系,然后加入增强子培养7天。
使用抗-His标签抗体(Abcam,ab18184)和抗-VHL抗体(Invitrogen,MA5-13940)通过蛋白质印迹法测定表达的PROTAC蛋白,蛋白质印迹的结果显示于图2。理论蛋白质大小为56kDa,并且PROTAC蛋白质从培养的第3天开始出现。培养5天后,His标签不再出现,表明它已从蛋白质上切割。
实施例2:证实PROTAC蛋白对癌细胞生长的抑制作用
用编码PROTAC的质粒转染癌细胞,并进行MTT测定以评估由该质粒表达的PROTAC蛋白的抗癌作用。使用Lipofectamine 3000(Invitrogen,L3000001),用不同量的质粒转染5x103 H358细胞(ATCC,CRL-5807),即具有人KRASG12C表型的非小细胞肺癌细胞,72小时后,通过MTT测定评估细胞活力(图3)。随着经处理的质粒浓度的增加,H358细胞活力下降。因此,确认了PROTAC蛋白质通过导入细胞的质粒表达并发挥作用。
实施例3:证实PROTAC蛋白对KRAS信号传导的抑制作用
为了证实在细胞中表达的PROTAC蛋白对靶蛋白的降解,使用Lipofectamine 3000(Invitrogen,L3000001),用实施例1中构建的质粒DNA转染H358细胞(ATCC,CRL-5807),即具有人KRASG12C表型的非小细胞肺癌细胞。转染后,在16、24和48小时裂解细胞以获得细胞裂解物。
为了分离活性KRAS,使用活性GTP酶试剂盒(Cell Signaling,11860S)加入80μgGST-Raf1-RBD,并将500μg蛋白质分配到旋转杯中。在4℃下反应1小时,然后在6000x g下离心15秒后,将柱转移到新的管中,并向其中加入400μl的1x裂解缓冲液。在6000x g下离心15秒后,将柱转移到新管中,并分配50μl 2x SDS缓冲液(200μL 5x SDS样品负载染料和300μl水的混合物),然后使其反应2分钟。在6000x g下离心2分钟后,在100℃下加热7分钟。通过11% SDS-PAGE电泳分离蛋白质(蛋白质负载量:20μl/道),并转移到硝酸纤维素膜上。为了测量对应于KRAS副信号的ERK1/2,将30μg蛋白通过11% SDS-PAGE电泳并转移到硝酸纤维素膜上。用溶解在T-TBS中的5%脱脂乳封闭1小时,将一抗以1:1000在T-TBS中稀释,在4℃下倒置反应过夜,用T-TBS洗涤3次,每次10分钟后,将二抗以1:3000在T-TBS中稀释,在室温下倒置反应1小时。用T-TBS洗涤三次,每次10分钟后,用ECL底物(Thermo,34580)进行化学发光,并用Amersham Imager680(GE)确认。在下表2中示出所使用的抗体的信息。
[表2]
所用的抗体信息
使用免疫印迹,用抗-His标签抗体鉴定PROTAC蛋白,并鉴定细胞中的Pan KRAS或活性KRAS(图4)。随着PROTAC蛋白的表达,活性KRAS的表达水平降低,但pan KRAS没有变化。因此,证实PROTAC蛋白仅选择性降解活性KRAS,而不降解正常的pan KRAS。
实施例4:将编码PROTAC蛋白的mRNA导入细胞
为了在细胞中表达PROTAC蛋白,构建mRNA而不是质粒。通过添加5'封端和3'聚A尾增加mRNA的稳定性。使用Lipofectamine MessengerMAX(Invitrogen,LMRNA003)进行转染。转染24小时后,裂解细胞以获得细胞裂解物。使用与实施例3中描述的方法相同的方式筛选活性KRAS。使用免疫印迹,用抗-His标签抗体(Abcam)鉴定由导入细胞的mRNA表达的PROTAC蛋白。证实活性KRAS的表达水平随着PROTAC蛋白的表达而降低(图5)。以mRNA形式导入的PROTAC蛋白被表达,因此作为靶蛋白的活性KRAS被降解。
工业实用性
与通过常规方法构建的PROTAC相比,根据本发明的PROTAC蛋白具有高溶解性,并且当应用于细胞时可以有效地降解内在的疾病蛋白,因此对于治疗癌症或炎性疾病是有效的。
上面已经详细描述了本发明的特定部分,对于本领域技术人员而言,显然这些特定描述仅是优选实施例,本发明的范围不受其限制。因此,本发明的实质范围将由所附权利要求及其等同物来限定。
序列表自由文本
附上电子文件。
<110> 纳米智能生物医学工程有限公司
首尔大学校产学协力团
<120> 具有细胞内递送功能的Bio PROTAC蛋白和包含该蛋白的药物组合物
<130> PF-B2964
<150> KR 2021-0075839
<151> 2021-06-11
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Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
180 185 190
Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp
195 200 205
Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Ser Ala
210 215 220
Ser Val Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
225 230 235 240
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
245 250 255
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Met Ile Pro Met Thr Phe Gly
260 265 270
Gln Gly Thr Lys Val Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Met
275 280 285
Glu Asn Arg Trp Gln Val Met Ile Val Trp Gln Val Asp Arg Met Arg
290 295 300
Ile Arg Thr Trp Lys Ser Leu Val Lys His His Met Tyr Val Ser Gly
305 310 315 320
