CN116056720A - 使用精胺酸酶治疗病毒感染的方法 - Google Patents
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Abstract
本发明提供的是关于精胺酸酶(例如,非聚乙二醇化精胺酸酶或聚乙二醇化精胺酸酶)在治疗病毒相关疾病或病症中的用途、精胺酸酶在治疗其他病原体相关疾病或病症中的用途,及包含精胺酸酶用于所述用途的试剂盒。
Description
相关申请
本申请要求2020年4月17日提交的美国临时专利申请号63/011,658的优先权及权益,出于所有目的其全部公开内容通过引用并入本文。
技术领域
本发明关于精胺酸酶(例如聚乙二醇化精胺酸酶)在治疗病毒相关疾病或病症中的用途、精胺酸酶(例如聚乙二醇化精胺酸酶)在治疗其他病原体相关疾病或病症中的用途,及包含用于所述用途的精胺酸酶(例如聚乙二醇化精胺酸酶)的试剂盒。
背景技术
尽管在治疗传染性疾病及病症中取得进展,但仍继续存在治疗挑战。举例而言,用于治疗的病原体可对治疗剂产生抗性。治疗抗性的发展频繁发生在抗生素抗性细菌的情形下(Blair等人,Molecular mechanisms of antibiotic resistance.Nat RevMicrobiol.2015年1月;13(1):42-51。)
此外,没有治疗可用于抑制所关注的病原体。在治疗多种类型的病毒的情形下,经常遭遇缺乏适合的治疗剂。病毒性疾病及病症的治疗由于缺乏可用的抗病毒疗法而尤其具有挑战性。
传染病,诸如由病毒感染引起的那些传染病,持续呈现显著的公共卫生风险。根据美国疾病控制及预防中心(U.S.Center for Disease Control and Prevention),2014年埃博拉病毒(Ebolavirus)爆发产生大约29,000个新病例,其中超过11,000例死亡。根据世界卫生组织(World Health Organization),截至2020年3月30日,由病毒SARS-CoV-2(COVID-19)在2019至2020年引起的冠状病毒大流行产生超过785,000例,且几乎有38,000例死亡。除潜在致死性病毒性疾病的感染风险以外,许多个体忍受慢性复发性病毒感染,诸如人乳头瘤病毒(HPV)或单纯疱疹病毒(HSV)。
因此,仍存在对用于传染性疾病及病症(包括与病毒相关的疾病及病症)的新的且有效的治疗的关键需求。亦需要有效针对多种病毒物种及病毒株的广谱抗病毒疗法。
发明内容
本文描述一种在治疗疾病或病症(例如病毒相关疾病或病症)中使用精胺酸酶(例如,非聚乙二醇化精胺酸酶或聚乙二醇化精胺酸酶)的方法。举例而言,本文描述一种治疗疾病或病症(例如,病毒相关疾病或病症)的方法,其中该方法包括施用治疗有效量的包含精胺酸酶(例如,非聚乙二醇化精胺酸酶或聚乙二醇化精胺酸酶)或其药学上可接受的盐的组合物。在一些实施方案中,该方法包括向患者(例如需要治疗的患者)施用治疗有效量的所述组合物。
在一些实施方案中,所述精胺酸酶(例如,非聚乙二醇化或聚乙二醇化精胺酸酶)或其药学上可接受的盐或包含所述精胺酸酶的组合物有效抑制病毒的基因组复制。在一些实施方案中,所述精胺酸酶或包含所述精胺酸酶或其药学上可接受的盐的组合物有效抑制病毒的传播。在一些实施方案中,所述精胺酸酶或其药学上可接受的盐或包含所述精胺酸酶的组合物有效抑制病毒基因表达。在一些实施方案中,所述精胺酸酶或其药学上可接受的盐或包含所述精胺酸酶的组合物有效抑制病毒的组装。本文还描述了含有精胺酸酶或其药学上可接受的盐,或包含精胺酸酶或其药学上可接受的盐的组合物的试剂盒。
尽管对于哺乳动物细胞中的过程(诸如细胞增殖及生长)至关重要,但氨基酸精氨酸由于代谢瓜胺酸得到精氨酸池的能力而被视为人类中的非必需氨基酸(Hecker等人(1990)Proc.Natl.Acad.Sci.USA.87(21):8612-6)。相比之下,许多病毒依赖于外源精氨酸以用于蛋白质合成(US 9,011,845B2)。本发明人已发现精氨酸酶及聚乙二醇化精氨酸酶有效耗尽精氨酸含量且呈现治疗病毒感染的出人意料的机制,具有靶向广谱病毒的能力。另外,本发明人已发现,通过非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶的精氨酸耗尽提供治疗先前未遇到的病毒或当前未存在经批准的治疗剂的病毒(诸如SARS-CoV-2(COVID-19))的方法。
本文描述一种治疗疾病或病症(例如,病毒相关疾病或病症)的方法,其中该方法包括施用治疗有效量的包含精氨酸酶(例如,非聚乙二醇化或聚乙二醇化精氨酸酶)或其药学上可接受的盐的组合物至需要其的患者。在本文所描述的一些实施方案中,聚乙二醇化精氨酸酶包含与精氨酸酶序列结合的聚至少一个乙二醇(PEG)分子。
在一些实施方案中,精氨酸酶与SEQ ID NO:1-41的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶与选自由SEQ ID NO:3-41组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶与SEQ IDNO:1或2的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶包含选自由SEQ ID NO:1-41组成的组的蛋白质序列。在一些实施方案中,精氨酸酶包含选自由SEQ ID NO:3-41组成的组的蛋白质序列。在一些实施方案中,精氨酸酶包含SEQ IDNO:1或2的蛋白质序列。
因此,在本文所描述的一些实施方案中,该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中所述精氨酸酶:与SEQ ID NO:1-41的蛋白质序列或其片段具有至少约90%序列同一性;与选自由SEQ ID NO:3-41组成的组的蛋白质序列或其片段具有至少约90%序列同一性;与SEQ ID NO:1或2的蛋白质序列或其片段具有至少约90%序列同一性;包含选自由SEQ ID NO:1-41组成的组的蛋白质序列;包含选自由SEQ ID NO:3-41组成的组的蛋白质序列;或包含SEQ ID NO:1或2的蛋白质序列。
因此,在一个方面,本发明提供治疗病毒相关疾病或病症的方法,该方法包含向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中非聚乙二醇化或聚乙二醇化精氨酸酶与SEQ ID NO:1或2或其片段具有至少约90%序列同一性,且其中病毒相关疾病或病症与选自由以下组成的组的病毒相关:冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施例中,病毒相关疾病或病症为病毒感染。举例而言,在一些实施方案中,病毒相关疾病或病症为选自由以下组成的组的病毒感染:冠状病毒感染、乳头瘤病毒感染、肺病毒感染、小核糖核酸病毒感染、黄病毒感染、甲病毒感染、埃博拉病毒感染、麻疹病毒感染、肠病毒感染、正肺病毒感染、慢病毒感染及肝病毒感染。
在另一方面,本发明提供一种治疗病毒相关疾病或病症的方法,该方法包含向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中非聚乙二醇化或聚乙二醇化精氨酸酶与选自由SEQ ID NO:3-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,病毒相关疾病或病症与选自由以下组成的组的病毒相关:RNA病毒、DNA病毒、冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、流感病毒、腺病毒、巨细胞病毒、多瘤病毒、痘病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。在一些实施方案中,病毒相关疾病或病症为病毒感染。举例而言,在一些实施方案中,病毒相关疾病或病症为选自由以下组成的组的病毒感染:RNA病毒感染、DNA病毒感染、冠状病毒感染、乳头瘤病毒感染、肺病毒感染、小核糖核酸病毒感染、流感病毒感染、腺病毒感染、巨细胞病毒感染、多瘤病毒感染、痘病毒感染、黄病毒感染、甲病毒感染、埃博拉病毒感染、麻疹病毒感染、肠病毒感染、正肺病毒感染、慢病毒感染及肝病毒感染。
在一些实施方案中,病毒相关疾病或病症局限于或影响患者的器官或组织。在一些实施方案中,病毒相关疾病或病症包含患者的器官或组织的病毒感染。在某些实施方案中,器官或组织可以为(但不限于)眼、耳、内耳、肺、气管、支气管、细支气管、肝脏、胆囊、胆管、肾脏、膀胱、睾丸、子宫颈、卵巢、子宫、皮肤或脑。举例而言,在某些实施方案中,器官或组织是选自由以下组成的组:眼、耳、内耳、肺、气管、支气管、细支气管、肝脏、胆囊、胆管、肾脏、膀胱、睾丸、子宫颈、卵巢、子宫、皮肤及脑。
在一些实施方案中,病毒相关疾病或病症可以为(但不限于):急性呼吸窘迫综合征;慢性阻塞性肺病(COPD);肺炎;抗药性肺炎;手足口病;变应性哮喘;或非变应性哮喘。在一些实施方案中,病毒相关疾病或病症是选自由以下组成的组:急性呼吸窘迫综合征;COPD;肺炎;抗药性肺炎;手足口病;变应性哮喘;及非变应性哮喘。
在各种实施方案中,本文公开一种抑制病毒基因组复制的方法、一种抑制病毒传播的方法、一种抑制病毒组装的方法、一种抑制病毒基因表现的方法及一种抑制病毒释放的方法。前述方法可以包括向有需要的患者施用治疗有效量的包含精氨酸酶(例如,包含SEQ ID NO:1或2的氨基酸序列的精氨酸酶或包含选自由SEQ ID NO:3-50及56组成的组的氨基酸序列的精氨酸酶)或其药学上可接受的盐的组合物。举例而言,本文提供一种抑制病毒的基因组复制的方法,该方法包含向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,所述精氨酸酶包含SEQ ID NO:1或2的氨基酸序列,其中所述精氨酸酶与SEQ ID NO:1或2或其片段具有至少约90%序列同一性,且其中病毒选自由以下组成的组:冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。在一些实施方案中,所述精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。
在另一方面,本文提供一种抑制病毒的基因组复制的方法,该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中所述精氨酸酶与选自由SEQ ID NO:3-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,病毒选自由以下组成的组:RNA病毒、DNA病毒、冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、流感病毒、腺病毒、巨细胞病毒、多瘤病毒、痘病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
在另一方面,本文提供一种抑制病毒传播的方法,该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,且其中精氨酸酶与包含SEQ ID NO:1或2的精氨酸酶氨基酸序列的蛋白质序列具有至少约90%序列同一性,其中病毒选自由以下组成的组:冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。
在另一方面,本文提供一种抑制病毒传播的方法,该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,且其中精氨酸酶与选自由SEQ ID NO:3-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,病毒选自由以下组成的组:RNA病毒、DNA病毒、冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、流感病毒、腺病毒、巨细胞病毒、多瘤病毒、痘病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
在另一方面,本文提供一种抑制病毒组装的方法,该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中精氨酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。
在另方面,本文提供一种抑制病毒基因表达的方法,该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中精氨酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,抑制包括抑制特定组的基因的基因表达。举例而言,在一些实施方案中,抑制包括抑制β基因表达、γ基因表达、或β基因表达及γ基因表达。
在另一方面,本文提供一种抑制病毒释放的方法,该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中精氨酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,病毒选自由以下组成的组:RNA病毒、DNA病毒、冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、流感病毒、腺病毒、巨细胞病毒、多瘤病毒、痘病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
在本文所描述的一些实施方案中,治疗病毒相关疾病或病症的方法包括一种治疗与冠状病毒相关的病毒相关疾病或病症的方法。本文亦描述一种抑制病毒基因组复制的方法、一种抑制病毒传播的方法、一种抑制病毒组装的方法、一种抑制病毒基因表达的方法及一种抑制病毒释放的方法,其中病毒为冠状病毒。在某些实施方案中,冠状病毒选自由以下组成的组:229Eα冠状病毒、NL63α冠状病毒、OC43β冠状病毒、HKU1β冠状病毒、中东呼吸综合征(Middle East Respiratory Syndrome,MERS)冠状病毒(MERS-CoV)、严重急性呼吸综合征(SARS)冠状病毒(SARS-CoV)及SARS-CoV-2(COVID-19)。
在本文所描述的一些实施方案中,治疗病毒相关疾病或病症的方法包括一种治疗与流感病毒相关的病毒相关疾病或病症的方法。本文亦描述一种抑制病毒基因组复制的方法、一种抑制病毒传播的方法、一种抑制病毒组装的方法、一种抑制病毒基因表达的方法及一种抑制病毒释放的方法,其中病毒为流感病毒。在某些实施方案中,流感病毒选自由以下组成的组:流感病毒A(例如,H1N1及H5N1)、流感病毒B、流感病毒C、流感病毒D。
在本文所描述的一些实施方案中,治疗病毒相关疾病或病症的方法包括一种治疗与腺病毒相关的病毒相关疾病或病症的方法。本文亦描述一种抑制病毒基因组复制的方法、一种抑制病毒传播的方法、一种抑制病毒组装的方法、一种抑制病毒基因表达的方法及一种抑制病毒释放的方法,其中病毒为腺病毒。在某些实施方案中,腺病毒为AdV5。
在本文所描述的一些实施方案中,病毒为抗药性病毒。
在一些实施方案中,本文所描述的方法进一步包括施用包含抗病毒剂的组合物。在一些实施方案中,施用包括施用治疗有效量的包含抗病毒剂的组合物。在一些实施方案中,向患者,例如需要治疗的患者施用包含抗病毒剂的组合物。在一些实施方案中,抗病毒剂选自由以下组成的组:拉米夫定(lamivudine)、干扰素α组合物(例如干扰素α(INN;HuIFN-α-Le))、VAP抗独特型抗体、恩夫韦地(enfuvirtide)、金刚烷胺(amantadine)、金刚乙胺(rimantadine)、普拉康那利(pleconaril)、阿昔洛韦(aciclovir)、齐多夫定(zidovudine)、福米韦生(fomivirsen)、吗啉基、蛋白酶抑制剂、双链RNA激活的细胞凋亡蛋白酶聚合体(DRACO)、利福平(Rifampicin)、扎那米韦(zanamivir)、帕拉米韦(peramivir)、丹诺普韦(danoprevir)、利托那韦(ritonavir)、瑞德西韦(remdesivir)及奥司他韦(oseltamivir)。在某些实施方案中,待治疗的病毒为流感病毒,且组合物包含扎那米韦。在某些实施方案中,待治疗的病毒为肝炎病毒,例如乙型肝炎病毒,且组合物包含拉米夫定。在某些实施方案中,在施用精氨酸酶之前、期间或之后施用抗病毒剂。举例而言,本文描述一种治疗疾病或病症(例如,病毒相关疾病或病症)的方法,其中该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶(例如,聚乙二醇化精氨酸酶)或其药学上可接受的盐的组合物,且该方法进一步包括施用(例如,向有需要的患者施用)包含抗病毒剂(例如,治疗有效量的包含抗病毒剂的组合物)的组合物。
本文亦描述一种抑制病毒的基因组复制的方法、一种抑制病毒传播的方法、一种抑制病毒组装的方法、一种抑制病毒基因表达的方法及一种抑制病毒释放的方法,其中所描述的方法包括向患者(例如有需要的患者)施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,且该方法进一步包括施用(例如,向有需要的患者施用)包含抗病毒剂(例如治疗有效量的包含抗病毒剂的组合物)的组合物。
在另一方面,本文提供一种治疗细菌疾病或病症的方法,该方法包括向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,该精氨酸酶选自由SEQ ID NO:1或2组成的组,其中该精氨酸酶与SEQ ID NO:1或2或其片段具有至少约90%序列同一性,且其中所述细菌疾病或病症与选自由以下组成的组的细菌相关:肺炎链球菌(Streptococcus pneumoniae)、肺炎支原体(Mycoplasma pneumoniae)、流感嗜血杆菌(Haemophilus influenzae)、嗜肺军团菌(Legionella pneumophila)、肠道沙门氏菌(Salmonella enterica)、邦戈尔沙门氏菌(Salmonella bongori)、大肠杆菌(Escherichiacoli)、幽门螺旋杆菌(Helicobacter pylori)、淋病双球菌(Neisseria gonorrhoeae)、脑膜炎双球菌(Neisseria meningitidis)、金黄色葡萄球菌(Staphylococcus aureus)、鲍曼氏不动杆菌(Acinetobacter baumannii)、伯克霍尔德菌(Burkholderia cepacian)、艰难梭菌(Clostridium difficile)、索氏梭菌(Clostridium sordellii)、肠杆菌科(Enterobacteriaceae)、粪肠球菌(Enterococcus faecalis)、肺炎克雷伯氏菌(Klebsiella pneumoniae)、摩氏摩根菌(Morganella morganii)、脓肿分枝杆菌(Mycobacterium abscessus)、结核分支杆菌(Mycobacterium tuberculosis)、诺如病毒(Norovirus)、铜绿假单胞菌(Psuedomonas aeruginosa)及嗜麦芽窄食单胞菌(Stenotrophomonas maltophilia)。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。
在另一方面,本文提供一种治疗细菌疾病或病症的方法,该方法包含向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中该精氨酸酶与选自由SEQ ID NO:3-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,细菌疾病或病症与选自由以下组成的组的细菌相关:肺炎衣原体(Chlamydia pneumoniae)、霍乱弧菌(Vibrio cholerae)、肺炎链球菌、肺炎支原体、流感嗜血杆菌、嗜肺军团菌、肠道沙门氏菌、邦戈尔沙门氏菌、大肠杆菌、幽门螺旋杆菌、淋病双球菌、脑膜炎双球菌、金黄色葡萄球菌、鲍曼氏不动杆菌、伯克霍尔德菌、艰难梭菌、索氏梭菌、肠杆菌科、粪肠球菌、肺炎克雷伯氏菌、摩氏摩根菌、脓肿分枝杆菌、结核分支杆菌、诺如病毒、铜绿假单胞菌及嗜麦芽窄食单胞菌。
在另一方面,本文提供一种治疗真菌疾病或病症的方法,该方法包含向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中该精氨酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,真菌疾病与选自由以下组成的组的真菌相关:肺囊虫属真菌(Pneumocystis fungus)、曲霉属真菌(Aspergillus fungus)及念珠菌属真菌(Candidafungus)。
在另一方面,本文提供一种治疗阿米巴原虫疾病或病症的方法,该方法包含向有需要的患者施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,其中该精氨酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,阿米巴原虫疾病或病症与选自由以下组成的组的阿米巴原虫相关:脆弱双核阿米巴(Dientamoeba fragilis)、溶组织内阿米巴(Entamoeba histolytica)、变形纤毛虫(Naegleria fowleri)、棘变形虫属(Acanthamoeba)、棘阿米巴角膜炎(Acanthamoeba keratitis)、巴氏阿米巴(Balamuthiamandrillaris)及双核匀变阿米巴(Sappinia diploidea)。
在一些实施方案中,精氨酸酶以每天每公斤体重约1ng至每天每公斤体重约1mg的剂量施用。
在一些实施方案中,施用为局部、非经肠、经口、经肺、气管内、鼻内、鞘内、经皮、皮下、眼内、玻璃体内、腹膜内或十二指肠内施用。剂量可包括或基本上由约1ng/kg至1mg/kg如本文所描述的精氨酸酶或其药学上可接受的盐组成。
在一些实施方案中,精氨酸酶包含包括蛋白质标签序列的氨基酸序列。举例而言,在一些实施例中,精氨酸酶包含SEQ ID NO:1-43的氨基酸序列及蛋白质标签序列。在一些实施例中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在某些实施方案中,蛋白质标签序列为SEQ ID NO:51的6xHis标签序列。在某些实施方案中,蛋白质标签序列位于精氨酸酶的氨基末端处。在某些实施方案中,蛋白质标签序列位于精氨酸酶的羧基末端处。
在一些实施方案中,聚乙二醇化精氨酸酶包含2、3、4或更多个与精氨酸酶序列结合的聚乙二醇分子。在一些实施方案中,聚乙二醇分子为约5kDa、约10kDa、约15kDa、约20kDa、约30kDa或约40kDa。在某些实施方案中,聚乙二醇为约10kDa至约30kDa或约20kDa至约40kDa。
在一些实施方案中,组合物进一步包含非天然金属辅因子。在某些实施方案中,非天然金属辅因子是选自由钴、锰、铁及锌组成的组。
在另一方面,本发明提供一种组合物,其包含:
精氨酸酶或其药学上可接受的盐,其中该精氨酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性;
抗病毒剂;及
药学上可接受的赋形剂。
在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,包含于本文所公开的组合物中的抗病毒剂选自由以下组成的组:拉米夫定、干扰素α组合物(例如干扰素α(INN;HuIFN-α-Le))、VAP抗独特型抗体、恩夫韦地、金刚烷胺、金刚乙胺、普拉康那利、阿昔洛韦、齐多夫定、福米韦生、吗啉基、蛋白酶抑制剂、双链RNA激活的细胞凋亡蛋白酶聚合体(DRACO)、利福平、扎那米韦、帕拉米韦、丹诺普韦、利托那韦、瑞德西韦及奥司他韦。
在一些实施方案中,包含于本文所公开的组合物中的精氨酸酶包括蛋白质标签序列。在一些实施方案中,蛋白质标签序列为SEQ ID NO:51的6xHis标签序列。在某些实施方案中,蛋白质标签序列位于精氨酸酶的氨基末端处。在某些实施方案中,其中蛋白质标签序列位于精氨酸酶的羧基末端处。
在一些实施方案中,包含于本文所公开的组合物中的聚乙二醇化精氨酸酶包含2、3、4或更多个与精氨酸酶序列结合的聚乙二醇分子。在一些实施方案中,聚乙二醇分子为约5kDa、约10kDa、约15kDa、约20kDa、约30kDa或约40kDa。在某些实施方案中,聚乙二醇分子为约10kDa至约30kDa或约20kDa至约40kDa。
在一些实施方案中,本文所描述的组合物进一步包含非天然金属辅因子。在某些实施方案中,非天然金属辅因子选自由钴、锰、铁及锌组成的组。
在另一方面,本文提供一种试剂盒,其包含:
精氨酸酶或其药学上可接受的盐,其中该精氨酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性;及
用于抑制病毒产生的缓冲剂、试剂及详细说明书。
在一些实施方案中,精氨酸酶为包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶。在一些实施方案中,试剂盒进一步包含抗病毒剂。在某些实施方案中,抗病毒剂选自由以下组成的组:拉米夫定、干扰素α组合物(例如干扰素α(INN;HuIFN-α-Le))、VAP抗独特型抗体、恩夫韦地、金刚烷胺、金刚乙胺、普拉康那利、阿昔洛韦、齐多夫定、福米韦生、吗啉基、蛋白酶抑制剂、双链RNA激活的细胞凋亡蛋白酶聚合体(DRACO)、利福平、扎那米韦、帕拉米韦、丹诺普韦、利托那韦、瑞德西韦及奥司他韦。
在一些实施方案中,试剂盒用于抑制冠状病毒产生。在某些实施方案中,冠状病毒选自由以下组成的组:229Eα冠状病毒、NL63α冠状病毒、OC43β冠状病毒、HKU1β冠状病毒、中东呼吸综合征(MERS)冠状病毒(MERS-CoV)、严重急性呼吸综合征(SARS)冠状病毒(SARS-CoV)及SARS-CoV-2(COVID-19)。
在一些实施方案中,包括于本文所描述的试剂盒中的精氨酸酶包括蛋白质标签序列。在某些实施方案中,蛋白质标签序列为SEQ ID NO:51的6xHis标签序列。在某些实施方案中,蛋白质标签序列位于精氨酸酶的氨基末端处。在某些实施方案中,蛋白质标签序列位于精氨酸酶的羧基末端处。
在一些实施方案中,包括于本文所描述的试剂盒中的聚乙二醇化精氨酸酶包含2、3、4或更多个与精氨酸酶序列结合的聚乙二醇分子。在一些实施方案中,聚乙二醇为约5kDa、约10kDa、约15kDa、约20kDa、约30kDa或约40kDa。在某些实施方案中,聚乙二醇为约10kDa至约30kDa或约20kDa至约40kDa。
在一些实施方案中,本文所描述的试剂盒进一步包含非天然金属辅因子。在某些实施方案中,非天然金属辅因子选自由钴、锰、铁及锌组成的组。
附图说明
图1描绘展示聚乙二醇化精氨酸酶对SARS-CoV的复制的剂量依赖性抑制作用的图。在邓尼特(Dunnett's)测试中,“*”及“**”分别表示p<0.05及0.01。
图2描绘展示聚乙二醇化精氨酸酶对SARS-CoV-2的复制的剂量依赖性抑制作用的图。在邓尼特测试中,“*”表示p<0.05。
图3描绘展示非聚乙二醇化精氨酸酶及聚乙二醇化精氨酸酶对MERS-CoV的复制的抑制作用的图。“%抑制”计算为(1-C「精氨酸酶」/C0)×100%,其中C[精氨酸酶]及C0分别为在用特定浓度的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶处理和无精氨酸酶处理后,培养物上清液中的病毒基因组复本数。各点表示一个独立量测。灰色曲线表示最佳拟合的双参数逻辑模型。
图4描绘展示非聚乙二醇化精氨酸酶及聚乙二醇化精氨酸酶对H1N1流感病毒A(大流行性H1N1/09)的复制的抑制作用的图。“%抑制”计算为(1-C「精氨酸酶」/C0)×100%,其中C[精氨酸酶]及C0分别为在用特定浓度的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶处理和无精氨酸酶处理后,培养物上清液中的病毒基因组复本数。各点表示一个独立量测。灰色曲线表示最佳拟合的双参数逻辑模型。
图5描绘展示聚乙二醇化精氨酸酶对H5N1流感病毒A(A/越南(Vietnam)/2013/04)的复制的剂量依赖性抑制作用的图。在邓尼特测试中,“***”表示p<0.001。
图6描绘展示非聚乙二醇化精氨酸酶及聚乙二醇化精氨酸酶对人腺病毒血清型5的复制的抑制作用的图。“%抑制”计算为(1-C「精氨酸酶」/C0)×100%,其中C[精氨酸酶]及C0分别为在用特定浓度的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶处理和无精氨酸酶处理后,培养物上清液中的病毒基因组复本数。各点表示一个独立量测。灰色曲线表示最佳拟合的双参数逻辑模型。
