CN111574588B - 多肽及其在抗埃博拉病毒中的应用 - Google Patents
多肽及其在抗埃博拉病毒中的应用 Download PDFInfo
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- CN111574588B CN111574588B CN202010460222.7A CN202010460222A CN111574588B CN 111574588 B CN111574588 B CN 111574588B CN 202010460222 A CN202010460222 A CN 202010460222A CN 111574588 B CN111574588 B CN 111574588B
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- pep
- polypeptide
- virus
- ebov
- cyclic polypeptide
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Abstract
本发明公开了多肽及其在抗埃博拉病毒中的应用。该环状多肽的氨基酸序列为下述(式Ⅰ)所示：X1X2X3X4X5X6X7X8(式Ⅰ)，(式Ⅰ)中，X1至X8均分别为一个氨基酸残基，所述X1为C，所述X2为E、D、H或Y，所述X3为Y，所述X4为F，所述X5为F，所述X6为W或V，所述X7为Y或H，所述X8为C；(式Ⅰ)中的X1与X8之间形成二硫键连接成环状。本发明的环状多肽能够通过与靶蛋白EBOV‑GPcl结合从而特异性抑制埃博拉病毒进入细胞，达到抗EBOV感染的效应。
Description
本申请是申请号为201810087839.1、申请日为2018年01月30日、发明创造名称为“与埃博拉病毒激活态包膜糖蛋白特异性结合的多肽及其在抗病毒中的应用”的分案申请。
技术领域
本发明涉及医药技术领域中多肽及其在抗埃博拉病毒中的应用。
背景技术
埃博拉病毒病(以往称作埃博拉出血热)是由丝状病毒科的埃博拉病毒(Ebolavirus，EBOV)所引起的一种急性出血性传染病，死亡率高达90％，是人类最致命的病毒性传染病之一。EBOV可以分为5个种:扎伊尔型(Zaire ebolavirus,Zaire-EBOV，ZEBOV)、苏丹型(Sudan ebolavirus,SUDV)、塔伊森林型(Tai Forest ebolavirus,TAFV)、本迪布焦型(Bundibugyo ebolavirus,BDBV)和莱斯顿型(Reston ebolavirus,RESTV)。其中，扎伊尔型埃博拉病毒致病力最强。目前对EBOV感染主要采取对症和支持治疗，尚没有经系统临床验证有效的特异性治疗药物和疫苗。随着全球人口流动性的增加以及EBOV超级扩散者的存在加之病毒自身的强致病性和易发生遗传变异等特点，EBOV已经成为潜在的全球健康威胁。因此有必要研究靶点明确、具有全新结构类型的抗EBOV药物，确保有能力预防EBOV感染和应对新传染病的爆发。
EBOV为单股负链RNA病毒，最外层被病毒包膜包裹，中心为螺旋状核衣壳。基因组长约18.9kb，编码七种结构蛋白，基因顺序为3-NP-VP35-VP40-GP-VP30-VP24-L-5。其中，包膜糖蛋白(glycoprotein，GP)是唯一负责病毒进入宿主细胞的蛋白。无论是覆盖在病毒表面，还是在感染过程中从受感染细胞脱落，GP都可以参与多种免疫应答反应，在病毒生命周期以及宿主-病原体相互作用过程中扮演重要角色，是抑制EBOV感染的潜在有效靶点。由于病毒的进入阶段是病毒复制周期中的第一个也是必不可少的步骤，阻断EBOV-GP介导的病毒进入将有效抑制病毒感染及由其引起的细胞毒性，同时也可降低药物耐药性的发生。EBOV-GP进入溶酶体后会发生酶切，酶切之后的激活态的糖蛋白(Primed GP，GPcl)可以和内吞体受体-人源胆固醇转运蛋白(Niemann-Pick C1，NPC1)直接相互作用，从而引发病毒与宿主细胞内的膜融合过程。
发明内容
本发明所要解决的技术问题是如何特异性抑制埃博拉病毒进入细胞，以抗EBOV感染。
为了解决以上技术问题，本发明提供了环状多肽或其药用盐。