Lys Ala Arg Gly Trp Phe Tyr Arg His His Tyr Glu Ser Pro His Pro
325 330 335
Arg Ile Ser Ser Glu Val His Ile Pro Leu Gly Asp Ala Arg Leu Val
340 345 350
Ile Thr Thr Tyr Trp Gly Leu His Thr Gly Glu Arg Asp Trp His Leu
355 360 365
Gly Gln Gly Val Ser Ile Glu Trp Arg Lys Lys Arg Tyr Ser Thr Gln
370 375 380
Val Asp Pro Glu Leu Ala Asp Gln Leu Ile His Leu Tyr Tyr Phe Asp
385 390 395 400
Cys Phe Ser Asp Ser Ala Ile Arg Lys Ala Leu Leu Gly His Ile Val
405 410 415
Ser Pro Arg Cys Glu Tyr Gln Ala Gly His Asn Lys Val Gly Ser Leu
420 425 430
Gln Tyr Leu Ala Leu Ala Ala Leu Ile Thr Pro Lys Lys Ile Lys Pro
435 440 445
Pro Leu Pro Ser Val Thr Lys Leu Thr Glu Asp Arg Trp Asn Lys Pro
450 455 460
Gln Lys Thr Lys Gly His Arg Gly Ser His Thr Met Asn Gly His Glu
465 470 475 480
Asn Leu Tyr Phe Gln Gly Gly Ser Gly Gly Ser Gly Gly Ser His His
485 490 495
His His His His His His
500
<210> 6
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 嵌合蛋白
<400> 6
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Thr Phe Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Tyr Ile Ser Arg Thr Ser Lys Thr Ile Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Arg Phe Phe Asp Tyr Trp Gly Gln Gly Thr
115 120 125
Leu Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser
130 135 140
Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln
145 150 155 160
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
165 170 175
Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln
180 185 190
Lys Pro Gly Glu Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Val Leu
195 200 205
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Ser Val Met Ile Pro Met Thr Phe Gly Gln Gly Thr
245 250 255
Lys Val Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Met Glu Asn Arg
260 265 270
Trp Gln Val Met Ile Val Trp Gln Val Asp Arg Met Arg Ile Arg Thr
275 280 285
Trp Lys Ser Leu Val Lys His His Met Tyr Val Ser Gly Lys Ala Arg
290 295 300
Gly Trp Phe Tyr Arg His His Tyr Glu Ser Pro His Pro Arg Ile Ser
305 310 315 320
Ser Glu Val His Ile Pro Leu Gly Asp Ala Arg Leu Val Ile Thr Thr
325 330 335
Tyr Trp Gly Leu His Thr Gly Glu Arg Asp Trp His Leu Gly Gln Gly
340 345 350
Val Ser Ile Glu Trp Arg Lys Lys Arg Tyr Ser Thr Gln Val Asp Pro
355 360 365
Glu Leu Ala Asp Gln Leu Ile His Leu Tyr Tyr Phe Asp Cys Phe Ser
370 375 380
Asp Ser Ala Ile Arg Lys Ala Leu Leu Gly His Ile Val Ser Pro Arg
385 390 395 400
Cys Glu Tyr Gln Ala Gly His Asn Lys Val Gly Ser Leu Gln Tyr Leu
405 410 415
Ala Leu Ala Ala Leu Ile Thr Pro Lys Lys Ile Lys Pro Pro Leu Pro
420 425 430
Ser Val Thr Lys Leu Thr Glu Asp Arg Trp Asn Lys Pro Gln Lys Thr
435 440 445
Lys Gly His Arg Gly Ser His Thr Met Asn Gly His Gly Gly Gly Gly
450 455 460
Ser Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg Glu