下文进一步详细描述本发明的各个方面及实施方案。
具体实施方式
本发明提供一种使用聚乙二醇化精氨酸酶治疗疾病及病症,例如病毒相关疾病及病症的方法。
除非上下文不当,否则如本文所使用,术语“一(a及an)”意谓“一或多个”且包括复数。
如本文所使用,术语“聚乙二醇化精氨酸酶”意谓通过至少一个聚乙二醇(PEG)分子的结合而修饰的精氨酸酶蛋白质序列,且术语“非聚乙二醇化精氨酸酶”意谓不具有与其结合的PEG分子的精氨酸酶蛋白质序列。在不受理论束缚的情况下,相信PEG与蛋白质(例如精氨酸酶)结合增加蛋白质稳定性、增加蛋白质循环时间且使免疫反应性最小化。如本文所使用的“聚乙二醇化”是指使PEG的一或多个分子与氨基酸,例如蛋白质或肽(例如精氨酸酶蛋白质)的氨基酸结合的过程。聚乙二醇化可以经由PEG共价或非共价连接至所关注化合物来达成。较佳地,聚乙二醇化经由共价PEG连接达成。聚乙二醇化可以例如经由PEG与氨基结合、硫醇结合、碳水化合物氧化、N末端氨基酸结合或转谷氨酰胺酶介导的酶结合来达成。聚乙二醇化方法为本领域中已知且描述于例如Fee及Babu(2010)“Protein PEGylation:Anoverview of chemistry and process considerations”,European PharmaceuticalReview,1:1-24。经历聚乙二醇化的蛋白质、肽及氨基酸在本文中称为“聚乙二醇化”蛋白质、肽及氨基酸。
在一些实施方案中,精氨酸酶为人精氨酸酶,例如包含SEQ ID NO:1的氨基酸序列的重组人精氨酸酶I。在一些实施方案中,精氨酸酶包含人精氨酸酶I的催化结构域,其包含SEQ ID NO:2的氨基酸序列。在一些实施方案中,聚乙二醇化精氨酸酶具有至少一个与精氨酸酶的氨基酸残基或与超过一个氨基酸残基共价连接的聚乙二醇(PEG)分子。在一些实施方案中,至少一个PEG分子与精氨酸酶的赖氨酸残基或与超过一个赖氨酸残基共价连接。在一些实施方案中,至少一个PEG分子与精氨酸酶的半胱氨酸残基或与超过一个半胱氨酸残基共价连接。在一些实施方案中,至少一个PEG分子与一或多个赖氨酸残基、一或多个半胱氨酸残基、一或多个组氨酸残基、一或多个精氨酸残基、一或多个天冬氨酸残基、一或多个谷氨酸残基、一或多个丝氨酸残基、一或多个苏氨酸残基、一或多个酪氨酸残基、氨基(N-)末端氨基或羧基(C-)末端羧酸基共价连接。在一些实施方案中,PEG的分子量为约5KDa、约10kDa、约15kDa、约20kDa、约30kDa或约40kDa。在一些实施方案中,PEG的分子量为约10kDa至约30kDa或约20kDa至约40kDa。
在一些实施方案中,精氨酸酶的聚乙二醇化通过使用偶合剂使PEG分子与精氨酸酶共价结合来达成。偶合剂的实例包括(但不限于)甲氧基聚乙二醇-琥珀酰亚胺基丙酸酯(mPEG-SPA)、mPEG-琥珀酰亚胺基丁酸酯(mPEG-SBA)、mPEG-琥珀酰亚胺基琥珀酸酯(mPEG-SS)、mPEG-琥珀酰亚胺基碳酸酯(mPEG-SC)、mPEG-琥珀酰亚胺戊二酸酯(mPEG-SG)、mPEG-N-羟基-琥珀酰亚胺(mPEG-NHS)、mPEG-三氟乙基磺酸酯及mPEG-醛。在一些实施方案中,偶合剂为平均分子量为5000的甲氧基聚乙二醇-琥珀酰亚胺基丙酸酯5000。
在一些实施方案中,本申请中所公开的聚乙二醇化精氨酸酶包括重组人精氨酸酶,例如重组人精氨酸酶I,其中重组人精氨酸酶I具有至少一个与重组人精氨酸酶I的氨基酸残基或与超过一个氨基酸残基共价连接的PEG分子。在一些实施方案中,聚乙二醇化精氨酸酶(例如聚乙二醇化重组人精氨酸酶I)具有每精氨酸酶约6-12个PEG分子。在一些实施方案中,PEG分子与聚乙二醇化精氨酸酶(例如聚乙二醇化重组人精氨酸酶I)的赖氨酸残基或与超过一个赖氨酸残基共价连接。在一些实施方案中,PEG分子与聚乙二醇化精氨酸酶(例如聚乙二醇化重组人精氨酸酶I)的半胱氨酸残基或与超过一个半胱氨酸残基共价连接。在一些实施方案中,PEG分子与聚乙二醇化精氨酸酶(例如聚乙二醇化重组人精氨酸酶I)的一或多个赖氨酸残基、一或多个半胱氨酸残基、一或多个组氨酸残基、一或多个精氨酸残基、一或多个天冬氨酸残基、一或多个谷氨酸残基、一或多个丝氨酸残基、一或多个苏氨酸残基、一或多个酪氨酸残基、氨基(N-)末端氨基或羧基(C-)末端羧酸基共价连接。
在一些实施方案中,本文所描述的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)包括末端蛋白质序列(例如,N末端或C末端蛋白质序列)。可以添加末端蛋白质序列,例如以便于蛋白质纯化或蛋白质识别。适合的末端蛋白质序列的实例包括但不限于6×组氨酸(6×His)标签(SEQ ID NO:51)、Flag标签(SEQ ID NO:52)、V5标签(SEQ IDNO:53)、Myc标签(SEQ ID NO:54)及红细胞凝集素(HA)标签(SEQ ID NO:55)。在一些实施方案中,本文所描述的聚乙二醇化精氨酸酶(例如本文所描述的聚乙二醇化重组人精氨酸酶)包括重组精氨酸酶,其中重组精氨酸酶在其氨基末端处具有六个额外组氨酸残基,及至少一个与重组精氨酸酶的氨基酸残基或与超过一个氨基酸残基共价连接的PEG分子。在一些实施方案中,重组精氨酸酶每精氨酸酶具有约6-12个PEG分子。在一些实施方案中,PEG分子与重组精氨酸酶的赖氨酸残基或与超过一个赖氨酸残基共价连接。在一些实施方案中,本文所描述的聚乙二醇化精氨酸酶(例如本文所描述的聚乙二醇化重组人精氨酸酶)包括重组精氨酸酶,其中重组精氨酸酶在其氨基末端处具有6xHis标签、Flag标签、V5标签、Myc标签或HA标签,及至少一个与重组精氨酸酶的氨基酸残基或与超过一个氨基酸残基共价连接的PEG分子。在一些实施方案中,本文所描述的聚乙二醇化精氨酸酶(例如本文所描述的聚乙二醇化重组人精氨酸酶)包括重组精氨酸酶,其中重组精氨酸酶在其羧基末端处具有6xHis标签、Flag标签、V5标签、Myc标签或HA标签,及至少一个与重组精氨酸酶的氨基酸残基或与超过一个氨基酸残基共价连接的PEG分子。
在一些实施方案中,本文所描述的聚乙二醇化精氨酸酶(例如本文所描述的聚乙二醇化重组人精氨酸酶I)包括重组精氨酸酶I,其中重组精氨酸酶在其氨基末端处具有6xHis标签,及至少一个与重组人精氨酸酶I的氨基酸残基或与超过一个氨基酸残基共价连接的PEG分子。在一些实施方案中,重组人精氨酸酶I每精氨酸酶具有约6-12个PEG分子。在一些实施方案中,PEG分子与重组人精氨酸酶I的赖氨酸残基或与超过一个赖氨酸残基共价连接。在一些实施方案中,本文所描述的聚乙二醇化重组人精氨酸酶I包括在其氨基末端处的6xHis标签、Flag标签、V5标签、Myc标签或HA标签,及至少一个与重组人精氨酸酶I的氨基酸残基或与超过一个氨基酸残基共价连接的PEG分子。在一些实施方案中,本文所描述的聚乙二醇化重组人精氨酸酶I在其羧基末端处具有6xHis标签、Flag标签、V5标签、Myc标签或HA标签,及至少一个与重组人精氨酸酶I的氨基酸残基或与超过一个氨基酸残基共价连接的PEG分子。
如本文所使用,术语“抗药性病原体”意谓病原体,例如病毒,其已产生抵抗治疗剂(例如抗病毒治疗剂)的作用的能力,该治疗剂能够在病原体产生使得其对用该治疗剂的治疗具有抗性的一些特征(例如基因突变)之前对该病原体进行治疗。在一些实施方案中,抗药性病原体为抗药性病毒。在一些实施方案中,抗药性病原体为抗药性细菌。在一些实施方案中,抗药性病原体为抗药性真菌。在一些实施方案中,抗药性病原体为抗药性阿米巴原虫。
如本文所使用,术语“疾病或病症”意谓任何病理病况,包括但不限于由病原体引起的那些。在一些实施方案中,疾病或病症为病毒疾病或病症,亦即,由病毒引起。在一些实施方案中,疾病或病症是与特定病原体或病原体类型相关。在特定实施方案中,与特定病原体或病原体类型相关的疾病或病症为由特定病原体或病原体类型引起的疾病或病症。举例而言,病毒疾病或病症可以与特定病毒(例如SARS-CoV-2)或特定组的病毒(例如特定病毒属,例如冠状病毒)相关。类似地,细菌疾病或病症可以与特定细菌或特定组的细菌相关;真菌疾病或病症可以与特定真菌或特定组的真菌相关;且阿米巴原虫疾病或病症可以与特定阿米巴原虫或特定组的阿米巴原虫相关。
如本文所使用,术语“感染”意谓通常不存在于宿主(例如患者)内的病原体(例如病毒)的侵入及增殖。感染可不引起症状且为亚临床的,或其可引起症状且在临床上明显。感染可保持局部化,或其可例如通过血液或淋巴管扩散,从而变为全身性。
如本文所使用,术语“预防”是指经设计且用于预防疾病或病症发生的药物或治疗。
如本文所使用,术语“治疗(treat/treatment/treating)”及其类似词在本文中用于一般意谓获得期望的药理学和/或生理学作用。该效果就完全或部分预防疾病或其症状而言可以是预防性的,和/或就部分或完全治愈疾病和/或可归因于该疾病的不良影响而言可以是治疗性的。如本文所使用的术语“治疗”涵盖哺乳动物,尤其人的疾病的任何治疗,且包括:(a)预防疾病在可能易患该疾病但尚未诊断出患有该疾病的个体中发生;(b)抑制疾病,即预防疾病的严重程度或范围增加;(c)减轻疾病,即引起疾病的部分或完全改善;或(d)预防疾病复发,即在该疾病的症状的先前成功治疗或该疾病的治疗之后预防该疾病返回至活动状态。
“个人”、“患者”或“个体”在本文中可互换使用且包括任何动物,例如哺乳动物,例如小鼠、大鼠、其他啮齿动物、兔、狗、猫、猪、牛、绵羊、马或灵长类动物,且最佳为人。本文所揭示的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶化合物及其组合物可以施用至哺乳动物,诸如人。本文所揭示的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶化合物可以施用至其他哺乳动物,诸如需要兽医治疗的动物,例如家畜(例如狗、猫及其类似动物)、农畜(例如牛、绵羊、猪、马及其类似动物)及实验室动物(例如大鼠、小鼠、天竺鼠及其类似动物)。患者可为诊断具有罹患疾病或病症(例如传染性疾病或病症)的高风险的个体(例如免疫功能不全个体),已诊断患有疾病或病症(例如传染性疾病或病症)的某人,先前罹患疾病或病症(例如传染性疾病或病症)的某人,或针对疾病或病症(例如传染性疾病或病症)的症状或适应症评估的个体。
如本文所使用的术语“有需要的患者”是指罹患疾病或病症(例如传染性疾病或病症)的任一症状或表现的患者、可罹患疾病或病症(例如传染性疾病或病症)的任一症状或表现的患者或可能受益于本发明用于治疗或预防疾病或病症(例如传染性疾病或病症)的方法的任何患者。有需要的患者可包括经诊断具有罹患疾病或病症(例如传染性疾病或病症)的风险的患者、过去已罹患疾病或病症(例如传染性疾病或病症)的患者或先前已针对疾病或病症(例如传染性疾病或病症)进行治疗的患者。
如本文所使用,术语“药学上可接受的组合物”意谓包含至少一种与一或多种药学上可接受的载体一起配制的化合物(例如本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)的组合物。
如本文所使用,术语“药学上可接受的盐”是指可存在于本发明组合物中使用的化合物(例如精氨酸酶化合物(例如非聚乙二醇化或聚乙二醇化精氨酸酶化合物))中的酸性或碱性基团的盐。本质上呈碱性的本发明组合物中所包括的化合物能够与各种无机酸及有机酸形成广泛多种盐。可用以制备此类碱性化合物的药学上可接受的酸加成盐的酸为形成无毒酸加成盐的那些酸,所述酸加成盐即含有药理学上可接受的阴离子的盐,包括(但不限于)苹果酸盐、草酸盐、氯化物盐、溴化物盐、碘盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、丁二酸盐、顺丁烯二酸盐、龙胆酸盐、反丁烯二酸盐、葡糖酸盐、葡糖醛酸盐、葡糖二酸盐(saccharate)、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐及双羟萘酸盐(即1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))。包括氨基部分的本发明组合物中所包括的化合物可与各种氨基酸(除上文所提及的酸的外)形成药学上可接受的盐。本发明组合物中所包括的本质上呈酸性的化合物能够与各种药理学上可接受的阳离子形成碱盐。此类盐的实例包括碱金属盐或碱土金属盐,尤其钙盐、镁盐、钠盐、锂盐、锌盐、钾盐及铁盐。
如本文所使用,术语“药学上可接受的赋形剂”意谓辅助向个体施用活性剂和/或由个体吸收的物质,且可以包括于本发明的组合物中而不会对患者产生显著的不良毒理学作用。药学上可接受的赋形剂的非限制性实例包括水、NaCl、生理盐水溶液(诸如磷酸盐缓冲生理盐水溶液)、乳液(例如,诸如油/水或水/油乳液)、乳酸林格氏液(lactated Ringer's)、正蔗糖、正葡萄糖、黏合剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、调味剂、盐溶液(诸如林格氏溶液(Ringer's solution))、醇、油、明胶、碳水化合物(诸如乳糖、直链淀粉或淀粉)、脂肪酸酯、羟甲织维素、聚乙烯吡咯啶及颜色及类似物。这样的制剂可以经灭菌且视需要与不会不利地与本发明的IL-34抑制剂反应的助剂(诸如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、用于影响渗透压的盐、缓冲剂、着色剂和/或芳族物质及其类似物)混合。关于赋形剂的实例,参见Martin,Remington's Pharmaceutical Sciences,第15版,MackPubl.Co.,Easton,PA(1975)。
如本文所使用,如本文所使用的术语“治疗有效量”、“有效量”或“药学上有效量”是指当施用至患者时足以至少部分治疗病况的试剂(例如本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)的量。治疗有效量将视病况的严重程度、组分的施用途径及所治疗患者的年龄、体重等而变化。因此,有效量的所公开的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶为治疗疾病或病症(例如患者的传染性疾病或病症)所必需的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶的量,使得施用药剂预防个体的疾病或病症发生,预防疾病或病症进展或减轻或完全改善疾病或病症的一些或所有相关症状,例如引起感染的清除。
如本文所使用,术语“施用”是指通过任何适合途径施用,例如经口施用、以栓剂形式施用、局部接触、静脉内、非经肠、腹膜内、肌内、病灶内、鞘内、颅内、鼻内或皮下施用,或向个体植入缓慢释放装置,例如小型渗透泵。施用是通过任何途径,包括非经肠及经黏膜(例如经颊、舌下、经腭、经牙龈、经鼻、经阴道、经直肠或经皮)。非经肠施用包括例如静脉内、肌内、动脉内、皮内、皮下、腹膜内、心室内、鞘内及颅内。在一些实施方案中,本文所描述的方法可以包括通过吸入施用。举例而言,在一些实施方案中,本文所描述的方法可以包括通过患者的经口腔吸入、经鼻腔吸入或经口腔及鼻腔吸入施用本文所描述的组合物。通过吸入施用可以使用本领域中已知的装置,例如喷雾器或吸入器(例如定量吸入器或干粉吸入器)达成。其他递送模式包括(但不限于)使用脂质体配制物、静脉内输注、经皮贴片等。
“共同施用”意谓在施用一或多种额外治疗剂(例如,抗病毒剂)的同时、之前或之后施用本文所描述的化合物或组合物。本文所描述的化合物或组合物可以单独施用或可以共同施用至患者。共同施用意谓包括个别或组合地(超过一种化合物或试剂)同时或相继施用化合物或组合物。因此,制剂还可以在需要时与其他活性物质组合(例如以减少代谢降解或提供用于疾病预防或治疗的额外治疗剂)。
以上说明描述本发明的多个方面及实施方案。本专利申请案特别涵盖所述方面及实施方案的所有组合及排列。
II.精氨酸酶(非聚乙二醇化及聚乙二醇化精氨酸酶)
本发明的实施方案包括调节微环境中的氨基酸浓度的方法。本发明的实施方案调节氨基酸浓度作为治疗疾病(例如病毒感染)的治疗方法。在某些实施方案中,调节氨基酸浓度以抑制病毒复制且防止有害发炎。在本发明的实施方案中,精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)作为抗病毒剂施用。本发明的实施方案可用以治疗大范围的病毒疾病或病症,包括病毒感染。在本发明的某些实施方案中,可向感染有病毒的患者施用精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)。可施用精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)以耗尽受体中的精氨酸。精氨酸的耗尽可抑制病毒复制或病毒传播。精氨酸的耗尽可减少经感染个体中的发炎性免疫反应。施用精氨酸酶(例如非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)或其药学上可接受的盐或其组合物可以有效治疗或预防病毒疾病或病症、细菌疾病或病症、真菌疾病或病症和/或阿米巴原虫疾病或病症。施用精氨酸酶(例如非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)或其药学上可接受的盐或其组合物可以有效抑制与病原体(例如病毒)相关的特定过程。举例而言,施用精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)或其药学上可接受的盐或其组合物可以有效抑制以下中的任一者或全部:自细胞的病毒释放、病毒传播、病毒基因组复制、病毒基因表达或病毒组装。
精氨酸酶为含锰酶且为尿素循环的最终酶。特定言的,精氨酸酶催化L-精氨酸转化为L-鸟氨酸及尿素。在大部分哺乳动物中,存在精氨酸酶的两种同功酶:精氨酸酶I,其在尿素循环中起作用且主要位于肝脏的细胞质中;及精氨酸酶II,其可调节细胞中的精氨酸/鸟氨酸浓度。聚乙二醇化为聚乙二醇(PEG)聚合物链共价连接至另一分子(诸如药物或蛋白质)的过程。聚乙二醇化可为试剂遮蔽宿主的免疫系统且可向该试剂提供提高的溶解度、活动性及寿命。本文所描述的聚乙二醇化精氨酸酶配制物包括已聚乙二醇化的精氨酸酶I的配制物。
使精氨酸酶与PEG偶合提高精氨酸酶的稳定性及功效。举例而言,尽管天然精氨酸酶在数分钟内自循环清除(Savoca等人,1984),但大鼠中的PEG-精氨酸酶MW5000的单次注射足以达成接近完全的精氨酸耗尽大约3天(Cheng等人,2007)。
精氨酸酶为具有由数个螺旋环绕的平行八股β片的α/β折叠的同型三聚酶。酶含有与酶的功能性一体化的二核金属簇。天然精氨酸酶与Mn2+配合。
在一些实施方案中,本发明涵盖其中Mn2+经另一金属置换的突变体精氨酸。举例而言,在一些实施方案中,本文所描述的聚乙二醇化精氨酸酶与钴、铁或锌离子而非锰离子配合。当与具有天然金属辅因子Mn2+的天然人精氨酸酶相比时,人精氨酸酶中金属辅因子的取代可以对生理条件下的L-精氨酸水解速率及稳定性发挥有益作用。Mn2+经其他二价阳离子的取代可以用于使酶的最适pH偏移至较低值且因此在生理条件下达成高速率的L-精氨酸水解。人精氨酸酶蛋白质具有两个Mn(II)位点;因此,任一个或两个位点可以经取代以产生带有非天然金属辅因子的突变精氨酸酶。在一些实施方案中,金属为钴(Co2+)。在一些实施方案中,并入Co2+代替Mn2+在生理pH下产生显著更高活性。适用于结合至钴的突变精氨酸酶提供于US10,098,933中。在一些实施方案中,金属为锌(Zn2+)。在一些实施方案中,金属为铁(Fe2+)。
在一些实施方案中,精氨酸酶蛋白质在金属结合位点处包含至少一个氨基酸取代。精氨酸酶的结构包括含有两个Mn2+离子的活性位点裂隙,其中更深入定位的离子称为MnA,其与H101、D124、D128、D232及桥接氢氧化物配位。另一金属称为MnB且由H126、D124、D232、D234及桥接氢氧化物配位(Chrianson及Cox,1999)。包含精氨酸酶I的第一壳的金属结合位点的残基为H101、D124、H126、D128、D232及D234,且对于第二壳为W122、D181及S230。类似地,包含精氨酸酶II的第一壳的金属结合位点的残基为H120、D143、H145、D147、D251、D253,且对于第二壳为W141、D200、S249。在一些实施方案中,精氨酸酶为突变体精氨酸酶。在某些实施方案中,精氨酸酶为C303P变异体。在一些实施方案中,精氨酸酶包含Fc结构域蛋白融合。在一些实施方案中,长血清持久性改良精氨酸酶作为治疗剂的用途。
在一些实施方案中,精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)用于治疗病原性疾病或病症,包括(但不限于)病毒疾病或病症、细菌疾病或病症、真菌疾病或病症及阿米巴原虫疾病或病症。在一些实施方案中,精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)用于治疗病原性感染,包括(但不限于)病毒感染、细菌感染、真菌感染及阿米巴原虫感染。在一些实施方案中,精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)有效针对RNA病毒感染及DNA病毒感染(包括包膜及非包膜病毒两者)。在一些实施方案中,精氨酸酶(例如非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)经口或以吸入剂配制物(例如,口服吸入剂配制物、鼻吸入剂配制物或鼻吸入剂及口服吸入剂配制物)形式施用。在一些实施方案中,将精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)并入至注射组合物中。
在某些实施方案中可与PEG结合以形成本发明的聚乙二醇化精氨酸酶的精氨酸酶的示例性氨基酸序列提供于表1中。
表1.示例性精氨酸酶序列
在本文所描述的一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含源自特定物种的精氨酸酶氨基酸序列。举例而言,在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含衍生自智人(亦即人)精氨酸酶序列、热溶芽孢杆菌(Bacillus caldovelox)精氨酸酶序列或野猪(Sus scrofa)精氨酸酶序列的精氨酸酶氨基酸序列。在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含精氨酸酶的特定部分的氨基酸序列(例如,包含精氨酸酶序列的酶结构域的氨基酸序列(例如SEQ IDNO:2、42或43))。在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含氨基酸序列,该氨基酸序列包含人精氨酸酶序列的酶结构域(例如SEQ ID NO:2)。
在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与人精氨酸酶有关的氨基酸序列。人精氨酸酶的实例包括NCBI基因ID:383中所描述的基因、mRNA及蛋白质序列,包括NCBI参考序列NP_001231367.1、NCBI参考序列NP_000036.2及NCBI参考序列NP_001355949.1的蛋白质序列。在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与SEQ ID NO:1有关的氨基酸序列。举例而言,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶可以包含与SEQ ID NO:1至少约90%(例如约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或约100%)相同的精氨酸酶序列。
在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与人精氨酸酶的酶结构域有关的氨基酸序列。在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与SEQ ID NO:2有关的氨基酸序列。举例而言,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶可以包含与SEQ ID NO:2至少约90%(例如约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或约100%)相同的氨基酸序列。
在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与热溶芽孢杆菌精氨酸酶有关的氨基酸序列。热溶芽孢杆菌精氨酸酶的实例为NCBI GenBank条目:AAB06939.1的蛋白质序列及其相关基因及mRNA序列。在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与SEQ ID NO:10有关的氨基酸序列。举例而言,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶可以包含与SEQ ID NO:10至少约90%(例如约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或约100%)相同的精氨酸酶序列。
在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与野猪精氨酸酶有关的氨基酸序列。野猪精氨酸酶的实例包括NCBI基因ID:397115中所描述的基因、mRNA及蛋白质序列,包括NCBI参考序列XP_020938406.1、NCBI参考序列XP_005659247.1、NCBI参考序列XP_020938398.1及NCBI参考序列XP_020938404.1的蛋白质序列。在一些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与SEQ ID NO:31有关的氨基酸序列。举例而言,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶可以包含与SEQ ID NO:31至少约90%(例如约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或约100%)相同的精氨酸酶序列。
在一些实施方案中,重组精氨酸酶或其功能片段(例如精氨酸酶蛋白质的酶结构域)可以例如活体内从细菌细胞、昆虫细胞、哺乳动物细胞、合成细胞或活体外从无细胞系统或化学合成表达/产生。重组精氨酸酶I可以通过简并密码中的密码子的任何组合编码。在一些实施方案中,核苷酸经利用遗传密码置换,使得密码子变为编码相同氨基酸残基的不同密码子。在一些实施方案中,改变表1中所描述的精氨酸酶序列的半胱氨酸残基的特质(identity)可导致蛋白质聚集在溶液中减少:约2%、约5%、约10%、约15%、约20%、约25%、约30%、约35%、约40%、约45%、约50%、约55%、约60%、约65%、约70%、约75%、约80%、约85%、约90%或约95%。
在一些实施方案中,改变表1中所描述的精氨酸酶序列的半胱氨酸残基的特质可导致溶液中的精氨酸酶蛋白质不超过1%聚集、不超过2%聚集、不超过5%聚集、不超过10%聚集、不超过15%聚集、不超过20%聚集、不超过25%聚集、不超过30%聚集、不超过35%聚集、不超过40%聚集、不超过45%聚集、不超过50%聚集、不超过55%聚集、不超过60%聚集、不超过65%聚集、不超过70%聚集、不超过75%聚集、不超过80%聚集、不超过85%聚集、不超过90%聚集或不超过95%聚集。
在一些实施方案中,改变精氨酸酶蛋白质序列的一或多个氨基酸的特质可以减少重组精氨酸酶I在溶液中的聚集分布。在一些情况下,重组精氨酸酶I或其功能片段包含1个氨基酸突变、2个氨基酸突变、3个氨基酸突变、4个氨基酸突变、5个氨基酸突变、6个氨基酸突变、7个氨基酸突变、8个氨基酸突变、9个氨基酸突变、10个氨基酸突变、11个氨基酸突变、12个氨基酸突变、13个氨基酸突变、14个氨基酸突变、15个氨基酸突变、16个氨基酸突变、17个氨基酸突变、18个氨基酸突变、19个氨基酸突变、20个氨基酸突变、21个氨基酸突变、22个氨基酸突变、23个氨基酸突变、24个氨基酸突变、25个氨基酸突变、26个氨基酸突变、27个氨基酸突变、28个氨基酸突变、29个氨基酸突变、30个氨基酸突变、31个氨基酸突变、32个氨基酸突变、33个氨基酸突变、34个氨基酸突变、35个氨基酸突变、36个氨基酸突变、37个氨基酸突变、38个氨基酸突变、39个氨基酸突变、40个氨基酸突变、41个氨基酸突变、42个氨基酸突变、43个氨基酸突变、44个氨基酸突变、45个氨基酸突变、46个氨基酸突变、47个氨基酸突变、48个氨基酸突变、49个氨基酸突变或50个氨基酸突变。在一些实施方案中,突变的氨基酸为半胱氨酸。在一些实施方案中,氨基酸突变为半胱氨酸至苯丙氨酸(C→F)突变、半胱氨酸至丝氨酸(C→S)突变、半胱氨酸至异亮氨酸(C→I)突变或半胱氨酸至丙氨酸(C→A)突变。