465 470 475 480
Asn Leu Tyr Phe Gln Gly Gly Ser Gly Gly Ser Gly Gly Ser His His
485 490 495
His His His His His His
500
<210> 7
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 结合到RAS超家族的结合剂
<400> 7
Leu Thr Pro His Lys His His Lys His Leu His Ala
1 5 10
<210> 8
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 结合到RAS超家族的结合剂
<400> 8
Trp Pro Gly Lys His His Asn His Tyr Leu Arg Ser
1 5 10
<210> 9
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 结合到RAS超家族的结合剂
<400> 9
His Asp Gly Tyr Trp Trp His Ser Met Thr Met Trp
1 5 10
<210> 10
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 结合到RAS超家族的结合剂
<400> 10
Leu Ile His Pro Met Thr Val Lys His Val His Leu
1 5 10
<210> 11
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 结合到RAS超家族的结合剂
<400> 11
Gly Ser His Trp His Phe Pro Lys His Gln Gln Gln
1 5 10
<210> 12
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 结合到RAS超家族的结合剂
<400> 12
Gly Ser His Trp His Phe Pro Lys His Gln Gln His
1 5 10
<210> 13
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 结合到RAS超家族的结合剂
<400> 13
Trp Pro Gly Lys His His His His Tyr Leu Arg Arg
1 5 10
<210> 14
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 结合到RAS超家族的结合剂
<400> 14
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Phe
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Arg Thr Ser Lys Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu
115 120 125
Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Glu Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Val Leu Gln Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln Ser Val Met Ile Pro Met Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 15
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 15
Gly Gly Gly Gly Ser His Arg Arg Cys Asn Lys Asn Asn Lys Lys Arg
1 5 10 15
<210> 16
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 16
Gly Gly Gly Gly Ser His Arg Arg Cys Asn Pro Asn Asn Lys Lys Arg
1 5 10 15
<210> 17
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 17
Gly Gly Gly Gly Ser Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg
1 5 10 15
Arg Arg Arg
<210> 18
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 18
Gly Gly Gly Gly Ser Gly Lys Cys Ser Thr Arg Gly Arg Lys Cys Cys
1 5 10 15
Arg Arg Lys Lys
20
<210> 19
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 19
Gly Gly Gly Gly Ser Asn Arg Pro Asp Ser Ala Gln Phe Trp Leu His
1 5 10 15
His Arg Arg
<210> 20
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 20
His Arg Arg Cys Asn Lys Asn Asn Lys Lys Arg Gly Gly Gly Gly Ser
1 5 10 15
<210> 21
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 21
His Arg Arg Cys Asn Pro Asn Asn Lys Lys Arg Gly Gly Gly Gly Ser
1 5 10 15
<210> 22
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 22
Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg Gly Gly
1 5 10 15
Gly Gly Ser
<210> 23
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 23
Gly Lys Cys Ser Thr Arg Gly Arg Lys Cys Cys Arg Arg Lys Lys Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 24
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 癌细胞穿透功能肽
<400> 24
Asn Arg Pro Asp Ser Ala Gln Phe Trp Leu His His Arg Arg Arg Gly
1 5 10 15
Gly Gly Gly Ser
20
Claims (17)
1.一种具有以下化学式1或化学式2的结构的PROTAC蛋白:
[化学式1]
PEP-[L1*(TB-L2-UR)n]m;
[化学式2]
在化学式1或化学式2中,
(i)PEP是抗体或抗体片段,或细胞穿透肽,
(ii)L1和L2是接头,L1和L2彼此相同或不同,并且L1与TB或L2结合,
(iii)TB是与靶蛋白结合的结合剂或缀合物,
(iv)UR是与泛素连接酶结合的配体,和
(iv)n和m各自独立地为1至10的整数。
2.根据权利要求1所述的PROTAC蛋白,其中,所述靶蛋白选自由突变的RAS超家族、激酶、转录因子和磷酸酶组成的组。
3.根据权利要求2所述的PROTAC蛋白,其中,所述RAS超家族选自由KRAS、HRAS和NRAS组成的组。
4.根据权利要求1所述的PROTAC蛋白,其中,所述TB选自由以下组成的组:突变的RAS超家族抑制剂、激酶抑制剂、磷酸酶抑制剂、热激蛋白90抑制剂、MDM2抑制剂、HDAC抑制剂、人赖氨酸甲基转移酶抑制剂、血管生成抑制剂、免疫抑制化合物、靶向人BET含溴结构域蛋白的化合物、靶向芳基烃受体的化合物、靶向EGF(上皮生长因子)受体激酶的化合物、靶向FKBP的化合物、靶向雄激素受体的化合物、靶向雌激素受体的化合物、靶向甲状腺激素受体的化合物、靶向HIV蛋白酶的化合物、靶向HIV整合酶的化合物、靶向HCV蛋白酶的化合物、靶向酰基蛋白硫酯酶-l的化合物的化合物和靶向酰基蛋白硫酯酶-2的化合物。
5.根据权利要求1所述的PROTAC蛋白,其中,所述TB是包括选自SEQID NO:7至SEQ IDNO:14中的任一氨基酸的肽。
6.根据权利要求1所述的PROTAC蛋白,其中,所述UR是与E3连接酶结合的配体,所述E3连接酶选自由XIAP、VHL蛋白、IAPs、cereblon和MDM2组成的组。
7.根据权利要求1所述的PROTAC蛋白,其中,所述抗体为与选自由以下组成的组的至少一种多肽结合的抗体或其片段:EGFR、DLL3、EDAR、CLL1、BMPR1B、E16、STEAP1、0772P、MPF、NaPi2b、Sema 5b、PSCA hlg、ETBR、MSG783、STEAP2、TrpM4、CRIPTO、CD21、CD79b、FcRH2、B7-H4、HER2、NCA、MDP、IL20Rct、brevican、EphB2R、ASLG659、PSCA、GEDA、BAFF-R、CD22、CD79a、CXCRS、HLA-DOB、P2X5、CD72、LY64、FcRH1、IRTA2、TENB2、PMEL17、TMEFF1、GDNF-Ra1、Ly6E、TMEM46、Ly6G6D、LGR5、RET、LY6K、GPR19、GPR54、ASPHD1、酪氨酸酶、TMEM118、GPR172A、MUC16和CD33。
8.根据权利要求7所述的PROTAC蛋白,其中,所述抗体是单克隆抗体或其变体。
9.根据权利要求8所述的PROTAC蛋白,其中,所述单克隆抗体选自由曲司珠单抗、西妥昔单抗、利妥昔单抗、维布妥昔单抗、吉妥珠单抗、伊组单抗、沙西妥珠单抗、阿仑珠单抗和尼妥组单抗组成的组。
10.一种核酸,其编码根据权利要求1所述的PROTAC蛋白质。
11.一种药物组合物,其包括根据权利要求1至9中任一项所述的PROTAC蛋白或根据权利要求10所述的核酸。
12.根据权利要求11所述的药物组合物,其中,用于治疗或预防癌症或炎性疾病。
13.根据权利要求12所述的药物组合物,其中,用于治疗或预防选自由以下组成的组的疾病:癌症、哮喘、自身免疫性疾病、类风湿性关节炎、多发性硬化症、睫状体疾病、腭裂、糖尿病、心脏病、高血压、炎性肠病、精神发育迟缓、情绪障碍、肥胖症、屈光不正、不育症、恩格尔曼综合症、卡纳万氏病、慢性消化系统疾病、恰克-马利-杜斯氏症、囊性纤维化、迪谢内肌营养不良、血色素沉积症、血友病、克兰费尔特综合征、神经纤维瘤病、苯丙酮尿症、常染色体显性多囊性肿瘤(PKD1或PKD2)、普拉德-威利综合征、镰状细胞贫血、泰-萨克斯病、特纳综合征、HIV感染疾病和HCV感染疾病。
14.根据权利要求12所述的药物组合物,其中,所述癌症选自由以下组成的组:鳞状细胞癌,基底细胞癌,腺癌,肝细胞癌,肾细胞癌,膀胱癌,肠癌,乳腺癌,宫颈癌,子宫癌,结肠癌,食道癌,头部癌,肾癌,肝癌,肺癌,卵巢癌,胰腺癌,前列腺癌,胃癌,白血病,良性和恶性淋巴瘤,良性和恶性黑色素瘤,骨髓增生性疾病,肉瘤,包括尤因肉瘤、血管肉瘤、卡波西肉瘤、脂肉瘤、肌瘤、神经上皮肉瘤、滑膜肉瘤、神经肉瘤、星形细胞瘤、少突胶质细胞瘤、室管膜瘤、胶质母细胞瘤、神经母细胞瘤、神经节细胞瘤、神经节细胞胶质瘤、髓母细胞瘤、松果体细胞瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和神经鞘瘤,睾丸癌,甲状腺癌,癌肉瘤,霍奇金病,维尔姆斯瘤和畸胎癌。
15.根据权利要求12所述的药物组合物,其中所述炎性疾病选自由关节炎、自身免疫性疾病、帕金森病、痴呆、肝炎和病毒感染组成的组。
16.根据权利要求12所述的药物组合物,其中,通过口服、肠胃外、吸入喷雾、局部、直肠、鼻或植入储器途径给药。
17.根据权利要求16所述的药物组合物,其中,在口服或胃肠外给药时,使用纳米颗粒或脂质体作为载体给药。
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