在一些实施方案中,精氨酸酶蛋白质序列可以包括(但不限于)以下突变中的一或多个:半胱氨酸至苯丙氨酸(C→F)突变、半胱氨酸至丝氨酸(C→S)突变、半胱氨酸至异亮氨酸(C→I)突变、半胱氨酸至丙氨酸(C→A)突变、天冬氨酸至谷氨酸(D→E)突变、天冬氨酸至丝氨酸(D→S)突变、丝氨酸至半胱氨酸(S→C)突变、丝氨酸至丙氨酸(S→A)突变或丝氨酸至甘氨酸(S→G)突变。
在一些实施方案中,重组精氨酸酶I可以具有经工程改造至重组核酸序列中的分子标签(在本文中替代地称为“表位标签”)。在一些实施方案中,分子标签包含氨基酸序列,例如6xHis标签、Flag标签、V5标签、myc标签、谷胱甘肽-S-转移酶(GST)标签、麦芽糖结合蛋白(MBP)标签、几丁质结合蛋白(CBP)标签或红细胞凝集素(HA)标签氨基酸序列。分子标签可以促进重组精氨酸酶自粗表达系统的纯化。在一些实施方案中,本文所描述的精氨酸酶包含SEQ ID NO:1-43中的任一者的氨基酸序列及分子标签氨基酸序列(例如6xHis标签(例如具有N末端甲硫氨酸的6个组氨酸卷标)、Flag标签、V5标签、myc标签、GST标签、MBP标签、CBP标签或HA标签氨基酸序列),其中该分子标签序列接近SEQ ID NO:1-43的氨基酸序列的N末端或C末端。在一些实施方案中,本文所描述的聚乙二醇化精氨酸酶包含至少一个与包含SEQ ID NO:1-43中的任一者的氨基酸序列及分子标签氨基酸序列(例如6xHis标签(例如具有N末端甲硫氨酸的6个组氨酸标签)、Flag标签、V5标签、myc标签、GST标签、MBP标签、CBP标签或HA标签氨基酸序列)的蛋白质结合的PEG分子,其中该分子标签序列接近SEQ ID NO:1-43的氨基酸序列的N末端或C末端。
SEQ ID NO:56为精氨酸酶蛋白质序列,其包含SEQ ID NO:1及在N末端处具有甲硫氨酸的6xHis标签。在某些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶包含与SEQ ID NO:56至少约90%(例如至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%或约100%)相同的精氨酸酶序列。
SEQ ID NO:44-50为包含相对于SEQ ID NO:1一或多个氨基酸突变且包括N末端聚组氨酸(6×His)标签蛋白质序列的精氨酸酶蛋白质序列。SEQ ID NO:44包含相对于SEQ IDNO:1的聚组氨酸标签及C303→A303突变。SEQ ID NO:45包含相对于SEQ ID NO:1的聚组氨酸标签及C168→A168突变。SEQ ID NO:46包含相对于SEQ ID NO:1的聚组氨酸标签及C45→A45突变。SEQ ID NO:47包含相对于SEQ ID NO:1的聚组氨酸标签、C303→A303及C168→A168双突变。SEQ ID NO:48包含相对于SEQ ID NO:1的聚组氨酸标签、C303→A303及C45→A45双突变。SEQ ID NO:49包含相对于SEQ ID NO:1的聚组氨酸标签、C168→A168及C45→A45双突变。SEQ ID NO:50包含相对于SEQ ID NO:1的聚组氨酸标签、C303→A303、C168→A168及C45→A45三突变。
本文所描述的方法可以包括施用治疗有效量的包含SEQ ID NO:44-50的氨基酸序列的精氨酸酶或其药学上可接受的盐。在一些实施方案中,本文所描述的方法可以包括施用治疗有效量的包含精氨酸酶或其药学上可接受的盐的组合物,该精氨酸酶包含SEQ IDNO:44-50的氨基酸序列。
本文所描述的方法可以包括施用治疗有效量的包含至少一个与精氨酸酶结合的聚乙二醇分子的聚乙二醇化精氨酸酶或其药学上可接受的盐,该精氨酸酶包含SEQ ID NO:44-50的氨基酸序列。在一些实施方案中,本文所描述的方法可以包括施用治疗有效量的包含聚乙二醇化精氨酸酶或其药学上可接受的盐的组合物,其中所述聚乙二醇化精氨酸酶包含至少一个与精氨酸酶结合的聚乙二醇分子,该精氨酸酶包含SEQ ID NO:44-50的氨基酸序列。
分子标签为本领域中已知的。表位标签的示例性氨基酸序列显示于表2中。
表2.示例性分子标签
本文所描述的方法可以包括施用聚乙二醇化精氨酸酶,例如施用至需要治疗的患者。聚乙二醇(PEG)为包括(-O-CH2-CH2-)主链的聚醚。一般而言,PEG为以下通式的化合物:
PEG高度可溶于水中,展现低免疫原性,且无毒(参见Herzberger等人(2016)Polymerization of Ethylene Oxide,Propylene Oxide,and Other Alkylene Oxides:Synthesis,Novel Polymer Architectures,and Bioconjugation.Chemical Reviews:116,2170-2243)。聚乙二醇化可以改良精氨酸酶的药物动力学,产生持久的持续时间、改良的安全性(例如较低毒性、免疫原性及抗原性)、增加的功效、降低的给药频率、改良的药物溶解度及稳定性、降低的蛋白分解及控制的药物释放(Roberts等人,2002,Adv Drug DelivRev,54:459-76)。在一些实施方案中,PEG有助于增加精氨酸酶的半衰期。
如本文所描述,精氨酸酶或其功能片段(例如精氨酸酶蛋白质的酶结构域)可以经各种类型的PEG分子修饰。在一些实施方案中,PEG寡聚物为甲氧基聚(乙二醇)琥珀酰亚胺丙酸酯(mPEG-SPA)。在一些实施方案中,PEG寡聚物为甲氧基聚(乙二醇)丙酸(mPEG-酸)。在一些情况下,本发明提供一种药物组合物,其包含与至少一个聚乙二醇寡聚物结合的纯化重组人精氨酸酶I蛋白。在一些情况下,聚乙二醇化重组人精氨酸酶I蛋白与至少两个聚乙二醇寡聚物结合。在一些情况下,聚乙二醇寡聚物重量为约20千道尔顿至约40千道尔顿。在一些情况下,聚乙二醇化重组人精氨酸酶I蛋白与约4个聚乙二醇分子至约13个聚乙二醇分子结合。在一些情况下,聚乙二醇寡聚物重量为约5道尔顿。
精氨酸酶或其功能片段与所关注的聚合物聚乙二醇的共价连接可以改变精氨酸酶的物理化学特征。可以通过结合至PEG而改变的物理化学特征的实例包括免疫原性、体外及体内生物活性、吸收速率及生物利用度、生物分布、药物动力学(PK)及药效学分布(PD)及毒性。在一些实施方案中,聚乙二醇化精氨酸酶具有降低的免疫原性。-NH2、-COOH、-OH、-SH及双硫键为可以与PEG寡聚物反应的精氨酸酶的氨基酸侧链中的化学基团的实例。在一些实施方案中,N末端中的氨及C末端中的羧基亦可以与PEG寡聚物反应。
用于蛋白质聚乙二醇化的PEG试剂可以为活化PEG。活化PEG可以用于胺聚乙二醇化、硫醇聚乙二醇化或N末端聚乙二醇化。PEG试剂可以不同长度、形状及化学性质商购,使其与蛋白质的特定官能团反应以用于其共价连接。PEG的商业提供者的非限制性实例包括NOF公司(NOF Corporation)(日本);SunBio(韩国);Chirotech技术有限责任公司(Chirotech Technology Limited)(UK);JenKem(中国);创造型PEGWorks(CreativePEGWorks)(USA)、西格玛-奥德里奇(Sigma-Aldrich)(Milwaukee,WI)、Dendritech(Midland,MI)或PolysciencesTM(Warrington,PA)。
适用于本文所描述的实施方案的市售PEG的非限制性实例包括(但不限于)可获自内克塔治疗(Nektar Therapeutics)(San Carlos,CA)的那些,例如mPEG-NH2(Mw为约10kDa,约20kDa)、甲氧基PEG琥珀酰亚胺基α-甲基丁酸酯(SMB)、SMB-PEG-SMB、甲氧基PEG琥珀酰亚胺基丙酸酯(mPEG-SPA)、支链PEG N-羟基琥珀酰亚胺(mPEG2-NHS)、mPEG-CM-HBA-NHS、NHS-HBA-CM-PEG-CM-HBA-NHS、mPEG-丁醛、丁醛-PEG-丁醛、支链PEG丁醛(mPEG2-丁醛)、邻-吡啶基硫酯(mPEG-OPTE)、mPEG顺丁烯二酰亚胺(MAL)、MAL-PEG-MAL、支链PEG顺丁烯二酰亚胺(mPEG2-MAL)、叉状顺丁烯二酰亚胺(mPEG-MAL2及mPEG2-MAL2)、mPEG-邻-吡啶基二硫化物(mPEG-OPSS)、OPSS-PEG-OPSS、mPEG-SH、SH-PEG-SH、胺-PEG-酸、Boc-PEG-NHS、Fmoc-PEG-NHS、MAL-PEG-NHS、乙烯基砜-PEG-NHS及丙烯酸-PEG-NHS酯。
可以用于胺聚乙二醇化的PEG的非限制性实例包括例如由Jenken技术(USA)制造的PEG,诸如:Y形PEG NHS酯、Y形PEG羧基、葡萄糖PEG NHS酯、半乳糖PEG NHS酯、甲氧基PEG琥珀酰亚胺基羧甲基酯、甲氧基PEG羧基、甲氧基PEG琥珀酰亚胺基丁酸酯、甲氧基PEG琥珀酰亚胺基己酸酯、甲氧基PEG己酸、甲氧基PEG琥珀酰亚胺基琥珀酰胺、甲氧基PEG琥珀酰亚胺基戊二酰胺、甲氧基PEG琥珀酰亚胺基碳酸酯、甲氧基PEG硝基苯基碳酸酯、甲氧基PEG琥珀酰亚胺基琥珀酸酯、甲氧基PEG琥珀酰亚胺基戊二酸酯。可以用于硫醇聚乙二醇化中的PEG的非限制性实例包括Y形PEG顺丁烯二酰亚氨、甲氧基PEG顺丁烯二酰亚氨、甲氧基PEG乙烯基砜、甲氧基PEG硫醇。可以用于N末端聚乙二醇化的PEG的非限制性实例包括例如由Jenken技术USA制造的PEG,诸如:Y形PEG醛、Y形PEG乙醛、Y形PEG丙醛及甲氧基PEG丙醛。
在一些实施方案中,精氨酸酶I或其功能片段可以具有小于其所连接的PEG寡聚物的分子量。PEG寡聚物的分子量可以为例如不超过100千道尔顿(kDa)、不超过95kDa、不超过90kDa、不超过85kDa、不超过80kDa、不超过75kDa、不超过70kDa、不超过65kDa、不超过60kDa、不超过55kDa、不超过50kDa、不超过45kDa、不超过40kDa、不超过35kDa、不超过30kDa、不超过25kDa、不超过20kDa、不超过15kDa、不超过10kDa、不超过5kDa、不超过1kDa或不超过500道尔顿(Da)。
在一些实施方案中,PEG分子的分子量可以大于500Da、大于1千道尔顿(kDa)、大于5kDa、大于10kDa、大于15kDa、大于20kDa、大于25kDa、大于30kDa、大于35kDa、大于40kDa、大于45kDa、大于50kDa、大于55kDa、大于60kDa、大于65kDa、大于70kDa、大于75kDa、大于80kDa、大于85kDa、大于90kDa、大于95kDa、大于100kDa。
在一些实施方案中,PEG寡聚物的分子量可以为约1kDa至约5kDa、约1kDa至约10kDa、约10kDa至约20kDa、约10kDa至约30kDa、约10kDa至约40kDa、约10kDa至约50kDa、约20kDa至约30kDa、约20kDa至约40kDa、约20kDa至约50kDa、约30kDa至约40kDa、约30kDa至约50kDa。
在某些实施方案中,PEG寡聚物的分子量为约5kDa。在某些实施方案中,PEG寡聚物的分子量为约20kDa至约40kDa。
III.治疗性应用
在某些实施方案中,疾病或病症是由病原体感染的结果,该病原体例如细菌、病毒、真菌、原虫(例如阿米巴原虫)、藻或朊蛋白。胞内病原体包括兼性胞内寄生虫,其能够在宿主细胞内部或外部存活且繁殖;及无法在其宿主细胞外部繁殖的绝对胞内寄生虫。在某些实施方案中,胞内病原体为疾病或病症中的致病病原体。在某些实施方案中,胞内病原体在细胞内休眠、潜伏或共生,但可以在病原体的生命周期后期引起疾病或病症。胞内病原体感染可以为急性或慢性的。在某些实施方案中,由胞内病原体介导的疾病或病症为慢性感染。在某些实施方案中,由胞内病原体介导的疾病或病症为急性感染。
治疗病毒疾病及病症
在某些实施方案中,疾病或病症是由病毒引起的。在某些实施方案中,病毒选自由以下组成的组:反转录病毒(例如人类免疫缺陷病毒(HIV)、猿猴免疫缺陷病毒(SIV)、人T细胞嗜淋巴细胞病毒(HTLV)-1、HTLV-2、HTLV-3、HTLV-4)、埃博拉病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、单纯疱疹病毒(HSV)(例如HSV-1、HSV-2、水痘带状疱疹病毒、巨细胞病毒)、腺病毒、正黏病毒(例如流感病毒A、流感病毒B、流感病毒C、流感病毒D、托高土病毒(thogotovirus))、黄病毒(例如登革热病毒、寨卡病毒)、西尼罗河病毒、裂谷热病毒、沙粒病毒、克里米亚刚果出血热病毒、埃可病毒、鼻病毒、柯萨奇病毒、冠状病毒(例如严重急性呼吸综合征冠状病毒(SARS-CoV)、严重急性呼吸综合征冠状病毒2(SARS-CoV-2)及中东呼吸综合征相关冠状病毒(MERS-CoV))、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、德国麻疹病毒、微小病毒(例如腺相关病毒)、痘苗病毒、天花病毒、软疣病毒、牛白血病病毒、脊髓灰质炎病毒、狂犬病病毒、多瘤病毒(例如JC病毒、BK病毒)、甲病毒及风疹病毒(例如德国麻疹病毒)。在某些实施方案中,疾病或病症是由除肝炎病毒和/或HIV以外的病毒引起。
在某些实施方案中,本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶用于治疗由病毒感染引起的疾病或病症,例如选自由以下组成的组的疾病或病症:获得性免疫缺陷综合征(AIDS)、HTLV-1相关脊髓病/热带痉挛性截瘫、埃博拉病毒疾病、甲型肝炎、乙型肝炎、丙型肝炎、疱疹、带状疱疹、急性水痘、单核细胞增多症、呼吸道感染、肺炎、流感、登革热、脑炎(例如,日本脑炎)、西尼罗河热(West Nile fever)、裂谷热(Rift Valleyfever)、克里米亚刚果出血热、夸塞纳森林病(Kyasanur Forest disease)、黄热病、寨卡热(Zika fever)、无菌性脑膜炎、心肌炎、感冒、肺部感染、传染性软疣、地方性牛白血病、冠状病毒疾病2019(COVID-19)、流行性腮腺炎、胃肠炎、麻疹、风疹、掌掴病、天花、疣(例如,生殖器疣)、传染性软疣、脊髓灰质炎、狂犬病及玫瑰糠疹。
在一些实施方案中,病毒疾病或病症由人类免疫缺陷病毒(HIV)引起。HIV是指感染免疫系统细胞(例如CD4+T细胞、巨噬细胞及小神经胶质细胞)的两个反转录病毒物种(HIV-1,HIV-2)。HIV可以发展为获得性免疫缺陷综合征(AIDS)。在一些实施方案中,病毒疾病或病症是由人乳头瘤病毒(HPV)引起的。HPV为可导致疣(例如生殖器疣)的性传播感染。在一些实施方案中,病毒疾病或病症是由疱疹病毒,例如丙型肝炎病毒(HCV)或巨细胞病毒(CMV)引起的。丙型肝炎主要影响肝脏且通常导致肝病和/或肝硬化。巨细胞病毒(CMV),例如人巨细胞病毒,与肺炎及单核细胞增多症相关。在一些实施方案中,病毒疾病或病症是由黄病毒,例如埃博拉病毒、寨卡病毒或西尼罗河病毒引起的。埃博拉病毒引起埃博拉病毒疾病(EVD),病毒出血热。
在一些实施方案中,病毒为RNA病毒(具有由RNA构成的基因组)。RNA病毒可为单链RNA(ssRNA)或双链RNA(dsRNA)。与DNA病毒相比,RNA病毒具有高突变率,因为RNA聚合酶不具有校读能力(参见Steinhauer DA,Holland JJ(1987).“Rapid evolution of RNAviruses”.Annu.Rev.Microbiol.41:409-33)。示例性RNA病毒包括(但不限于)布尼亚病毒(bunyaviruses)(例如,汉坦病毒(hantavirus))、冠状病毒(例如MERS-CoV、SARS-CoV、SARS-CoV-2)、黄病毒(例如,黄热病病毒、西尼罗河病毒、登革热病毒)、肝炎病毒(例如,甲型肝炎病毒、丙型肝炎病毒、戊型肝炎病毒)、流感病毒(例如,A型流感病毒、B型流感病毒、C型流感病毒)、麻疹病毒、腮腺炎病毒、诺如病毒(例如,诺沃克病毒(Norwalk virus))、脊髓灰质炎病毒、呼吸道合胞病毒(RSV)、反转录病毒(例如,人类免疫缺陷病毒-1(HIV-1))及环曲病毒(toroviruses)。在一些实施方案中,RNA病毒为流感病毒,例如A型流感。在一些实施方案中,A型流感病毒为H1N1A型流感病毒(大流行性H1N1/09)。在一些实施方案中,A型流感病毒为H5N1 A型流感病毒(A/越南/2013/04)。在一些实施方案中,RNA病毒为RSV。在一些实施方案中,RNA病毒为MERS-CoV。在一些实施方案中,RNA病毒为SARS-CoV2。在一些实施方案中,RNA病毒为ZIKA。
通过基因组的类型将RNA病毒分类(双链、反义(-)或正义(+)单链)。双链RNA病毒含有许多不同RNA分子,各自编码一或多种病毒蛋白质。正义ssRNA病毒直接将其基因组用作mRNA;宿主细胞内的核糖体将mRNA翻译成单一蛋白质,该单一蛋白质接着经修饰以形成病毒复制所需的各种蛋白质。一种此类蛋白质为RNA依赖性RNA聚合酶(RNA复制酶),其复制病毒RNA以形成双链、复制形式。反义ssRNA病毒具有由RNA复制酶复制的基因组,以产生用于复制的正义RNA。因此,病毒包含RNA复制酶。接着,所得正义RNA充当病毒mRNA且由宿主核糖体翻译。在一些实施方案中,病毒为dsRNA病毒。在一些实施方案中,病毒为反义ssRNA病毒。在一些实施方案中,病毒为正义ssRNA病毒。在一些实施方案中,正义ssRNA病毒为冠状病毒。
有时亦称为2019或2019-nCoV的新颖冠状病毒的SARS-CoV2为正义单链RNA病毒。SARS-CoV2具有四种结构蛋白,称为S(刺突)、E(包膜)、M(膜)及N(核蛋白壳)蛋白。N蛋白将RNA基因组保持在一起;S、E及M蛋白形成病毒包膜。刺突蛋白使病毒连接至宿主细胞(诸如人细胞中的ACE2受体)的膜。SARS-CoV2为全球大流行性2019冠状病毒疾病(COVID19)的高传染性、致病性病毒剂。
在一些实施方案中,病毒为DNA病毒(具有由DNA构成的基因组)。示例性DNA病毒包括(但不限于)微小病毒(例如,腺相关病毒)、腺病毒、非洲猪瘟病毒(asfarviruses)、疱疹病毒(例如,单纯疱疹病毒1及2(HSV-1及HSV-2)、EB病毒(Epstein-Barr virus;EBV)、巨细胞病毒(CMV)、乳头瘤病毒(例如,HPV)、多瘤病毒(例如,猴空泡病毒40(SV40))及痘病毒(例如,痘苗病毒、牛痘病毒、天花病毒、禽痘病毒、羊痘病毒、黏液瘤病毒)。在某些实施方案中,DNA病毒为腺病毒,例如AdV5。在某些实施方案中,DNA病毒为肠病毒,例如EV71。在某些实施方案中,DNA病毒为疱疹病毒,例如HSV-1。
在一些实施方案中,感染局限于例如器官或例如组织。在一些实施方案中,感染局限于器官,包括但不限于眼、耳、内耳、肺、气管、支气管、细支气管、肝脏、胆囊、胆管、肾脏、膀胱、睾丸、子宫颈、卵巢、子宫、皮肤或脑。在某些实施方案中,感染为病毒感染(例如HSV-1、HSV-2、VZV、CMV)且局限于眼。在某些实施方案中,感染为腺病毒感染且局限于眼。在某些实施方案中,感染为细菌感染(例如衣原体)且局限于眼。
在一些实施方案中,感染为慢性的。如本文所使用,“慢性”是指持续延长时段或复发的感染。在一些实施方案中,感染为急性的。如本文所使用,“急性”是指持续时间短的感染。
定量病毒复制的方法为现有技术中已知的。在一些实施方案中,使用噬菌斑分析测定病毒计数。在一些实施方案中,使用病灶形成分析(FFA)测定病毒计数。在一些实施方案中,使用终点稀释分析测定病毒计数。在一些实施方案中,使用酶联免疫吸附分析(ELISA)测定病毒计数。在一些实施方案中,使用可调电阻式脉冲感测(TRPS)测定病毒计数以检测个别病毒颗粒。在一些实施方案中,病毒复制如下测定:定量宿主细胞死亡的量或百分比,例如体外,例如使用碘化丙锭(PI)以识别死细胞、定量形态圆化细胞的量或通过免疫荧光显微术识别凋亡标记物。在一些实施方案中,病毒计数是通过测量病毒滴度或感染复数(MOI)或通过进行噬菌斑分析、焦点形成分析及终点稀释分析、病毒蛋白质定量分析(例如红细胞凝集分析、二辛可宁酸分析(BCA)或单向免疫扩散分析(SRID)分析)、穿透电子显微术分析、可调电阻式脉冲感测(TRPS)分析、流式细胞术分析、定量PCR(qPCR)分析或酶联免疫吸附分析(ELISA)来测定。在一些实施方案中,病毒复制是通过定量病毒核酸(例如病毒DNA或病毒RNA)含量来测定。
定量病毒传播的方法为现有技术中已知的。在一些实施方案中,使用流行病学模型化来定量病毒传播(参见例如Graw等人,(2016)Modeling Viral Spread.Annu RevVirol,3(1))。在一些实施方案中,在体外,例如在细胞培养物中,例如使用显微术,例如使用穿透电子显微术(TEM)评估病毒传播。
定量病毒组装的方法为现有技术中已知的。在一些实施方案中,使用统计模型化来测定病毒组装(参见例如Clement等人,(2018)Viral Capsid Assembly:A QuantifiedUncertainty Approach.J Comp Biol,25(1))。在一些实施方案中,使用生物化学技术测定病毒组装以确定蛋白壳复合物形成,例如免疫共沉淀,例如蛋白质免疫印迹法。在一些实施方案中,通过流式细胞术测定病毒组装以检测共定位病毒蛋白质(参见例如Stoffel,C.L.等人(2005).“Rapid Determination of Baculovirus Titer by a Dual Channel VirusCounter”American Biotechnology Laboratory.37(22):24-25)。
病毒基因编码病毒感染过程、多步骤过程(包括例如连接至宿主细胞、穿透、去包封、病毒基因转录级联、病毒蛋白表达、病毒基因组复制、病毒包装及组装、包封、运输及成熟、释放及外溢及宿主细胞-细胞传播)所需的元件。β基因为对应于病毒感染的早期步骤(例如病毒基因组复制)的那些基因。γ基因为对应于病毒感染的晚期步骤(例如外溢)的那些基因。定量病毒基因表达的方法为现有技术中已知的。在一些实施方案中,病毒基因表达是使用反转录酶及定量聚合酶链反应(RT-qPCR)测定。在一些实施方案中,RNA测序(RNA-Seq)用于测定病毒基因表达。在一些实施方案中,使用DNA印迹法定量病毒DNA。在一些实施方案中,定量β基因表达。在一些实施方案中,定量γ基因表达。在一些实施方案中,定量β基因表达及γ基因表达。在一些实施方案中,定量整个病毒基因组的表达。
定量病毒释放的方法为现有技术中已知的。在一些实施方案中,通过生物化学分析,例如蛋白质免疫印迹法,例如代谢标记测定病毒释放(参见例如Yadav等人,(2012).“Afacile quantitative assay for viral particle genesis reveals cooperativity invirion assembly and saturation of an antiviral protein.”Virology.429(2):155-162)。在一些实施方案中,通过ELISA测定病毒释放。在一些实施方案中,使用电子显微术,例如穿透电子显微术(TEM)测定病毒释放。在一些实施方案中,病毒释放通过用于检测样品,例如血清中的病毒粒子的感染性量测来测定。在一些实施方案中,病毒释放是通过定量活体内血清或体外培养上清液中的病毒DNA或病毒RNA来测定。
在某些实施方案中,如本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶以相比于未施用精氨酸酶或聚乙二醇化精氨酸酶的被感染细胞、组织或个体,足以将被感染细胞、组织或个体中的病毒复制、病毒传播、病毒组装、病毒感染及病毒释放中的一或多种减少至少约5%、至少约10%、至少约15%、至少约20%、至少约25%、至少约30%、至少约35%、至少约40%、至少约45%、至少约50%、至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%或约100%的量施用。
治疗其他疾病及病症
在某些实施方案中,疾病或病症是由细菌,例如细菌感染引起的。在某些实施方案中,细菌是选自由以下组成的组:衣原体(例如沙眼衣原体(C.trachomatis)、大肠杆菌(例如致肠病性大肠杆菌(enteropathogenic E.coli)、肠出血性大肠杆菌(enterohemorrhagic E.coli)、致肾盂肾炎大肠杆菌(uropathogenic E.coli)、肠侵袭性大肠杆菌(enteroinvasive E.coli))、幽门螺杆菌(Helicobacter pylori)、分支杆菌(Mycobacterium)(例如结核分枝杆菌(M.tuberculosis)、麻风分枝杆菌(M.leprae)、弥漫型麻风分枝杆菌(M.lepromatosis))、李斯特菌属(Listeria)(例如单核细胞增多性李斯特菌(L.monocytogenes))、志贺氏菌属(Shigella)(例如福氏志贺氏菌(S.flexneri))、葡萄球菌属(Staphylococcus)(例如金黄色葡萄球菌(S.aureus))、链球菌属(Streptococcus)(例如化脓性链球菌(S.pyogenes))、链霉菌属(Streptomyces)、肺炎球菌(Pneumococcus)、脑膜炎双球菌(Meningococcus)、淋病球菌(Gonococcus)、克雷伯氏菌属(Klebsiella)(例如肺炎克雷伯氏菌(K.pneumoniae))、变形杆菌属(Proteus)、沙雷氏菌属(Serratia)、假单胞菌属(Pseudomonas)(例如铜绿假单胞菌(P.aeruginosa))、军团菌属(Legionella)、不动杆菌属(Acinetobacter)(例如鲍氏不动杆菌(A.baumannii))、棒状杆菌属(Corynebacterium)(例如白喉棒状杆菌(C.diphtheria))、柯克斯氏体属(Coxiella)(例如伯纳特柯克斯氏体(C.burnetii))、芽孢杆菌属(Bacillus)(例如炭疽芽胞杆菌(B.anthricis))、拟杆菌属(Bacteroides)、博德特氏菌属(Bordetella)、肠球菌属(Enterococcus)(例如粪肠球菌(E.faecalis))、弗朗西斯氏菌属(Francisella)(例如土拉弗朗西斯氏菌菌(F.tularensis))、流感嗜血杆菌(Haemophilus influenza)、奈瑟氏菌属(Neisseria)(例如脑膜炎双球菌(N.meningitides)、淋球双球菌(N.gonorrhoeae))、立克次体(Rickettsia)、沙门氏菌(Salmonella)(例如鼠伤寒沙门杆菌(S.typhimurium))、霍乱弧菌、梭菌属(Clostridium)(例如破伤风梭菌(C.tetan)、肉毒梭菌(C.botulinum))、耶尔森菌属(Yersinia)(例如鼠疫杆菌(Y.pestis))、疏螺旋体属(Borrielia)(例如伯氏疏螺旋体(B.burgdorferi))、布鲁氏菌属(Brucella)、伯克氏菌属(Burkholderia)、弯曲菌属(Campylobacter)及支原体属(Mycoplasma)。
在某些实施方案中,本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶用于治疗由细菌(例如,胞内细菌感染)引起的疾病或病症。本文所描述的方法可以用于治疗例如选自由以下组成的组的细菌疾病或病症:衣原体、肺结核、胃溃疡、麻风病、李斯特菌病、涎腺炎、细菌引起的腹泻或食物中毒、链球菌咽喉炎、猩红热、脓疱症、蜂窝组织炎、肺炎、脑膜炎、细菌性心内膜炎、憩室炎、散播性淋球菌感染(disseminated gonococcemia)、败血性关节炎、淋球菌新生儿眼炎、泌尿道感染、软组织感染、脊柱关节病(例如强直性脊柱炎)、军团菌病(legionellosis)(例如军团病(Legionnaires'disease)、庞提亚克热(Pontiac fever))、白喉、沙门氏菌病、炭疽、霍乱、破伤风、肉毒中毒、筋膜炎、气性坏疽、牙菌斑、莱姆病、布鲁氏菌病(brucellosis)、类鼻疽、Q热病、兔热病(tularemia)、淋病、斑疹伤寒、支原体肺炎、胃肠炎及轻度肺炎(walking pneumonia)。
在某些实施方案中,疾病或病症是由真菌引起。在某些实施方案中,真菌是选自由以下组成的组:念珠菌属(Candida)(例如白色念珠菌(C.albicans)、克鲁斯念珠菌(C.krusei)、格拉布勒他念珠菌(C.glabrata)、热带念珠菌(C.tropicalis))、隐球菌属(Cryptococcus)(例如新生隐球菌(C.neoformans)、加特隐球菌(C.gattii))、曲霉属(Aspergillus)(例如烟曲菌(A.fumigatus)、黑曲菌(A.niger))、毛霉目(Mucorales)(例如毛霉属(M.mucor)、犁头霉属(M.absidia)、根霉属(M.rhizopus))、孢子丝菌属(Sporothrix)(例如申克孢子丝菌(S.schenkii))、芽生菌属(Blastomyces)(例如皮炎芽生菌(B.dermatitidis))、副球孢子菌属(Paracoccidioides)(例如巴西副球孢子菌(P.brasiliensis))、球孢子菌属(Coccidioides)(例如粗球孢子菌(C.immitis))、组织孢浆菌属(Histoplasma)(例如荚膜组织胞浆菌(H.capsulatum))、枝顶孢属(Acremonium)、蛙粪霉属(Basidiobolus)(例如蛙生蛙粪霉(B.ranarum))、枝孢瓶霉(Cladophialophora)(例如班替枝孢瓶霉(C.bantiana))、小克银汉霉属(Cunninghamella)(例如灰色小克银汉霉(C.bertholletiae))、表皮癣菌属(Epidermophyton)、外瓶霉属(Exophiala)、突脐蠕孢属(Exserohilum)、着色霉属(Fonsecaea)(例如裴氏着色霉(F.pedrosoi))、外瓶霉属(Hortaea)(例如威尼克外瓶霉(H.werneckii))、芽生菌属(Lacazia)(例如人豚共患芽生菌(L.loboi))、小球腔菌属(Leptosphaeria)(例如十字花科小球腔菌(L.maculans))、马拉杜分支菌属(Madurella)(例如足马杜拉分支菌(M.mycetomatis))、马拉色菌属(Malassezia)、小芽孢菌属(Microsporum)、毛霉属(Mucor)、新龟甲形菌属(Neotestudina)、甲霉菌(Onychocola)、芽生菌(Phialophora)、毛孢子菌属(Piedraia)、肺囊虫属(Pneumocystis)(例如卡式肺囊虫(P.jirovecii))、假性霉样菌属(Pseudallescheria)(例如波氏假性霉样菌(P.boydii))、棘壳孢属(Pyrenochaeta)、根毛霉属(Rhizomucor)、丝孢菌属(Scedosporium)、柱顶孢属(Scytalidium)、孢子丝菌属(Sporothrix)、发癣菌属(Trichophyton)、毛孢子菌属(Trichosporon)及接合菌纲(Zygomycete)。
在某些实施方案中,本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶用于治疗由胞内真菌感染引起的疾病或病症,例如选自由以下组成的组的疾病或病症:念珠菌病、隐球菌病、曲菌病、毛霉菌病、孢子丝菌病、芽生菌病、巴西副球孢子菌病、球孢子菌病、组织浆菌病、足菌肿、甲真菌病、透明丝孢霉病、皮下接合菌病、大脑脓肿、暗色丝孢霉病、着色芽生菌病、足分支菌病、肺毛霉菌病、体癣、头癣、股癣、足癣、甲癣、黑癣、瘢瘤性芽米菌病、黑腿病、足分支菌病、花斑癣、马拉色菌毛囊炎、类固醇痤疮、脂溢性皮炎、新生儿头脓疱病、毛霉菌病、足分支菌病、黑色发结节病、肺囊虫肺炎、假霉样真菌病、赛多孢子菌病、孢子丝菌病及接合菌病。
在某些实施方案中,疾病或病症是由原虫引起。在一些实施方案中,原虫是阿米巴原虫。在某些实施方案中,阿米巴原虫是选自由以下组成的组:顶复虫类(疟原虫(例如,间日疟原虫(P.vivax)、恶性疟原虫(P.falciparum)、卵形疟原虫(P.ovale)、三日疟原虫(P.malariae)、刚地弓形虫(Toxoplasma gondii)、小球隐孢子虫(Cryptosporidiumparvum)、微小巴倍虫(Babesia microti)、环孢子虫(Cyclospora cayetanensis)、壁丽囊等孢虫(Cystoisospora belli))、锥虫属(Trypanosoma)(例如,布氏锥虫(Trypanosomabrucei)、克氏锥虫(Trypanosoma cruzi);及利什曼原虫(Leishmania)(例如,杜氏利什曼原虫(Leishmania donovani))。
在某些实施方案中,本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶用于治疗由胞内阿米巴原虫感染而引起的疾病或病症,例如选自由以下组成的组的疾病或病症:巴贝虫病、疟疾、隐孢子虫病、圆孢子虫病、等孢子虫病、弓形虫病、锥虫病、恰加斯病(Chagas disease)及利什曼病(leishmaniasis)。
在某些实施方案中,传染性疾病或病症是由藻类引起。在某些实施方案中,藻类是原壁菌属(Prototheca)。在某些实施方案中,本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶用于治疗由胞内藻类感染引起的疾病或病症(例如原藻病(protothecosis))。
在某些实施方案中,传染性疾病或病症是由朊蛋白引起。在某些实施方案中,本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶用于治疗由胞内朊蛋白感染引起的疾病或病症,例如选自由以下组成的组的疾病或病症:克雅氏病(Creutzfeldt-Jakobdisease)、变异型克雅氏病、格斯特曼–斯特劳斯勒–申克综合征(Gerstmann-Straussler-Scheinker syndrome)、致死性家族性失眠症及库鲁病(kuru)。
IV.组合疗法
本发明的治疗方法可以用作单一疗法或与一或多种可以用于治疗疾病或病症(例如感染)的其他疗法(例如抗感染剂)组合使用。如本文所使用,术语“组合”应理解为意谓在个体患病期间向个体递送两种或两种以上不同的治疗,使得对于患者的治疗效果在一时间点处重叠。在某些实施方案中,当开始提供第二种治疗时,第一种治疗的提供仍在发生以使得就施用而言存在重叠。这在本文中有时是指“同时/同步”或“同时递送”。在其他实施方案中,一种治疗的递送在另一治疗的递送开始之前结束。在任一情况的某些实施方案中,治疗归因于组合施用而更有效。举例而言,与在不存在第一治疗的情况下施用第二治疗时所发现相比,第二治疗更有效,例如使用较少第二治疗即可发现同等作用,或第二治疗以更大的程度减少症状,或对于第一治疗可发现类似情形。在某些实施方案中,递送使得症状或与疾病相关的其他参数超过在另一治疗不存在下递送一种治疗将观测到的结果。两种治疗的作用可部分加合,完全加合或大于加合。递送可以使得所递送的第一治疗的作用在递送第二治疗时仍可被检测。
因此,在某些实施方案中,个体已接受、正在接受或计划接受一或多种适用于治疗疾病或病症的其他疗法。在某些实施方案中,本发明的治疗方法进一步包含向个体施用一或多种适用于治疗疾病或病症,例如感染的其他疗法。在某些实施方案中,所述一或多种其他疗法包含改善胞内病原体感染的一或多种症状的试剂。在某些实施方案中,所述一或多种其他疗法包含手术移除经感染的组织。
应理解,本文所揭示的使用方法可以与试剂(例如改善与胞内病原体相关的疾病或病症的一或多种症状的抗感染剂)组合使用。举例而言,本文所揭示的使用方法可以与抗病毒剂组合使用。
适用于治疗胞内病原体感染的疗法在本领域中是通常已知的且由例如Kamaruzzaman等人(2017)BR.J.PHARMACOL.174(14):2225-36及DeClercq等人(2016)CLIN.MICROBIOL.REV.29(3):695-747综述。在某些实施方案中,抗感染剂抑制或降低胞内病原体的生存力、增殖、传染性和/或毒力。胞内病原体可通过以潜伏状态存在来逃避免疫监视及攻击。因此,在某些实施方案中,抗感染剂逆转胞内病原体的潜伏,使得感染可以由宿主的免疫系统识别。
在某些实施方案中,胞内病原体为病毒,且抗感染剂为抗病毒剂。可以用于组合中的示例性抗病毒剂包括(但不限于)阿巴卡韦(abacavir)、阿昔洛韦(acyclovir)、阿德福韦(adefovir)、安普那韦(amprenavir)、阿扎那韦(atazanavir)、西多福韦(cidofovir)、达芦那韦(darunavir)、地拉韦啶(delavirdine)、地达诺新(didanosine)、多可沙诺(docosanol)、依法韦仑(efavirenz)、埃替格韦(elvitegravir)、恩曲他滨(emtricitabine)、恩夫韦地(enfuvirtide)、恩替卡韦(entecavir)、依曲韦林(etravirine)、泛昔洛韦(famciclovir)、膦甲酸(foscarnet)、福米韦生(fomivirsen)、更昔洛韦(ganciclovir)、茚地那韦(indinavir)、碘苷(idoxuridine)、拉米夫定(lamivudine)、洛匹那韦(lopinavir)、马拉韦罗(maraviroc)、MK-2048、奈非那韦(nelfinavir)、奈韦拉平(nevirapine)、喷昔洛韦(penciclovir)、雷特格韦(raltegravir)、利匹韦林(rilpivirine)、利托那韦(ritonavir)、沙奎那韦(saquinavir)、司他夫定(stavudine)、泰诺福韦(tenofovir)、曲氟尿苷(trifluridine)、伐昔洛韦(valaciclovir)、缬更昔洛韦(valganciclovir)、阿糖腺苷(vidarabine)、伊巴他滨(ibacitabine)、金刚烷胺(amantadine)、奥司他韦(oseltamivir)、金刚乙胺(rimantidine)、替拉那韦(tipranavir)、扎西他滨(zalcitabine)、扎那米韦(zanamivir)、帕拉米韦(peramivir)、丹诺普韦(danoprevir)、瑞德西韦(remdesivir)及齐多夫定(zidovudine)。特定言的,在胞内病原体为HIV的情况下,可以用于组合中的示例性抗HIV试剂包括(但不限于)核苷/核苷酸反转录酶抑制剂(例如拉米夫定、阿巴卡韦、齐多夫定、司他夫定、地达诺新、恩曲他滨及泰诺福韦)、非核苷反转录酶抑制剂(例如地拉韦啶、依法韦仑、依曲韦林及奈韦拉平)、蛋白酶抑制剂(例如安普那韦、福沙那韦(fosamprenavir)、阿扎那韦、达芦那韦、茚地那韦、洛匹那韦、利托那韦、奈非那韦、沙奎那韦及替拉那韦)、融合或进入抑制剂(例如恩夫韦地及马拉韦罗)、整合酶抑制剂(例如雷特格韦、卡博特韦)及延迟-逆转试剂(例如HDAC抑制剂(例如伏立诺他(vorinostat))及TLR7激动剂(例如GS-9620,例如美国专利出版物第US20160008374A1中所描述))。
在某些实施方案中,胞内病原体为细菌,且抗感染剂为抗菌剂。可以用于组合中的示例性抗菌剂包括(但不限于)万古霉素(vancomycin)、甲硝唑(metronidazole)、庆大霉素(gentamicin)、粘菌素(colistin)、非达霉素(fidaxomicin)、特拉万星(telavancin)、奥利万星(oritavancin)、达巴万星(dalbavancin)、达托霉素(daptomycin)、头孢氨苄(cephalexin)、头孢呋辛(cefuroxime)、头孢羟氨苄(cefadroxil)、头孢唑林(cefazolin)、先锋霉素(cephalothin)、头孢克洛(cefaclor)、头孢孟多(cefamandole)、头孢西丁(cefoxitin)、头孢罗齐(cefprozil)、头孢托罗(ceftobiprole)、西普罗(cipro)、左氟沙星(Levaquin)、菲宁达(floxin)、加替沙星(tequin)、威洛速(avelox)、诺氟沙星(norflox)、四环素(tetracycline)、二甲胺四环素(minocycline)、土霉素(oxytetracycline)、多西环素(doxycycline)、阿莫西林(amoxicillin)、氨比西林(ampicillin)、青霉素V(penicillinV)、双氯西林(dicloxacillin)、羧苄西林(carbenicillin)、甲氧西林(methicillin)、厄他培南(ertapenem)、多尼培南(doripenem)、亚胺培南/西司他丁(imipenem/cilastatin)、美罗培南(meropenem)、阿米卡星(amikacin)、卡那霉素(kanamycin)、新霉素(neomycin)、奈替霉素(netilmicin)、托普霉素(tobramycin)、巴龙霉素(paromomycin)、头孢克肟(cefixime)、头孢地尼(cefdinir)、头孢托仑(cefditoren)、头孢哌酮(cefoperazone)、头孢噻肟(cefotaxime)、头孢他啶(ceftazidime)、头孢布坦(ceftibuten)、头孢唑肟(ceftizoxime)、头孢曲松(ceftriaxone)、头孢西丁(cefoxotin)及链霉素(streptomycin)。
在某些实施方案中,胞内病原体为真菌,且抗感染剂为抗真菌剂。可以用于组合中的示性例抗真菌剂包括(但不限于)游霉素(natamycin)、龟裂杀菌素(rimocidin)、非律平(filipin)、制霉菌素(nystatin)、两性霉素B(amphotericin B)、坎底辛(candicin)及哈霉素(hamycin)、咪康唑(miconazole)、酮康唑(ketoconazole)、克霉唑(clotrimazole)、益康唑(econazole)、奥莫康唑(omoconazole)、联苯苄唑(bifonazole)、布康唑(butoconazole)、芬替康唑(fenticonazole)、异康唑(isoconazole)、奥昔康唑(oxiconazole)、舍他康唑(sertaconazole)、硫康唑(sulconazole)、噻康唑(tioconazole)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、艾沙康唑(isavuconazole)、拉夫康唑(ravuconazole)、泊沙康唑(posaconazole)、伏立康唑(voriconazole)、特康唑(terconazole)及阿巴康唑(albaconazole)、阿巴芬净(abafungin)、特比萘芬(terbinafine)、萘替芬(naftifine)、布替萘芬(butenafine)、阿尼芬净(anidulafungin)、卡泊芬净(caspofungin)、米卡芬净(micafungin)、蓼二醛(polygodial)、苯甲酸(benzoic acid)、环吡酮(ciclopirox)、托萘酯(tolnaftate)、十一碳烯酸(undecylenic acid)、氟胞嘧啶或5-氟胞嘧啶、灰黄霉素(griseofulvin)及卤卤丙炔氧苯(haloprogin)。
在某些实施方案中,胞内病原体为原虫,且抗感染剂为原虫剂。可以用于组合中的示例性抗原虫剂包括(但不限于)奎宁(quinine)(任选地与克林霉素(clindamycin)组合)、氯奎(chloroquine)、阿莫地喹(amodiaquine)、青蒿素(artemisinin)及其衍生物(例如蒿甲醚(artemether)、青蒿琥酯(artesunate)、二氢青蒿素(dihydroartemisinin)、蒿乙醚(arteether))、多西环素(doxycycline)、乙胺嘧啶(pyrimethamine)、甲氟喹(mefloquine)、卤泛曲林(halofantrine)、羟氯奎(hydroxychloroquine)、依氟鸟氨酸(eflornithine)、硝唑尼特(nitazoxanide)、奥硝唑(ornidazole)、巴龙霉素(paromomycin)、戊烷脒(pentamidine)、伯氨喹(primaquine)、乙胺嘧啶、氯胍(proguanil)(任选地与阿托伐醌(atovaquone)组合)、磺酰胺(例如磺胺多辛(sulfadoxine)、磺胺甲氧哒嗪(sulfamethoxypyridazine))、他非诺喹(tafenoquine)及替硝唑(tinidazole)。在特定实施方案中,胞内病原体为疟原虫(例如间日疟原虫、恶性疟原虫、卵形疟原虫、三日疟原虫),且抗感染剂为抗疟疾剂。可以用于组合中的示例性抗疟疾剂包括(但不限于)奎宁(任选地与克林霉素组合)、氯奎、阿莫地喹、青蒿素及其衍生物(例如,蒿甲醚、青蒿琥酯、二氢青蒿素、蒿乙醚)、多西环素、卤泛曲林、甲氟喹、伯氨喹、氯胍(任选地与阿托伐醌组合)、磺酰胺(例如磺胺多辛、磺胺甲氧哒嗪)、他非诺喹。应理解,许多这些抗疟疾剂可以组合使用,尤其用于治疗严重和/或急性感染。
在某些实施方案中,胞内病原体为藻类,且抗感染剂为抗藻类试剂。可以用于组合中的示例性抗藻类试剂包括(但不限于)酮康唑、伊曲康唑、氟康唑及伏立康唑。
在某些实施方案中,胞内病原体为朊蛋白,且抗感染剂为抗朊蛋白剂。可以用于组合中的示例性抗朊蛋白剂包括(但不限于)戊聚糖多硫酸酯、奎纳克林、硫黄素(thioflavine)、两性霉素B、四环素、三环抗抑郁剂(例如地昔帕明(desipramine))及氯化锂。
可用作治疗传染病的组合疗法的一部分的另一类药剂是免疫疗法,例如免疫检查点抑制剂。示例性免疫检查点抑制剂包括抑制以下中的一或多者的药剂:(i)细胞毒性T淋巴细胞相关抗原4(CTLA4);(ii)程序化细胞死亡蛋白1(PD1);(iii)PDL1;(iv)LAG3;(v)B7-H3;(vi)B7-H4;及(vii)TIM3。
可以根据特定感染的诊断选择适当疗法。其中个体感染有多个病原体(例如多个胞内病原体,例如多个病毒感染),用于治疗这些感染的两种或两种以上适当疗法可与本文所描述的聚乙二醇化精氨酸酶组合使用。
V.药物组合物及递送方法
本发明的特征还在于含有治疗有效量的本文所描述的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶的药物组合物。所述组合物可以被配制用于多种药物递送系统。该组合物中还可以包括一或多种生理学上可接受的赋形剂或载体以用于适当配制。用于本发明中的合适的配制剂见于Remington's Pharmaceutical Sciences,Mack PublishingCompany,Philadelphia,Pa.,第17版,1985中。药物递送方法的简要综述参见例如Langer(Science 249:1527-1533,1990)。
非经肠递送
本发明的静脉内药物递送配制物可含于袋、笔或注射器中。在某些实施方案中,袋可连接至包含管和/或针的通道。在某些实施方案中,配制物可为冻干配制物或液体配制物。在某些实施方案中,配制物可经冷冻干燥(冻干)且含于约12-60个小瓶中。在某些实施方案中,配制物可经冷冻干燥且可在一个小瓶中含有约45mg冷冻干燥配制物。在某些实施方案中,在一个小瓶中可含有约40mg至约100mg冷冻干燥配制物。在某些实施方案中,将来自小瓶(例如12、27或45个小瓶)的冷冻干燥配制物合并以获得静脉内药物配制物中的治疗剂量的聚乙二醇化精氨酸酶。在某些实施方案中,配制物可为液体配制物且按约250mg/小瓶至约1000mg/小瓶储存。在某些实施方案中,配制物可为液体配制物且按约600mg/小瓶储存。在某些实施方案中,配制物可为液体配制物且按约250mg/小瓶储存。
非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶可以液态水性医药配制物形式存在,该配制物包括在形成配制物的缓冲溶液中的治疗有效量的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶。
这些组合物可通过常规灭菌技术灭菌,或可经无菌过滤。所得水溶液可经包装以按原样使用,或经冻干,冻干制剂在施用之前与无菌水性载体组合。制剂的pH通常在3与11之间,更佳在5与9之间或在6与8之间,且最佳在7与8之间,诸如7至7.5。呈固体形式的所得组合物可以多个单剂量单元包装,各单元含有固定量的以上提及的一或多种药剂。呈固体形式的组合物也可以灵活的数量包装于容器中。
在某些实施方案中,本发明提供保质期延长的配制物,其包括本发明的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶,与甘露醇、单水合柠檬酸、柠檬酸钠、二水合磷酸氢二钠、二水合磷酸二氢钠、氯化钠、聚山梨醇酯80、水及氢氧化钠中的一或多者组合。
在某些实施方案中,制备包括本发明的蛋白质于pH缓冲溶液中的水性配制物。缓冲液可具有范围为约4至约8,例如约4.5至约6.0或约4.8至约5.5的pH或可具有约5.0至约5.2的pH。亦希望上述pH值的中间范围为本发明的一部分。举例而言,预期包括使用任何上述值的组合作为上限和/或下限的值范围。将pH控制在此范围内的缓冲剂的实例包括乙酸盐(例如乙酸钠)、丁二酸盐(诸如丁二酸钠)、葡糖酸盐、组氨酸、柠檬酸盐及其他有机酸缓冲剂。
在某些实施方案中,配制物包括含有柠檬酸盐及磷酸盐以将pH维持于约4至约8的范围内的缓冲液系统。在某些实施方案中,pH范围可为约4.5至约6.0,或约pH 4.8至约5.5,或在约5.0至约5.2的pH范围内。在某些实施方案中,该缓冲液系统包括单水合柠檬酸、柠檬酸钠、二水合磷酸氢二钠和/或二水合磷酸二氢钠。在某些实施方案中,该缓冲液系统包括约1.3mg/mL柠檬酸(例如1.305mg/mL)、约0.3mg/mL柠檬酸钠(例如0.305mg/mL)、约1.5mg/mL二水合磷酸氢二钠(例如1.53mg/mL)、约0.9mg/mL二水合磷酸二氢钠(例如0.86mg/mL)及约6.2mg/mL氯化钠(例如6.165mg/mL)。在某些实施方案中,缓冲液系统包括约1至约1.5mg/mL柠檬酸、约0.25至约0.5mg/mL柠檬酸钠、约1.25至约1.75mg/mL二水合磷酸氢二钠、约0.7至约1.1mg/mL二水合磷酸二氢钠及约6.0至约6.4mg/mL氯化钠。在某些实施方案中,配制物的pH值是用氢氧化钠调整。
配制物中亦可包括充当张力剂的多元醇。添加至配制物中的多元醇的量可根据配制物的所需等渗性而改变。在某些实施方案中,水性配制物可以是等渗的。多元醇添加量亦可根据多元醇的分子量来改变。举例而言,相较于二醣(诸如海藻糖),可添加较低量的单醣(例如甘露醇)。在某些实施方案中,可作为张力剂用于配制物中的多元醇是甘露醇。在某些实施方案中,甘露醇浓度可为约5至约20mg/mL。在某些实施方案中,甘露醇浓度可为约7.5至约15mg/mL。在某些实施方案中,甘露醇浓度可为约10至约14mg/mL。在某些实施方案中,甘露醇浓度可为约12mg/mL。在某些实施方案中,配制物中可包括多元醇山梨醇。
亦可将去垢剂或表面活性剂添加至配制物中。示例性去垢剂包括非离子去垢剂,诸如聚山梨醇酯(例如聚山梨醇酯20、80等)或泊洛沙姆(poloxamers)(例如泊洛沙姆188)。所添加的去垢剂的量可以使配制物中微粒的形成降至最低和/或减少吸附。在某些实施方案中,配制物可包括表面活性剂聚山梨醇酯。在某些实施方案中,配制物可含有去垢剂聚山梨醇酯80或Tween80。Tween 80为用于描述聚氧乙烯(20)山梨醇酐单油酸酯(参见Fiedler,Lexikon der Hifsstoffe,Editio Cantor Verlag Aulendorf,第4版,1996)的术语。在某些实施方案中,配制物可含有在约0.1mg/mL与约10mg/mL之间,或在约0.5mg/mL与约5mg/mL之间的聚山梨醇酯80。在某些实施方案中,配制物中可添加约0.1%聚山梨醇酯80。
在实施方案中,本文所描述的组合物配制为液体配制物。液体配制物可以10mg/mL浓度存在于USP/Ph Eur I型50R小瓶中,该小瓶用橡胶塞封闭且用铝褶密封盖密封。该橡胶塞可由符合USP及Ph Eur的弹性体制成。在某些实施方案中,液体配制物可用0.9%生理盐水溶液稀释。
在某些实施方案中,本文所描述的组合物可制备为10mg/mL浓度溶液与稳定含量的糖的组合。在某些实施方案中,液体配制物可在水性载体中制备。在某些实施方案中,稳定剂可以不超过可能引起静脉内给药所不期望或不适合的黏度的量添加。在某些实施方案中,糖可为二醣,例如蔗糖。在某些实施方案中,液体配制物亦可包括缓冲剂、表面活性剂及防腐剂中的一或多者。
在某些实施方案中,液体配制物的pH可通过添加药学上可接受的酸和/或碱设定。在某些实施方案中,药学上可接受的酸可为盐酸。在某些实施方案中,碱可为氢氧化钠。
除聚集外,脱氨基是在发酵、收集/细胞澄清、纯化、药物物质/药品储存期间及在样品分析期间可能产生的肽及蛋白质的常见产物变异体。脱氨基为蛋白质损失NH3,从而形成可以经历水解的丁二酰亚胺中间物。丁二酰亚胺中间物引起亲本肽质量减少17道尔顿(dalton)。后续水解引起质量增加18道尔顿。丁二酰亚胺中间物因在水性条件下不稳定而难以分离。因此,脱氨基通常可检测为1道尔顿质量增加。天冬酰氨脱氨基产生天冬氨酸或异天冬氨酸。影响脱氨基速率的参数包括pH、温度、溶剂介电常数、离子强度、初始序列、局部多肽构象及三级结构。与肽链中的Asn相邻的氨基酸残基影响脱氨基速率。蛋白质序列中在Asn之后的Gly及Ser使得更易于脱氨基。
在某些实施方案中,本发明的组合物可在防止蛋白产物脱氨基的pH及湿度条件下保存。
本文所描述的组合物可以包括水性载体。本文中所关注的水性载体为药学上可接受的(对于施用人而言安全且无毒)且可用于制备液体配制物。说明性载体包括无菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH缓冲溶液(例如磷酸盐缓冲生理盐水)、无菌生理盐水溶液、林格氏溶液或右旋糖溶液。
防腐剂可任选地添加至本文所描述的配制物中以减少细菌作用。防腐剂的添加可例如促进多次使用(多剂量)配制物的产生。
在特定情况下,诸如当患者在医院经由静脉内途径接受所有药物时,静脉内(IV)配制物可为优选的施用途径。在某些实施方案中,液体配制物在施用之前用0.9%氯化钠溶液稀释。在某些实施方案中,用于注射的经稀释药品是等渗的且适合于通过静脉内输注来施用。
在某些实施方案中,盐或缓冲液组分的添加量可为10mM-200mM。盐和/或缓冲剂是药学上可接受的,且衍生自多种已知酸(无机及有机酸)与“成碱”金属或胺。在某些实施方案中,缓冲液可为磷酸盐缓冲液。在某些实施方案中,缓冲液可为甘氨酸盐、碳酸盐、柠檬酸盐缓冲液,在此情况下,钠、钾或铵离子可以充当平衡离子。
在某些实施方案中,冻干药品可由水性载体构成。本文所关注的水性载体是药学上可接受(例如对于施用人而言为安全且无毒的)且可用于制备液体配制物的水性载体。说明性载体包括无菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH缓冲溶液(例如磷酸盐缓冲生理盐水)、无菌生理盐水溶液、林格氏溶液或右旋糖溶液。
本发明的精氨酸酶(例如非聚乙二醇化或聚乙二醇化精氨酸酶)可以存在于包括精氨酸酶及冻干保护剂的冻干配制物中。冻干保护剂可为糖,例如二醣。在某些实施方案中,冻干保护剂可为蔗糖或麦芽糖。冻干配制物亦可包括缓冲剂、表面活性剂、增体剂和/或防腐剂中的一或多者。可用于稳定冻干药品的蔗糖或麦芽糖的量可为至少1:2重量比的蛋白质比蔗糖或麦芽糖。在某些实施方案中,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶与蔗糖或麦芽糖的重量比可为1:2至1:5。
在某些实施方案中,配制物在冻干前的pH可通过添加药学上可接受的酸和/或碱来设定。在某些实施方案中,药学上可接受的酸可为盐酸。在某些实施方案中,药学上可接受的碱可为氢氧化钠。在冻干前,含有本发明的蛋白质的溶液的pH可在6至8之间调整。在某些实施方案中,冻干药品的pH范围可为7至8。
在某些实施方案中,可添加“增体剂”。“增体剂”为使冻干混合物的质量增加且促成冻干块的物理结构(例如有助于产生维持开孔结构的基本上均一的冻干块)的化合物。说明性增体剂包括甘露醇、甘氨酸、聚乙二醇及山梨醇。本发明的冻干配制物可含有此类增体剂。
在某些实施方案中,本文所描述的冻干药品用无菌注射用水、USP(SWFI)或0.9%氯化钠注射液USP重构。在重构期间,将冻干粉末溶解成溶液。
在某些实施方案中,本文所描述的冻干组合物构成至约4.5mL注射用水且用0.9%生理盐水溶液(氯化钠溶液)稀释。
在一些实施方案中,本发明的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶是局部施用且可配制成多种可局部施用的组合物,诸如溶液、悬浮液、洗剂、凝胶、糊剂、药用棒、香膏、乳膏及软膏。此类药物组合物可以含有增溶剂、稳定剂、张力增强剂、缓冲液及防腐剂。
在一些实施方案中,如本文所揭示的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)的递送是经由吸入途径。吸入可经由口腔和/或鼻腔介导。在一些实施方案中,吸入藉助于喷雾器或吸入器(例如定量吸入器或干粉吸入器)。在某些实施方案中,递送是经由吸入液雾。在某些实施方案中,递送是经由吸入固体。在一些实施方案中,固体是纳米级的且与纳米粒子、纳米金刚石或纳米碳组合配制,或包装在脂质体或基于脂质体的包装中。
肠内施用
在一些实施方案中,本文涵盖适用于经口递送所公开的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)的组合物,例如包括肠溶包衣(例如,耐胃包衣)的片剂,以使得组合物可将精氨酸酶递送至(例如)患者的胃肠道。
举例而言,提供包含包括所公开的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)及药学上可接受的赋形剂的颗粒剂(例如,至少部分由所述颗粒剂形成)的用于经口施用的片剂。此类片剂可包有肠溶包衣。预期片剂可包括药学上可接受的赋形剂,诸如填充剂、黏合剂、崩解剂和/或润滑剂,以及着色剂、脱模剂、包衣剂、甜味剂、调味剂(诸如冬青、橙子、木糖醇、山梨醇、果糖及麦芽糊精)及芳香剂、防腐剂和/或抗氧化剂。
在一些实施方案中,所涵盖的医药配制物包括颗粒内相,所述颗粒内相包括所公开的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)及药学上可接受的盐及药学上可接受的填充剂。举例而言,所揭示的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶及填充剂可任选地与其他赋形剂掺合在一起且形成为颗粒剂。在一些实施例中,颗粒内相可使用湿式造粒形成,例如将液体(例如水)添加至掺合的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶及填充剂,且随后组合经干燥、研磨和/或筛分以产生颗粒。本领域技术人员将了解,其他方法可用于实现颗粒内相。
在一些实施方案中,所涵盖的配制物包括颗粒外相,其可包括一或多种药学上可接受的赋形剂,且其可与颗粒内相掺合以形成所公开的配制物。
所公开的配制物可包括包括填充剂的颗粒内相。示例性填充剂包括(但不限于)纤维素、明胶、磷酸钙、乳糖、蔗糖、葡萄糖、甘露醇、山梨醇、微晶纤维素、果胶、聚丙烯酸酯、右旋糖、乙酸纤维素、羟丙基甲基纤维素、部分预胶凝化淀粉、碳酸钙及其他包括其组合。
在一些实施方案中,所公开的配制物可包括颗粒内相和/或颗粒外相,其包括黏合剂,其可通常用于将医药配制物的成分保持在一起。本发明的示例性黏合剂可包括(但不限于)以下:淀粉、糖、纤维素或改性纤维素,诸如羟丙基纤维素、乳糖、预胶凝化玉米淀粉、聚乙烯吡咯啶酮、羟丙基纤维素、羟丙基甲基纤维素、低取代羟丙基纤维素、羧甲基纤维素钠、甲基纤维素、乙基纤维素、糖醇及其他包括其组合。
例如包括颗粒内相和/或颗粒外相的预期配制物可包括崩解剂,诸如(但不限于)淀粉、纤维素、交联聚乙烯吡咯啶酮、羟基乙酸淀粉钠、羧甲基纤维素钠、海藻酸盐、玉米淀粉、交联羧甲基纤维素钠、交联羧甲基纤维素、低取代羟丙基纤维素、阿拉伯胶及其他包括其组合。举例而言,颗粒内相和/或颗粒外相可包括崩解剂。
在一些实施方案中,所涵盖的配制物包括包含所公开的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶及选自以下的赋形剂的颗粒内相:甘露醇、微晶纤维素、羟丙基甲基纤维素及羟基乙酸淀粉钠或其组合,及包含以下中的一或多者的颗粒外相:微晶纤维素、羟基乙酸淀粉钠及硬脂酸镁或其混合物。
在一些实施方案中,预期配制物可包括润滑剂,例如颗粒外相可含有润滑剂。润滑剂包括(但不限于)滑石、二氧化硅、脂肪、硬脂酸甘油酯、硬脂酸镁、磷酸钙、二氧化硅、硅酸钙、磷酸钙、胶态二氧化硅、金属硬脂酸盐、氢化植物油、玉米淀粉、苯甲酸钠、聚乙二醇、乙酸钠、硬脂酸钙、月桂基硫酸钠、氯化钠、月桂基硫酸镁、滑石及硬脂酸。
在一些实施方案中,本文所描述的组合物包含肠溶包衣。一般而言,肠溶衣产生用于控制药物沿消化道吸收的位置的口服药物的屏障。肠溶包衣可包括根据pH以不同速率分解的聚合物。肠溶包衣可包括例如邻苯二甲酸乙酸纤维素、丙烯酸甲酯-甲基丙烯酸共聚物、乙酸丁二酸纤维素、邻苯二甲酸羟丙基甲基纤维素、甲基丙烯酸甲酯-甲基丙烯酸共聚物、丙烯酸乙酯-甲基丙烯酸共聚物、C型甲基丙烯酸共聚物、聚乙酸乙烯酯-邻苯二甲酸酯及邻苯二甲酸乙酸纤维素。
示例性肠溶包衣包括AMB、级别。在一些实施例中,肠溶包衣可包含预期片剂的重量的约5%至约10%、约5%至约20%、约8%至约15%、约8%至约20%、约10%至约20%、或约12%至约20%或约18%。举例而言,肠溶包衣可包括丙烯酸乙酯-甲基丙烯酸共聚物。
剂量
本文中所描述的药物组合物中的活性成分的实际剂量水平可变化,以便获得可有效实现特定患者、组合物及施用模式所需治疗反应且对患者无毒性的活性成分的量。
特定剂量可以为各患者的均一剂量,例如每日1ng/kg至1mg/kg蛋白质。或者,可以根据患者的大致体重或表面积定制患者的剂量。确定适当剂量的其他因素可以包括待治疗或预防的疾病或病况、疾病的严重程度、施用途径以及患者的年龄、性别及医学状况。本领域技术人员依常规方式,尤其根据剂量信息及本文所揭示的分析,进一步改进为确定适当治疗剂量所必需的计算。亦可以通过使用用于确定剂量的已知分析,结合使用适当的剂量响应数据来确定剂量。可以在监测疾病进展时调整个别患者的剂量。可以测量患者中的精氨酸酶的血液含量以了解是否需要调整剂量以达到或维持有效浓度。药物基因组学可用于确定哪些精氨酸酶及其剂量最可能对既定个体有效(Schmitz等人,Clinica Chimica Acta308:43-53,2001;Steimer等人,Clinica Chimica Acta 308:33-41,2001)。
本文所描述的药物组合物可以呈适合于单次施用精确剂量的单位剂型。在单位剂型中,将配制物分成含有适量一或多种化合物的单位剂量。单位剂量可以呈含有离散量配制物的包装形式。非限制性实例为包装片剂或胶囊及小瓶或安瓿中的粉剂。水性悬浮液组合物可以包装于不可再封闭的单剂量容器中。可以使用多剂量可再封闭容器,例如与防腐剂组合或不与防腐剂组合。在一些实施方案中,药物组合物不包含防腐剂。用于非经肠注射的配制物可以以单位剂型存在,例如在安瓿中,或在含防腐剂的多剂量容器中。
本文所描述的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)可以以下述范围存在于组合物中:约1mg至约2000mg、约5mg至约1000mg、约10mg至约500mg、约50mg至约250mg、约100mg至约200mg、约1mg至约50mg、约50mg至约100mg、约100mg至约150mg、约150mg至约200mg、约200mg至约250mg、约250mg至约300mg、约300mg至约350mg、约350mg至约400mg、约400mg至约450mg、约450mg至约500mg、约500mg至约550mg、约550mg至约600mg、约600mg至约650mg、约650mg至约700mg、约700mg至约750mg、约750mg至约800mg、约800mg至约850mg、约850mg至约900mg、约900mg至约950mg、或约950mg至约1000mg。
本文所描述的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)可以以约1mg、约2mg、约3mg、约4mg、约5mg、约10mg、约15mg、约20mg、约25mg、约30mg、约35mg、约40mg、约45mg、约50mg、约55mg、约60mg、约65mg、约70mg、约75mg、约80mg、约85mg、约90mg、约95mg、约100mg、约125mg、约150mg、约175mg、约200mg、约250mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约650mg、约700mg、约750mg、约800mg、约850mg、约900mg、约950mg、约1000mg、约1050mg、约1100mg、约1150mg、约1200mg、约1250mg、约1300mg、约1350mg、约1400mg、约1450mg、约1500mg、约1550mg、约1600mg、约1650mg、约1700mg、约1750mg、约1800mg、约1850mg、约1900mg、约1950mg或约2000mg的量存在于组合物中。
本文所描述的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)的治疗有效剂量可以为约1ng/kg至约10ng/kg、约1ng/kg至约100ng/kg、约1ng/kg至约1mg/kg、约1ng/kg至约10mg/kg、约1ng/kg至约100mg/kg、约1ng/kg至约250mg/kg、约1ng/kg至约500mg/kg、约1ng/kg至约750mg/kg、约1ng/kg至约1,000mg/kg、约1ng/kg至约1,250mg/kg、约1ng/kg至约1,500mg/kg、约1ng/kg至约1,750mg/kg、约1ng/kg至约2,000mg/kg、约10ng/kg至约100ng/kg、约10ng/kg至约1mg/kg、约10ng/kg至约10mg/kg、约10ng/kg至约100mg/kg、约10ng/kg至约500mg/kg、约10ng/kg至约750mg/kg、约10ng/kg至约1,000mg/kg、约10ng/kg至约1,250mg/kg、约10ng/kg至约1,500mg/kg、约10ng/kg至约2,000mg/kg、约100ng/kg至约1mg/kg、约100ng/kg至约10mg/kg、约100ng/kg至约1mg/kg100 mg/kg、约100ng/kg至约250mg/kg、约100ng/kg至约500mg/kg、约100ng/kg至约750mg/kg、约100ng/kg至约1,000mg/kg、约100ng/kg至约1,250mg/kg、约100ng/kg至约1,500mg/kg、约100ng/kg至约1,750mg/kg、约100ng/kg至约2,000mg/kg、约1mg/kg至约10mg/kg、约1mg/kg至约100mg/kg、约1mg/kg至约500mg/kg、约1mg/kg至约750mg/kg、约1mg/kg至约1,000mg/kg、约1mg/kg至约1,250mg/kg、约1mg/kg至约1,500mg/kg、约1mg/kg至约1,750mg/kg,约1mg/kg至约2,000mg/kg、约10mg/kg至约100mg/kg、约10mg/kg至约500mg/kg、约10mg/kg至约750mg/kg、约10mg/kg至约1,000mg/kg,约10mg/kg至约1,250mg/kg、约10mg/kg至约1,500mg/kg、约10mg/kg至约1,750mg/kg、约10mg/kg至约2,000mg/kg、约100mg/kg至约500mg/kg、约100mg/kg至约750mg/kg、约100mg/kg至约1,000mg/kg、约100mg/kg至约1,250mg/kg、约100mg/kg至约1,500mg/kg、约100mg/kg至约1,750mg/kg、约100mg/kg至约2,000mg/kg、约500mg/kg至约750mg/kg、约500mg/kg至约1,000mg/kg、约500mg/kg至约1,250mg/kg、约500mg/kg至约1,500mg/kg、约500mg/kg至约1,750mg/kg、约500mg/kg至约2,000mg/kg、约750mg/kg至约1,000mg/kg、约750mg/kg至约1,250mg/kg、约750mg/kg至约1,500mg/kg、约750mg/kg至约1,750mg/kg、约750mg/kg至约2,000mg/kg、约1,000mg/kg至约1,250mg/kg、约1,000mg/kg至约1,500mg/kg、约1,000mg/kg至约1,750mg/kg,或约1,000mg/kg至约2,000mg/kg。
在一些实施方案中,本文所描述的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)组合物的治疗有效剂量可以包括约1ng、约10ng,约50ng、约100ng、约200ng、约250ng、约300ng、约400ng、约500ng、约600ng、约700ng、约750ng、约800ng、约900ng、约1000ng、约10μg、约50μg、约100μg、约200μg、约250μg、约300μg、约400μg、约500μg、约600μg,约700μg、约750μg、约800μg、约900μg、约1000μg、约5mg、约10mg、约100mg、约200mg、约250mg、约300mg、约400mg、约500mg、约600mg、约700mg、约750mg、约800mg、约900mg、约1000mg、约1500mg、约2000mg、约3000mg、约4000mg、约5000mg、约6000mg、约7000mg、约8000mg、约9000mg或约10g的非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶。
在一些实施方案中,精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)的治疗有效量为约1mg/kg至约10mg/kg。在一些实施方案中,精氨酸酶的治疗有效量为约10mg/kg至约100mg/kg。在一些实施方案中,精氨酸酶的治疗有效量大于100mg/kg。
如本文所描述的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)(包含例如精氨酸酶蛋白质序列或其功能片段,例如精氨酸酶序列的催化域)可以在例如传染性疾病或病况的疾病或病况出现之前、期间或之后施用。在一些实施方案中,精氨酸酶可以用作预防剂且可以连续向具有病况或疾病倾向的个体施用以便减少疾病或病况出现的可能性。精氨酸酶可以在症状发作期间或症状发作后尽快地施用至个体。施用精氨酸酶可以紧接着在症状发作内开始,在症状发作的最初3小时内、在症状发作的最初6小时内、在症状发作的最初24小时内、在症状发作的48小时内或在自症状发作的任何时段内开始。本公开的精氨酸酶的施用可以持续治疗疾病或病症所需的时间长度,诸如约24小时至约48小时、约48小时至约1周、约1周至约2周、约2周至约1个月、约1个月至约3个月。在一些实施方案中,可以施用精氨酸酶持续至少24小时、至少48小时、至少72小时、至少96小时、至少1周、至少2周、至少3周、至少4周、至少1个月、至少2个月、至少3个月、至少4个月、至少5个月、至少6个月、至少7个月、至少8个月、至少9个月、至少10个月、至少11个月、至少12个月、至少1年、至少2年、至少3年、至少4年或至少5年,或一生。各个体的治疗时长可以不同。
在某些实施方案中,当个体无症状时,治疗开始。在一些实施方案中,在个体展示症状时开始治疗。传染性疾病或病症的症状包括(但不限于)发热、发冷、充血、疲乏、肌肉疼痛、头痛、喉咙痛、耳痛、腹泻、呕吐、脱水、休克、咳嗽、干咳嗽、打喷嚏、皮疹、呼吸短促、失嗅、肺炎、心率升高、低血压、癫痫、意识模糊、谵妄、幻觉、颤抖、协调受损、结膜炎、细胞因子风暴、器官衰竭及死亡。
如本文所使用,“细胞因子风暴”是指在本领域亦已知作为细胞因子释放症候群或细胞因子风暴症候群的免疫系统的急性过度反应;此类免疫反应为可以由传染性疾病或病症引起的全身性发炎反应症候群。细胞因子风暴病理学与在局部部位处开始且例如经由全身性循环扩散在全身的炎症相关。由病毒感染引起的细胞因子风暴病理学与急性肺损伤及急性呼吸窘迫综合征相关。细胞因子风暴病理学描述于例如Tisonick等人,(2012)“Intothe Eye of the Cytokine Storm”,Microbiol.Mol.Biol.Rev.,76(1):16-32。在某些实施方案中,传染性疾病或病症为COVID-19且症状为细胞因子风暴。在某些实施方案中,传染性疾病或病症为COVID-19且症状为肺炎。
在一些实施方案中,本文所描述的方法(例如,包括施用精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)、其药学上可接受的盐或其组合物的方法)有效调节细胞因子释放。在一些实施例中,本文所描述的方法(例如包括施用精氨酸酶、其药学上可接受的盐或其组合物的方法)有效调节白介素6(IL-6)或白介素γ(IFNγ)的表达。在一些实施方案中,本文所描述的方法(例如包括施用精氨酸酶、其药学上可接受的盐或其组合物的方法)有效调节肿瘤坏死因子(TNF)、IL-1β、MCP-1、IL-6、IFNγ、IL-10的表达或分泌。
所施用的量将视以下变量而定:诸如待治疗的疾病或感染的类型及程度、患者的总体健康及大小、精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)的活体内效能、医药配制物及施用途径。初始剂量可以增加以快速达成所需血液含量或组织含量。或者,初始剂量可以小于最佳剂量且剂量可在治疗过程中逐渐增加。人剂量可以例如在常规I期剂量递增研究中优化。给药频率可以视诸如施用途径、给药量及所治疗的疾病的因素而变化。示例性给药频率为每天三次、每天两次、每天一次、每两天一次、每三天一次、每四天一次、每五天一次、每六天一次、每周一次及每两周一次。
本文所描述的精氨酸酶(例如,非聚乙二醇化精氨酸酶或聚乙二醇化精氨酸酶)的施用可以为(但不限于)静脉内、动脉内、腹膜内、肌内、皮下、胸膜内、鞘内、腔内、通过吸入、经由导管灌注或通过直接病灶内注射。
以上说明描述本文所描述的方法、组合物及试剂盒的多个方面及实施方案。本专利申请案特别涵盖所述方面及实施方案的所有组合及排列。
实施例
现已一般性地描述本发明,将参考以下实施例更容易地理解本发明,所述实施例仅出于说明本发明的某些方面及实施方案的目的包括在内,且不意欲限制本发明。
实施例1:聚乙二醇化精氨酸酶抑制严重急性呼吸综合征相关的冠状病毒(SARSr-CoV)的复制
在此实施例中,测定聚乙二醇化精氨酸酶对SARSr-CoV菌株复制的作用。经检测的SARSr-CoV菌株包括分别引起2002-2004SARS爆发及COVID-19的SARS-CoV及SARS-CoV-2。
此实施例中所使用的聚乙二醇化精氨酸酶为BCT-100,其具有SEQ ID NO:56的序列且如美国专利第9,109,218号中所描述制备,除了在此实施例中使用具有N末端6×His标签的野生型人精氨酸酶1(即SEQ ID NO:56)。
在37℃及5% CO2下,将Vero E6细胞以单层形式维持在补充有10%胎牛血清(美国赛默飞世尔科技(Thermo Fisher Scientific,USA))的伊格尔(Eagle's)最小必需培养基(Minimum Essential Medium,MEM)中。细胞以2×105个细胞/mL的密度再悬浮于新鲜完全生长培养基中且接种于24孔培养盘中。细胞用不同剂量的聚乙二醇化精氨酸酶处理且以0.01的感染复数(MOI)感染SARS-CoV或SARS-CoV-2。在感染后48小时收集培养物上清液。所收集的上清液中SARS-CoV及SARS-CoV-2的病毒负荷使用中值组织培养物感染剂量(TCID50)分析定量。
观察聚乙二醇化精氨酸酶对SAR-CoV及SARS-CoV-2复制的剂量依赖性抑制作用(单因素方差分析测试(one-way ANOVA tests),p<0.01)。SARS-CoV及SARS-CoV-2复制的统计学显著抑制分别用≥1μg/mL的聚乙二醇化精氨酸酶(图1)及≥6.8μg/mL的聚乙二醇化精氨酸酶(图2)的治疗来观察(邓尼特测试(Dunnett's tests),p<0.05)。
实施例2:精氨酸酶抑制中东呼吸综合征相关的冠状病毒(MERS-CoV)的复制
在此实施例中,测定重组精氨酸酶对MERS-CoV复制的作用。
此实施例中所使用的非聚乙二醇化精氨酸为使用具有N末端6xHis标签的野生型人精氨酸酶1(即SEQ ID NO:56)。此实施例中所使用的聚乙二醇化精氨酸酶为BCT-100,其具有SEQ ID NO:56的序列且如美国专利第9,109,218号中所描述制备,除了在此实施例中使用具有N末端6×His标签的野生型人精氨酸酶1(即SEQ ID NO:56)。
在37℃及5% CO2下,将Huh-7细胞以单层形式维持在补充有10%胎牛血清的杜尔贝科氏改质的伊格尔培养基(Dulbecco's Modified Eagle Medium,DMEM)中。细胞以2×105个细胞/mL的密度再悬浮于新鲜完全生长培养基中且接种于24孔培养盘中。用1250、2500、5000或10000ng/mL非聚乙二醇化或聚乙二醇化精氨酸酶处理所接种的细胞,且以0.001的MOI感染MERS-CoV。在感染后24小时收集培养物上清液。使用定量反转录PCR(RT-qPCR)根据病毒基因组的拷贝数定量所收集上清液中的病毒滴度。
在精氨酸酶的所有测试浓度下观测到MERS-CoV复制的抑制,与聚乙二醇化无关(图3)。半最大抑制浓度(IC50)经由双参数逻辑模型分别估计为≤1325ng/mL及≤331ng/mL(95%置信界限)非聚乙二醇化精氨酸酶及聚乙二醇化精氨酸酶。
实施例3:精氨酸酶抑制流感病毒的复制
在此实施例中,测定重组精氨酸酶对流感病毒病毒株(包括猪流感病毒(H1N1)及禽流感病毒(H5N1))复制的作用。
此实施例中所使用的非聚乙二醇化精氨酸为使用具有N末端6×His标签的野生型人精氨酸酶1(即SEQ ID NO:56)。此实施例中所使用的聚乙二醇化精氨酸酶为BCT-100,其具有SEQ ID NO:56的序列且如美国专利第9,109,218号中所描述制备,除了在此实例中使用具有N末端6×His标签的野生型人精氨酸酶1(即SEQ ID NO:56)。
在37℃,5% CO2下,将MDCK细胞(ATCC)以单层形式培养于补充有10%胎牛血清的MEM中。细胞以1×105个细胞/mL的密度再悬浮于新鲜培养基中且接种于24孔培养盘中。将所接种的细胞以0.01的MOI感染流感病毒A H1N1(大流行性H1N1/09)或H5N1(A/越南/1203/2004),且用不同剂量的非聚乙二醇化(针对H1N1)或聚乙二醇化(针对H1N1及H5N1)精氨酸酶处理。感染后24小时收集培养物上清液。所收集的上清液中H1N1及H5N1的滴度分别使用RT-qPCR及TCID50分析来定量。
H1N1的复制在≥156ng/mL非聚乙二醇化或≥625ng/mL聚乙二醇化精氨酸酶存在下几乎完全消除(图4)。非聚乙二醇化或聚乙二醇化精氨酸酶对H1N1复制的IC50经由双参数逻辑模型分别估计为11ng/mL(96%置信区间:11-12ng/mL)及44ng/mL(95%置信区间:11-181ng/mL)。
还观察到聚乙二醇化精氨酸酶对H5N1复制的类似剂量依赖性抑制作用(单因素方差分析,F3,4=91.24,p<0.001;图5)。当分别用1μg/mL或2μg/mL聚乙二醇化精氨酸酶处理时,观察到42倍(即1.63-log10)或86倍(即1.94-log10)传染性滴度降低(邓奈特测试,p<0.001)。
实施例4:精氨酸酶抑制人腺病毒复制
在此实施例中,测定精氨酸酶对腺病毒病毒株(包括人腺病毒血清型5(HAdV-5))复制的作用。
此实施例中所使用的非聚乙二醇化精氨酸为使用具有N末端6×His标签的野生型人精氨酸酶1(即SEQ ID NO:56)。此实施例中所使用的聚乙二醇化精氨酸酶为BCT-100,其具有SEQ ID NO:56的序列且如美国专利第9,109,218号中所描述制备,除了在此实施例中使用具有N末端6×His标签的野生型人精氨酸酶1(即SEQ ID NO:56)。
在37℃,5% CO2下,将HEp-2细胞(ATCC)以单层形式培养于补充有10%胎牛血清的MEM中。细胞以1×105个细胞/mL的密度再悬浮于新鲜培养基中且接种于24孔培养盘中。用10、625、1250、2500、5000或10000ng/mL非聚乙二醇化或聚乙二醇化精氨酸酶处理所接种的细胞且以0.5的MOI感染HAdV-5。感染后24小时收集培养物上清液。使用RT-qPCR根据病毒基因组的拷贝数定量所收集上清液中的病毒负荷。
在≥625ng/mL非聚乙二醇化或1250ng/mL聚乙二醇化精氨酸酶存在下消除HAdV-5的复制(图6)。聚乙二醇化精氨酸酶对HAdV-5复制的IC50经由双参数逻辑模型估计为139ng/mL(95%置信区间=40-477ng/mL)。
通过引用并入
除非相反陈述,否则本文所提及的每个专利文献及科学文章中的全部公开出于所有目的以引用的方式并入本文中。
等同物
本发明可在不脱离其精神或基本特征的情况下以其他特定形式来表现。因此,前述实施方案应在所有方面中视为说明性的而非限制本文中所描述的本发明。因此,本发明的范围由随附的权利要求书而非前述说明来指示,且本文意欲涵盖权利要求等同含义及范围内出现的所有变化。
序列表
<110> 香港商康达医药科技有限公司
<120> 使用精胺酸酶治疗病毒感染的方法
<130> BCT-002TW
<140>
<141>
<150> 63/011,658
<151> 2020-04-17
<160> 57
<170> PatentIn version 3.5
<210> 1
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 1
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 2
<211> 134
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 2
His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala Arg Val His Pro
1 5 10 15
Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro
20 25 30
Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu
35 40 45
Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp
50 55 60
Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg
65 70 75 80
Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys
85 90 95
Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met
100 105 110
Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His
115 120 125
Leu Ser Phe Asp Val Asp
130
<210> 3
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 3
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 4
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 4
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 5
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 5
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 6
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 6
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 7
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 7
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 8
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 8
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 9
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 9
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 10
<211> 298
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 10
Met Lys Pro Ile Ser Ile Ile Gly Val Pro Met Asp Leu Gly Gln Thr
1 5 10 15
Arg Arg Gly Val Asp Met Gly Pro Ser Ala Met Arg Tyr Ala Gly Val
20 25 30
Ile Glu Arg Leu Glu Arg Leu His Tyr Asp Ile Glu Asp Leu Gly Asp
35 40 45
Ile Pro Ile Gly Lys Ala Glu Arg Leu His Glu Gln Gly Asp Ser Arg
50 55 60
Leu Arg Asn Leu Lys Ala Val Ala Glu Ala Asn Glu Lys Leu Ala Ala
65 70 75 80
Ala Val Asp Gln Trp Gln Arg Gly Arg Phe Pro Leu Val Leu Gly Gly
85 90 95
Asp His Ser Ile Ala Ile Gly Thr Leu Ala Gly Val Ala Lys His Tyr
100 105 110
Glu Arg Leu Gly Val Ile Trp Tyr Asp Ala His Gly Asp Val Asn Thr
115 120 125
Ala Glu Thr Ser Pro Ser Gly Asn Ile His Gly Met Pro Leu Ala Ala
130 135 140
Ser Leu Gly Phe Gly His Pro Ala Leu Thr Gln Ile Gly Gly Tyr Ser
145 150 155 160
Pro Lys Ile Lys Pro Glu His Val Val Leu Ile Gly Val Arg Ser Leu
165 170 175
Asp Glu Gly Glu Lys Lys Phe Ile Arg Glu Lys Gly Ile Lys Ile Tyr
180 185 190
Thr Met His Glu Val Asp Arg Leu Gly Met Thr Arg Val Met Glu Glu
195 200 205
Thr Ile Ala Tyr Leu Lys Glu Arg Thr Asp Gly Val His Leu Ser Leu
210 215 220
Asp Leu Asp Gly Leu Asp Pro Ser Asp Ala Pro Gly Val Gly Thr Pro
225 230 235 240
Val Ile Gly Gly Leu Thr Tyr Arg Glu Ser His Leu Ala Met Glu Met
245 250 255
Leu Ala Glu Ala Gln Ile Ile Thr Ser Ala Glu Phe Val Glu Val Asn
260 265 270
Pro Ile Leu Asp Glu Arg Asn Lys Thr Ala Ser Val Ala Val Ala Leu
275 280 285
Met Gly Ser Leu Phe Gly Glu Lys Leu Met
290 295
<210> 11
<211> 304
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 11
Met Lys Pro Ile Ser Ile Ile Gly Val Pro Met Asp Leu Gly Gln Thr
1 5 10 15
Arg Arg Gly Val Asp Met Gly Pro Ser Ala Met Arg Tyr Ala Gly Val
20 25 30
Ile Glu Arg Leu Glu Arg Leu His Tyr Asp Ile Glu Asp Leu Gly Asp
35 40 45
Ile Pro Ile Gly Lys Ala Glu Arg Leu His Glu Gln Gly Asp Ser Arg
50 55 60
Leu Arg Asn Leu Lys Ala Val Ala Glu Ala Asn Glu Lys Leu Ala Ala
65 70 75 80
Ala Val Asp Gln Trp Gln Arg Gly Arg Phe Pro Leu Val Leu Gly Gly
85 90 95
Asp His Ser Ile Ala Ile Gly Thr Leu Ala Gly Val Ala Lys His Tyr
100 105 110
Glu Arg Leu Gly Val Ile Trp Tyr Asp Ala His Gly Asp Val Asn Thr
115 120 125
Ala Glu Thr Ser Pro Ser Gly Asn Ile His Gly Met Pro Leu Ala Ala
130 135 140
Ser Leu Gly Phe Gly His Pro Ala Leu Thr Gln Ile Gly Gly Tyr Cys
145 150 155 160
Pro Lys Ile Lys Pro Glu His Val Val Leu Ile Gly Val Arg Ser Leu
165 170 175
Asp Glu Gly Glu Lys Lys Phe Ile Arg Glu Lys Gly Ile Lys Ile Tyr
180 185 190
Thr Met His Glu Val Asp Arg Leu Gly Met Thr Arg Val Met Glu Glu
195 200 205
Thr Ile Ala Tyr Leu Lys Glu Arg Thr Asp Gly Val His Leu Ser Leu
210 215 220
Asp Leu Asp Gly Leu Asp Pro Ser Asp Ala Pro Gly Val Gly Thr Pro
225 230 235 240
Val Ile Gly Gly Leu Thr Tyr Arg Glu Ser His Leu Ala Met Glu Met
245 250 255
Leu Ala Glu Ala Gln Ile Ile Thr Ser Ala Glu Phe Val Glu Val Asn
260 265 270
Pro Ile Leu Asp Glu Arg Asn Lys Thr Ala Ser Val Ala Val Ala Leu
275 280 285
Met Gly Ser Leu Phe Gly Glu Lys Leu Met His His His His His His
290 295 300
<210> 12
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 12
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 13
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 13
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 14
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 14
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 15
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 15
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 16
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 16
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 17
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 17
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 18
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 18
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 19
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 19
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 20
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 20
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 21
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 21
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 22
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 22
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 23
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 23
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 24
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 24
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 25
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 25
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 26
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 26
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 27
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 27
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ser Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 28
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 28
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ala Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 29
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 29
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 30
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 30
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Ala Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Ala Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 31
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 31
Met Ser Phe Lys Ser Gln Ser Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Ala Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Cys Phe Ala Asp Val Pro Asn Asp Thr Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Asn Gln Gln Leu
65 70 75 80
Ala Asp Val Val Ala Glu Ile Lys Lys Asn Gly Arg Thr Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Met Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Cys Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Thr Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Glu Lys Ile Pro Glu Val Pro
145 150 155 160
Gly Leu Ser Trp Val Thr Pro Cys Leu Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Ala Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Ile Glu Val Asp Lys Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Ala Phe Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Phe Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val His Gly Gly Leu Ser Tyr Arg Glu
245 250 255
Gly Ile Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Leu Val Leu Ala Cys Phe
290 295 300
Gly Val Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Lys Pro
305 310 315 320
Pro Lys
<210> 32
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 32
Met Ser Phe Lys Ser Gln Ser Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Ala Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Ser Phe Ala Asp Val Pro Asn Asp Thr Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Asn Gln Gln Leu
65 70 75 80
Ala Asp Val Val Ala Glu Ile Lys Lys Asn Gly Arg Thr Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Met Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Ser Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Thr Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Glu Lys Ile Pro Glu Val Pro
145 150 155 160
Gly Leu Ser Trp Val Thr Pro Ser Leu Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Ala Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Ile Glu Val Asp Lys Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Ala Phe Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Phe Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val His Gly Gly Leu Ser Tyr Arg Glu
245 250 255
Gly Ile Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Leu Val Leu Ala Ser Phe
290 295 300
Gly Val Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Lys Pro
305 310 315 320
Pro Lys
<210> 33
<211> 321
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 33
Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser Lys
1 5 10 15
Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg Lys
20 25 30
Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys Asp
35 40 45
Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe Gln
50 55 60
Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu Ala
65 70 75 80
Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val Leu
85 90 95
Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala Arg
100 105 110
Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp Ile
115 120 125
Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro Val
130 135 140
Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro Gly
145 150 155 160
Phe Ser Trp Val Thr Pro Ser Ile Ser Ala Lys Asp Ile Val Tyr Ile
165 170 175
Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr Leu
180 185 190
Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile Gly
195 200 205
Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys Arg
210 215 220
Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe Thr
225 230 235 240
Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu Gly
245 250 255
Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly Leu
260 265 270
Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu Val
275 280 285
Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ser Phe Gly
290 295 300
Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro Pro
305 310 315 320
Lys
<210> 34
<211> 321
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 符合或不符合
<400> 34
Xaa Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro
<210> 35
<211> 333
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 35
Ser Val His Ser Val Ala Val Ile Gly Ala Pro Phe Ser Gln Gly Gln
1 5 10 15
Lys Arg Lys Gly Val Glu His Gly Pro Ala Ala Ile Arg Glu Ala Gly
20 25 30
Leu Met Lys Arg Leu Ser Ser Leu Gly Cys His Leu Lys Asp Phe Gly
35 40 45
Asp Leu Ser Phe Thr Pro Val Pro Lys Asp Asp Leu Tyr Asn Asn Leu
50 55 60
Ile Val Asn Pro Arg Ser Val Gly Leu Ala Asn Gln Glu Leu Ala Glu
65 70 75 80
Val Val Ser Arg Ala Val Ser Asp Gly Tyr Ser Cys Val Thr Leu Gly
85 90 95
Gly Asp His Ser Leu Ala Ile Gly Thr Ile Ser Gly His Ala Arg His
100 105 110
Cys Pro Asp Leu Cys Val Val Trp Val Asp Ala His Ala Asp Ile Asn
115 120 125
Thr Pro Leu Thr Thr Ser Ser Gly Asn Leu His Gly Gln Pro Val Ser
130 135 140
Phe Leu Leu Arg Glu Leu Gln Asp Lys Val Pro Gln Leu Pro Gly Phe
145 150 155 160
Ser Trp Ile Lys Pro Cys Ile Ser Ser Ala Ser Ile Val Tyr Ile Gly
165 170 175
Leu Arg Asp Val Asp Pro Pro Glu His Phe Ile Leu Lys Asn Tyr Asp
180 185 190
Ile Gln Tyr Phe Ser Met Arg Asp Ile Asp Arg Leu Gly Ile Gln Lys
195 200 205
Val Met Glu Arg Thr Phe Asp Leu Leu Ile Gly Lys Arg Gln Arg Pro
210 215 220
Ile His Leu Ser Phe Asp Ile Asp Ala Phe Asp Pro Thr Leu Ala Pro
225 230 235 240
Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu Gly Met
245 250 255
Tyr Ile Ala Glu Glu Ile His Asn Thr Gly Leu Leu Ser Ala Leu Asp
260 265 270
Leu Val Glu Val Asn Pro Gln Leu Ala Thr Ser Glu Glu Glu Ala Lys
275 280 285
Thr Thr Ala Asn Leu Ala Val Asp Val Ile Ala Ser Ser Phe Gly Gln
290 295 300
Thr Arg Glu Gly Gly His Ile Val Tyr Asp Gln Leu Pro Thr Pro Ser
305 310 315 320
Ser Pro Asp Glu Ser Glu Asn Gln Ala Arg Val Arg Ile
325 330
<210> 36
<211> 321
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 甲硫氨酸或不存在
<400> 36
Xaa Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Ser Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro
<210> 37
<211> 321
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 甲硫氨酸或不存在
<400> 37
Xaa Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Cys Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro
<210> 38
<211> 321
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 甲硫氨酸或不存在
<400> 38
Xaa Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Gly Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro
<210> 39
<211> 321
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 甲硫氨酸或不存在
<400> 39
Xaa Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Phe Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro
<210> 40
<211> 321
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 甲硫氨酸或不存在
<400> 40
Xaa Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Ile Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro
<210> 41
<211> 321
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 甲硫氨酸或不存在
<400> 41
Xaa Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Glu Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ala Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro
<210> 42
<211> 138
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 42
Phe Pro Leu Val Leu Gly Gly Asp His Ser Ile Ala Ile Gly Thr Leu
1 5 10 15
Ala Gly Val Ala Lys His Tyr Glu Arg Leu Gly Val Ile Trp Tyr Asp
20 25 30
Ala His Gly Asp Val Asn Thr Ala Glu Thr Ser Pro Ser Gly Asn Ile
35 40 45
His Gly Met Pro Leu Ala Ala Ser Leu Gly Phe Gly His Pro Ala Leu
50 55 60
Thr Gln Ile Gly Gly Tyr Ser Pro Lys Ile Lys Pro Glu His Val Val
65 70 75 80
Leu Ile Gly Val Arg Ser Leu Asp Glu Gly Glu Lys Lys Phe Ile Arg
85 90 95
Glu Lys Gly Ile Lys Ile Tyr Thr Met His Glu Val Asp Arg Leu Gly
100 105 110
Met Thr Arg Val Met Glu Glu Thr Ile Ala Tyr Leu Lys Glu Arg Thr
115 120 125
Asp Gly Val His Leu Ser Leu Asp Leu Asp
130 135
<210> 43
<211> 134
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 43
His Ser Met Ala Ile Gly Ser Ile Ser Gly His Ala Arg Val His Pro
1 5 10 15
Asp Leu Cys Val Ile Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro
20 25 30
Leu Thr Thr Thr Thr Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu
35 40 45
Leu Lys Glu Leu Lys Glu Lys Ile Pro Glu Val Pro Gly Leu Ser Trp
50 55 60
Val Thr Pro Cys Leu Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg
65 70 75 80
Asp Val Asp Pro Ala Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys
85 90 95
Tyr Phe Ser Met Ile Glu Val Asp Lys Leu Gly Ile Gly Lys Val Met
100 105 110
Glu Glu Ala Phe Ser Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His
115 120 125
Leu Ser Phe Asp Val Asp
130
<210> 44
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 44
Met His His His His His His Met Ser Ala Lys Ser Arg Thr Ile Gly
1 5 10 15
Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val Glu
20 25 30
Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu Lys
35 40 45
Glu Gln Glu Cys Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala Asp
50 55 60
Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser Val
65 70 75 80
Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys Lys
85 90 95
Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala Ile
100 105 110
Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val Ile
115 120 125
Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr Ser
130 135 140
Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu Lys
145 150 155 160
Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Cys Ile
165 170 175
Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly
180 185 190
Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr
195 200 205
Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu Ser
210 215 220
Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp Val
225 230 235 240
Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val Val
245 250 255
Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile Tyr
260 265 270
Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro Ser
275 280 285
Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala Val
290 295 300
Ala Ile Thr Leu Ala Ala Phe Gly Leu Ala Arg Glu Gly Asn His Lys
305 310 315 320
Pro Ile Asp Tyr Leu Asn Pro Pro Lys
325
<210> 45
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 45
Met His His His His His His Met Ser Ala Lys Ser Arg Thr Ile Gly
1 5 10 15
Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val Glu
20 25 30
Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu Lys
35 40 45
Glu Gln Glu Cys Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala Asp
50 55 60
Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser Val
65 70 75 80
Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys Lys
85 90 95
Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala Ile
100 105 110
Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val Ile
115 120 125
Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr Ser
130 135 140
Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu Lys
145 150 155 160
Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Ala Ile
165 170 175
Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly
180 185 190
Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr
195 200 205
Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu Ser
210 215 220
Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp Val
225 230 235 240
Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val Val
245 250 255
Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile Tyr
260 265 270
Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro Ser
275 280 285
Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala Val
290 295 300
Ala Ile Thr Leu Ala Cys Phe Gly Leu Ala Arg Glu Gly Asn His Lys
305 310 315 320
Pro Ile Asp Tyr Leu Asn Pro Pro Lys
325
<210> 46
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 46
Met His His His His His His Met Ser Ala Lys Ser Arg Thr Ile Gly
1 5 10 15
Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val Glu
20 25 30
Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu Lys
35 40 45
Glu Gln Glu Ala Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala Asp
50 55 60
Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser Val
65 70 75 80
Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys Lys
85 90 95
Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala Ile
100 105 110
Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val Ile
115 120 125
Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr Ser
130 135 140
Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu Lys
145 150 155 160
Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Cys Ile
165 170 175
Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly
180 185 190
Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr
195 200 205
Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu Ser
210 215 220
Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp Val
225 230 235 240
Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val Val
245 250 255
Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile Tyr
260 265 270
Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro Ser
275 280 285
Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala Val
290 295 300
Ala Ile Thr Leu Ala Cys Phe Gly Leu Ala Arg Glu Gly Asn His Lys
305 310 315 320
Pro Ile Asp Tyr Leu Asn Pro Pro Lys
325
<210> 47
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 47
Met His His His His His His Met Ser Ala Lys Ser Arg Thr Ile Gly
1 5 10 15
Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val Glu
20 25 30
Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu Lys
35 40 45
Glu Gln Glu Cys Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala Asp
50 55 60
Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser Val
65 70 75 80
Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys Lys
85 90 95
Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala Ile
100 105 110
Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val Ile
115 120 125
Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr Ser
130 135 140
Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu Lys
145 150 155 160
Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Ala Ile
165 170 175
Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly
180 185 190
Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr
195 200 205
Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu Ser
210 215 220
Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp Val
225 230 235 240
Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val Val
245 250 255
Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile Tyr
260 265 270
Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro Ser
275 280 285
Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala Val
290 295 300
Ala Ile Thr Leu Ala Ala Phe Gly Leu Ala Arg Glu Gly Asn His Lys
305 310 315 320
Pro Ile Asp Tyr Leu Asn Pro Pro Lys
325
<210> 48
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 48
Met His His His His His His Met Ser Ala Lys Ser Arg Thr Ile Gly
1 5 10 15
Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val Glu
20 25 30
Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu Lys
35 40 45
Glu Gln Glu Ala Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala Asp
50 55 60
Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser Val
65 70 75 80
Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys Lys
85 90 95
Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala Ile
100 105 110
Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val Ile
115 120 125
Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr Ser
130 135 140
Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu Lys
145 150 155 160
Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Cys Ile
165 170 175
Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly
180 185 190
Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr
195 200 205
Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu Ser
210 215 220
Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp Val
225 230 235 240
Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val Val
245 250 255
Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile Tyr
260 265 270
Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro Ser
275 280 285
Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala Val
290 295 300
Ala Ile Thr Leu Ala Ala Phe Gly Leu Ala Arg Glu Gly Asn His Lys
305 310 315 320
Pro Ile Asp Tyr Leu Asn Pro Pro Lys
325
<210> 49
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 49
Met His His His His His His Met Ser Ala Lys Ser Arg Thr Ile Gly
1 5 10 15
Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val Glu
20 25 30
Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu Lys
35 40 45
Glu Gln Glu Ala Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala Asp
50 55 60
Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser Val
65 70 75 80
Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys Lys
85 90 95
Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala Ile
100 105 110
Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val Ile
115 120 125
Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr Ser
130 135 140
Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu Lys
145 150 155 160
Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Ala Ile
165 170 175
Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly
180 185 190
Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr
195 200 205
Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu Ser
210 215 220
Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp Val
225 230 235 240
Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val Val
245 250 255
Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile Tyr
260 265 270
Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro Ser
275 280 285
Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala Val
290 295 300
Ala Ile Thr Leu Ala Cys Phe Gly Leu Ala Arg Glu Gly Asn His Lys
305 310 315 320
Pro Ile Asp Tyr Leu Asn Pro Pro Lys
325
<210> 50
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 50
Met His His His His His His Met Ser Ala Lys Ser Arg Thr Ile Gly
1 5 10 15
Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val Glu
20 25 30
Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu Lys
35 40 45
Glu Gln Glu Ala Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala Asp
50 55 60
Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser Val
65 70 75 80
Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys Lys
85 90 95
Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala Ile
100 105 110
Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val Ile
115 120 125
Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr Ser
130 135 140
Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu Lys
145 150 155 160
Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Ala Ile
165 170 175
Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly
180 185 190
Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr
195 200 205
Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu Ser
210 215 220
Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp Val
225 230 235 240
Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val Val
245 250 255
Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile Tyr
260 265 270
Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro Ser
275 280 285
Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala Val
290 295 300
Ala Ile Thr Leu Ala Ala Phe Gly Leu Ala Arg Glu Gly Asn His Lys
305 310 315 320
Pro Ile Asp Tyr Leu Asn Pro Pro Lys
325
<210> 51
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成6×His标签
<400> 51
His His His His His His
1 5
<210> 52
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 52
Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
<210> 53
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列之描述:合成肽
<400> 53
Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu Asp Ser Thr
1 5 10
<210> 54
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 54
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
1 5 10
<210> 55
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 55
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
1 5
<210> 56
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 56
Met His His His His His His Met Ser Ala Lys Ser Arg Thr Ile Gly
1 5 10 15
Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val Glu
20 25 30
Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu Lys
35 40 45
Glu Gln Glu Cys Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala Asp
50 55 60
Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser Val
65 70 75 80
Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys Lys
85 90 95
Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala Ile
100 105 110
Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val Ile
115 120 125
Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr Ser
130 135 140
Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu Lys
145 150 155 160
Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Cys Ile
165 170 175
Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro Gly
180 185 190
Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met Thr
195 200 205
Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu Ser
210 215 220
Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp Val
225 230 235 240
Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val Val
245 250 255
Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile Tyr
260 265 270
Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro Ser
275 280 285
Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala Val
290 295 300
Ala Ile Thr Leu Ala Cys Phe Gly Leu Ala Arg Glu Gly Asn His Lys
305 310 315 320
Pro Ile Asp Tyr Leu Asn Pro Pro Lys
325
<210> 57
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 57
Met His His His His His His
1 5
Claims (91)
1.一种治疗病毒相关疾病或病症的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与SEQ ID NO:1或2或其片段具有至少约90%序列同一性,及
其中所述病毒相关疾病或病症与选自由以下组成的组的病毒相关:冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、黄病毒、甲病毒、埃博拉病毒(ebolavirus)、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
2.如权利要求1的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
3.如权利要求1或权利要求2的方法,其中所述病毒相关疾病或病症为选自由以下组成的组的病毒感染:冠状病毒感染、乳头瘤病毒感染、肺病毒感染、小核糖核酸病毒感染、黄病毒感染、甲病毒感染、埃博拉病毒感染、麻疹病毒感染、肠病毒感染、正肺病毒感染、慢病毒感染及肝病毒感染。
4.一种治疗病毒相关疾病或病症的方法,所述方法包括向需要其的患者施用治疗有销量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:3-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
5.如权利要求4的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
6.如权利要求4或权利要求5的方法,其中所述病毒相关疾病或病症与选自由以下组成的组的病毒相关:RNA病毒、DNA病毒、冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、流感病毒、腺病毒、巨细胞病毒、多瘤病毒、痘病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
7.如权利要求4-6中任一项的方法,其中所述病毒相关疾病或病症为选自由以下组成的组的病毒感染:RNA病毒感染、DNA病毒感染、冠状病毒感染、乳头瘤病毒感染、肺病毒感染、小核糖核酸病毒感染、流感病毒感染、腺病毒感染、巨细胞病毒感染、多瘤病毒感染、痘病毒感染、黄病毒感染、甲病毒感染、埃博拉病毒感染、麻疹病毒感染、肠病毒感染、正肺病毒感染、慢病毒感染及肝病毒感染。
8.如权利要求1-7中任一项的方法,其中所述病毒相关疾病或病症包含所述患者的器官或组织的病毒感染。
9.如权利要求8的方法,其中所述器官或所述组织选自由以下组成的组:眼、耳、内耳、肺、气管、支气管、细支气管、肝脏、胆囊、胆管、肾脏、膀胱、睾丸、子宫颈、卵巢、子宫、皮肤及脑。
10.如权利要求1-9中任一项的方法,其中所述病毒相关疾病或病症选自由以下组成的组:急性呼吸窘迫综合征;慢性阻塞性肺病(COPD);肺炎;抗药性肺炎;手足口病;变应性哮喘;及非变应性哮喘。
11.一种抑制病毒基因组复制的方法,所述方法包括向需要其的患者施用治疗有销量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与SEQ ID NO:1或2或其片段具有至少约90%序列同一性,及
其中所述病毒选自由以下组成的组:冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
12.如权利要求11的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
13.一种抑制病毒基因组复制的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:3-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
14.如权利要求13的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
15.如权利要求13或14的方法,其中所述病毒选自由以下组成的组:RNA病毒、DNA病毒、冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、流感病毒、腺病毒、巨细胞病毒、多瘤病毒、痘病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
16.一种抑制病毒传播的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:1或2组成的组的蛋白质序列具有至少约90%序列同一性,其中所述病毒选自由以下组成的组:冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
17.如权利要求16的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
18.一种抑制病毒传播的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:3-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
19.如权利要求18的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
20.如权利要求18或19的方法,其中所述病毒选自由以下组成的组:RNA病毒、DNA病毒、冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、流感病毒、腺病毒、巨细胞病毒、多瘤病毒、痘病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
21.一种抑制病毒组装的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其医药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
22.如权利要求21的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
23.一种抑制病毒基因表达的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
24.如权利要求23的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
25.如权利要求23或24的方法,其中所述抑制包含抑制β基因表达、γ基因表达或β基因表达和γ基因表达。
26.一种抑制病毒释放的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
27.如权利要求26的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
28.如权利要求23-27中任一项的方法,其中所述病毒选自由以下组成的组:RNA病毒、DNA病毒、冠状病毒、乳头瘤病毒、肺病毒、小核糖核酸病毒、流感病毒、腺病毒、巨细胞病毒、多瘤病毒、痘病毒、黄病毒、甲病毒、埃博拉病毒、麻疹病毒、肠病毒、正肺病毒、慢病毒及肝病毒。
29.如前述权利要求中任一项的方法,其中所述病毒为冠状病毒。
30.如权利要求29的方法,其中所述冠状病毒选自由以下组成的组:229Eα冠状病毒、NL63α冠状病毒、OC43β冠状病毒、HKU1β冠状病毒、中东呼吸综合征(Middle EastRespiratory Syndrome;MERS)冠状病毒(MERS-CoV)、严重急性呼吸综合征(SARS)冠状病毒(SARS-CoV)及SARS-CoV-2(COVID-19)。
31.如权利要求6-10、13-15和18-28中任一项的方法,其中所述病毒为流感病毒。
32.如权利要求31的方法,其中所述流感病毒选自由以下组成的组:流感病毒A(例如,H1N1及H5N1)、流感病毒B、流感病毒C、流感病毒D。
33.如权利要求6-10、13-15和18-28中任一项的方法,其中所述病毒为腺病毒。
34.如权利要求33的方法,其中所述腺病毒为AdV5。
35.如前述权利要求中任一项的方法,其中所述病毒为抗药性病毒。
36.如权利要求1-35中任一项的方法,其进一步包括施用包含抗病毒剂的组合物。
37.如权利要求36的方法,其中所述抗病毒剂选自由以下组成的组:拉米夫定(lamivudine)、干扰素α组合物、VAP抗独特型抗体、恩夫韦地(enfuvirtide)、金刚烷胺(amantadine)、金刚乙胺(rimantadine)、普拉康那利(pleconaril)、阿昔洛韦(aciclovir)、齐多夫定(zidovudine)、福米韦生(fomivirsen)、吗啉基、蛋白酶抑制剂、双链RNA激活的细胞凋亡蛋白酶聚合体(DRACO)、利福平(Rifampicin)、扎那米韦(zanamivir)、帕拉米韦(peramivir)、丹诺普韦(danoprevir)、利托那韦(ritonavir)、瑞德西韦(remdesivir)及奥司他韦(oseltamivir)。
38.如权利要求36或37的方法,其中在施用所述精胺酸酶之前、期间或之后施用所述抗病毒剂。
39.一种治疗细菌疾病或病症的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与SEQ ID NO:1或2或其片段具有至少约90%序列同一性,及
其中所述细菌疾病或病症与选自由以下组成的组的细菌相关:肺炎链球菌(Streptococcus pneumoniae)、肺炎支原体(Mycoplasma pneumoniae)、流感嗜血杆菌(Haemophilus influenzae)、嗜肺军团菌(Legionella pneumophila)、肠道沙门氏菌(Salmonella enterica)、邦戈尔沙门氏菌(Salmonella bongori)、大肠杆菌(Escherichiacoli)、幽门螺旋杆菌(Helicobacter pylori)、淋病双球菌(Neisseria gonorrhoeae)、脑膜炎双球菌(Neisseria meningitidis)、金黄色葡萄球菌(Staphylococcus aureus)、鲍曼氏不动杆菌(Acinetobacter baumannii)、洋葱伯克霍尔德菌(Burkholderia cepacian)、艰难梭菌(Clostridium difficile)、索氏梭菌(Clostridium sordellii)、肠杆菌科(Enterobacteriaceae)、粪肠球菌(Enterococcus faecalis)、肺炎克雷伯氏菌(Klebsiella pneumoniae)、摩氏摩根菌(Morganella morganii)、脓肿分枝杆菌(Mycobacterium abscessus)、结核分支杆菌(Mycobacterium tuberculosis)、诺如病毒(Norovirus)、铜绿假单胞菌(Psuedomonas aeruginosa)及嗜麦芽窄食单胞菌(Stenotrophomonas maltophilia)。
40.如权利要求39的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
41.一种治疗细菌疾病或病症的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:3-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
42.如权利要求41的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
43.如权利要求41或42的方法,其中所述细菌疾病或病症与选自由以下组成的组的细菌相关:肺炎衣原体(Chlamydia pneumoniae)、霍乱弧菌(Vibrio cholerae)、肺炎链球菌、肺炎支原体、流感嗜血杆菌、嗜肺军团菌、肠道沙门氏菌、邦戈尔沙门氏菌、大肠杆菌、幽门螺旋杆菌、淋病双球菌、脑膜炎双球菌、金黄色葡萄球菌、鲍曼氏不动杆菌、洋葱伯克霍尔德菌、艰难梭菌、索氏梭菌、肠杆菌科、粪肠球菌、肺炎克雷伯氏菌、摩氏摩根菌、脓肿分枝杆菌、结核分支杆菌、诺如病毒、铜绿假单胞菌及嗜麦芽窄食单胞菌。
44.一种治疗真菌疾病或病症的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
45.如权利要求44的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
46.如权利要求44或45的方法,其中所述真菌疾病与选自由以下组成的组的真菌相关:肺囊虫属(Pneumocystis)真菌、曲霉属(Aspergillus)真菌及念珠菌属(Candida)真菌。
47.一种阿米巴原虫疾病或病症的方法,所述方法包括向需要其的患者施用治疗有效量的包含精胺酸酶或其药学上可接受的盐的组合物,
其中所述精胺酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性。
48.如权利要求47的方法,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
49.如权利要求47或48的用途,其中所述阿米巴原虫疾病或病症与选自由以下组成的组的阿米巴原虫相关:脆弱双核阿米巴(Dientamoeba fragilis)、溶组织内阿米巴(Entamoeba histolytica)、变形纤毛虫(Naegleria fowleri)、棘变形虫属(Acanthamoeba)、棘阿米巴角膜炎(Acanthamoeba keratitis)、巴氏阿米巴(Balamuthiamandrillaris)及双核匀变阿米巴(Sappinia diploidea)。
50.如权利要求1-49中任一项的方法,其中所述精胺酸酶以每天每公斤体重约1ng至每天每公斤体重约1mg的剂量施用。
51.如权利要求1-50中任一项的方法,其中所述施用为局部、非经肠、经口、经肺、气管内、鼻内、鞘内、经皮、皮下、眼内、玻璃体内、腹膜内、十二指肠内或通过吸入。
52.如权利要求1-51中任一项的方法,其中所述精胺酸酶与选自由SEQ ID NO:3-43组成的组的蛋白质序列或其片段具有至少约90%序列同一性,并且其中所述精胺酸酶包含蛋白质标签序列。
53.如权利要求52的方法,其中所述蛋白质标签序列包含SEQ ID NO:51的6×His标签序列。
54.如权利要求52或53的方法,其中所述蛋白质标签序列位于所述精胺酸酶的氨基末端。
55.如权利要求52或53的方法,其中所述蛋白质标签序列位于所述精胺酸酶的羧基末端。
56.如权利要求1至55中任一项的方法,其中所述精胺酸酶为包含2、3、4或更多个与所述精胺酸酶结合的聚乙二醇分子的聚乙二醇化精胺酸酶。
57.如权利要求2、3、5-10、12、14、15、17、19、20、22、24、25、27-38、40、42、43、45、46和48-56中任一项的方法,其中所述聚乙二醇分子为约5kDa、约10kDa、约15kDa、约20kDa、约30kDa或约40kDa。
58.如权利要求2、3、5-10、12、14、15、17、19、20、22、24、25、27-38、40、42、43、45、46和48-56中任一项的方法,其中所述聚乙二醇为约10kDa至约30kDa或约20kDa至约40kDa。
59.如权利要求1至58中任一项的方法,其中所述组合物进一步包含非天然金属辅因子。
60.如权利要求59的方法,其中所述非天然金属辅因子选自由钴、锰、铁及锌组成的组。
61.一种组合物,其包含:
精胺酸酶或其药学上可接受的盐,
其中所述精胺酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性;
抗病毒剂;及
药学上可接受的赋形剂。
62.如权利要求61的组合物,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
63.如权利要求61或62的组合物,其中所述抗病毒剂选自由以下组成的组:拉米夫定、干扰素α组合物、VAP抗独特型抗体、恩夫韦地、金刚烷胺、金刚乙胺、普拉康那利、阿昔洛韦、齐多夫定、福米韦生、吗啉基、蛋白酶抑制剂、双链RNA激活的细胞凋亡蛋白酶聚合体(DRACO)、利福平、扎那米韦、帕拉米韦、丹诺普韦、利托那韦、瑞德西韦及奥司他韦。
64.如权利要求61-63中任一项的组合物,其中所述精胺酸酶与选自由SEQ ID NO:3-43组成的组的蛋白质序列或其片段具有至少约90%序列同一性,且其中所述精胺酸酶包括蛋白质标签序列。
65.如权利要求64的组合物,其中所述蛋白质标签序列包含SEQ ID NO:51的6×His标签序列。
66.如权利要求64或65的组合物,其中所述蛋白质标签序列位于所述精胺酸酶的氨基末端。
67.如权利要求64或65的组合物,其中所述蛋白质标签序列位于所述精胺酸酶的羧基末端。
68.如权利要求62至67中任一项的组合物,其中所述聚乙二醇化精胺酸酶包含2、3、4或更多个与所述精胺酸酶序列结合的聚乙二醇分子。
69.如权利要求62-68中任一项的组合物,其中所述聚乙二醇分子为约5kDa、约10kDa、约15kDa、约20kDa、约30kDa或约40kDa。
70.如权利要求62-68中任一项的组合物,其中所述聚乙二醇分子为约10kDa至约30kDa或约20kDa至约40kDa。
71.如权利要求61-70中任一项的组合物,其中所述组合物进一步包含非天然金属辅因子。
72.如权利要求71的组合物,其中所述非天然金属辅因子选自由钴、锰、铁及锌组成的组。
73.一种试剂盒,其包含:
精胺酸酶或其药学上可接受的盐,
其中所述精胺酸酶与选自由SEQ ID NO:1-50及56组成的组的蛋白质序列或其片段具有至少约90%序列同一性;及
用于抑制病毒产生的缓冲剂、试剂及详细说明。
74.如权利要求73的试剂盒,其中所述精胺酸酶为聚乙二醇化精胺酸酶,其包含至少一个与所述精胺酸酶结合的聚乙二醇分子。
75.如权利要求73或74的试剂盒,其进一步包含抗病毒剂。
76.如权利要求75的试剂盒,其中所述抗病毒剂选自由以下组成的组:拉米夫定、干扰素α组合物、VAP抗独特型抗体、恩夫韦地、金刚烷胺、金刚乙胺、普拉康那利、阿昔洛韦、齐多夫定、福米韦生、吗啉基、蛋白酶抑制剂、双链RNA激活的细胞凋亡蛋白酶聚合体(DRACO)、利福平、扎那米韦、帕拉米韦、丹诺普韦、利托那韦、瑞德西韦及奥司他韦。
77.如权利要求73至76中任一项的试剂盒,其中所述试剂盒用于抑制冠状病毒产生。
78.如权利要求77的试剂盒,其中所述冠状病毒选自由以下组成的组:229Eα冠状病毒、NL63α冠状病毒、OC43β冠状病毒、HKU1β冠状病毒、中东呼吸综合征(MERS)冠状病毒(MERS-CoV)、严重急性呼吸综合征(SARS)冠状病毒(SARS-CoV)及SARS-CoV-2(COVID-19)。
79.如权利要求73-76中任一项的试剂盒,其中所述病毒为流感病毒。
80.如权利要求79的试剂盒,其中所述流感病毒选自由以下组成的组:流感病毒A(例如,H1N1及H5N1)、流感病毒B、流感病毒C、流感病毒D。
81.如权利要求73-76中任一项的试剂盒,其中所述病毒为腺病毒。
82.如权利要求81的试剂盒,其中所述腺病毒为AdV5。
83.如权利要求73-82中任一项的试剂盒,其中所述精胺酸酶与选自由SEQ ID NO:3-43组成的组的蛋白质序列或其片段具有至少约90%序列同一性,且其中所述精胺酸酶包括蛋白质标签序列。
84.如权利要求83的试剂盒,其中所述蛋白质标签序列为SEQ ID NO:51的6×His标签序列。
85.如权利要求83或84的试剂盒,其中所述蛋白质标签序列位于所述精胺酸酶的氨基末端。
86.如权利要求83或84的试剂盒,其中所述蛋白质标签序列位于所述精胺酸酶的羧基末端。
87.如权利要求74至86中任一项的试剂盒,其中所述聚乙二醇化精胺酸酶包含2、3、4或更多个与所述精胺酸酶序列结合的聚乙二醇分子。
88.如权利要求74至87中任一项的试剂盒,其中所述聚乙二醇为约5kDa、约10kDa、约15kDa、约20kDa、约30kDa或约40kDa。
89.如权利要求74至87中任一项的试剂盒,其中所述聚乙二醇为约10kDa至约30kDa或约20kDa至约40kDa。
90.如权利要求73至89中任一项的试剂盒,其中所述试剂盒进一步包含非天然金属辅因子。
91.如权利要求90的试剂盒,其中所述非天然金属辅因子选自由钴、锰、铁及锌组成的组。
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US9382525B2 (en) * | 2009-03-26 | 2016-07-05 | The Hong Kong Polytechnic University | Site-directed pegylation of arginases and the use thereof as anti-cancer and anti-viral agents |
US8507245B2 (en) * | 2009-03-26 | 2013-08-13 | The Hong Kong Polytechnic University | Site-directed pegylation of arginases and the use thereof as anti-cancer and anti-viral agents |
US8679479B2 (en) * | 2009-06-29 | 2014-03-25 | Aerase, Inc. | Methods for purifying pegylated arginase |
CN103184209B (zh) * | 2011-12-27 | 2015-09-16 | 拜奥生物科技(上海)有限公司 | 人精氨酸酶和聚乙二醇化人精氨酸酶及其应用 |
US9011845B2 (en) * | 2012-06-26 | 2015-04-21 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Methods for treatment of inflammatory and infectious viral diseases |
US8877183B2 (en) * | 2012-06-26 | 2014-11-04 | National Institutes Of Health (Nih) | Methods for treatment of ocular diseases |
US9789169B2 (en) * | 2014-04-29 | 2017-10-17 | Bio-Cancer Treatment International Limited | Methods and compositions for modulating the immune system with arginase I |
CN106692961B (zh) * | 2015-11-17 | 2020-12-11 | 长春市福迪奥美科技有限公司 | 精氨酸酶组合物、精氨酸酶激活剂及其应用 |
US20200181597A1 (en) * | 2018-05-31 | 2020-06-11 | The Hong Kong Polytechnic University | Composition and Application of Arginine-depleting Agents for Cancer, Obesity, Metabolic Disorders, and Related Complications and Comorbidities |
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