本发明所提供的环状多肽或其药用盐中，所述环状多肽的氨基酸序列为下述(式Ⅰ)所示：
X1X2X3X4X5X6X7X8 (式Ⅰ)，
(式Ⅰ)中，X1至X8均分别为一个氨基酸残基，所述X1为C，所述X2为E、D、H或Y，所述X3为Y，所述X4为F，所述X5为F，所述X6为W或V，所述X7为Y或H，所述X8为C；(式Ⅰ)中的X1与X8之间形成二硫键连接成环状。
上述环状多肽或其药用盐中，所述环状多肽可为Pep-3.3、Pep-3.2、Pep-3.1或Pep-3.10；所述Pep-3.3的氨基酸序列为序列表中的SEQ ID No.1，所述Pep-3.2的氨基酸序列为序列表中的SEQ ID No.2，所述Pep-3.1的氨基酸序列为序列表中的SEQ ID No.3，所述Pep-3.10的氨基酸序列为序列表中的SEQ ID No.4。
上述环状多肽的衍生物也属于本发明的保护范围。
上述环状多肽的衍生物可为d1、d2、d3、d4或d5；所述d1为在所述环状多肽的氨基末端连接氨基端保护基和/或在所述环状多肽的羧基末端连接羧基端保护基得到的连接物；
所述d2为在所述环状多肽的氨基末端和/或羧基末端添加氨基酸残基得到的能与GPcl(病毒的激活态包膜糖蛋白)特异性结合的多肽；
所述d3为在所述环状多肽的氨基末端和/或羧基末端连接寡肽得到的能与GPcl特异性结合的多肽；
所述d4为所述环状多肽被蛋白质、聚乙二醇或马来酰亚胺修饰得到的修饰物；
所述d5为在所述环状多肽的氨基末端和/或羧基末端连接亲脂性化合物得到的能与GPcl特异性结合的多肽。
下述PM1或PM2的多聚体也属于本发明的保护范围：
PM1、由所述环状多肽或其药用盐形成的多聚体；
PM2、由所述衍生物形成的多聚体。
上述环状多肽、其药用盐、或其衍生物中，所述环状多肽的序列中的每个大写字母均为氨基酸的缩写，氨基酸的缩写具有本领域公知的含义，例如：C为半胱氨酸，D为天冬氨酸，E为谷氨酸、Y为酪氨酸、F为苯丙氨酸、W为色氨酸、V为缬氨酸、H为组氨酸等。所述环状多肽序列中的所有氨基酸可为L型氨基酸，其中的一个或多个(如2-5个、2-4个或2-3个)氨基酸也可以用构象为D型的氨基酸、人工修饰的氨基酸、自然界存在的稀有氨基酸等进行替换，以提高环状多肽的生物利用度、稳定性和/或抗病毒活性。其中D型氨基酸是指与组成蛋白质的L型氨基酸相对应的氨基酸；人工修饰的氨基酸指经过甲基化、磷酸化等修饰的组成蛋白质的常见L型氨基酸；自然界存在的稀有氨基酸包括组成蛋白质的不常见氨基酸和不组成蛋白质的氨基酸，例如5-羟基赖氨酸、甲基组氨酸、γ氨基丁酸、高丝氨酸等。
上述环状多肽、其药用盐、或其衍生物中，亲脂性化合物可以连接在末端氨基酸的侧链上，也可直接连接在肽链上。
上述环状多肽、其药用盐、或其衍生物中，本发明的环状多肽的氨基末端可含有氨基端保护基，所述氨基端保护基可为乙酰基、氨基、马来酰基、琥珀酰基、叔丁氧羰基或苄氧或其他疏水基团或大分子载体基团中的任一基团；本发明的环状多肽的羧基末端可含有羧基端保护基，所述羧基端保护基可为氨基、酰胺基、羧基、或叔丁氧羰基或其他疏水基团或大分子载体基团中的任一基团。
包含下述C1)和C2)的组合物也属于本发明的保护范围：C1)为C11)、C12)或/和C13)；所述C11)为上述环状多肽或其药用盐；所述C12)为上述衍生物；所述C13)为上述多聚体；
C2)药学上可接受的载体或辅料；
所述组合物具有下述F1)-F3)中的至少一种功能：
F1)抗病毒；
F2)治疗和/或预防和/或辅助治疗病毒感染所致疾病；
F3)抑制病毒侵入细胞。
上述组合物中，所述F1)-F3)中，所述病毒可为埃博拉病毒(扎伊尔型、苏丹型、塔伊森林型、本迪布焦型和/或莱斯顿型)，或马尔堡病毒(MARV)。
上述C11)、上述C12)、上述C13)或/和C14)在制备E1)-E3)中至少一种产品中的应用也属于本发明的保护范围：
所述C14)为上述组合物；
所述E1)为抗病毒的产品，如药物或疫苗；
所述E2)为治疗和/或预防和/或辅助治疗病毒感染所致疾病的产品，如药物或疫苗；
所述E3)为抑制病毒侵入细胞的产品，如药物或疫苗；
上述应用中，所述E1)-E3)中，所述病毒可为埃博拉病毒(扎伊尔型、苏丹型、塔伊森林型、本迪布焦型和/或莱斯顿型)，或马尔堡病毒。
本发明提供了药用化合物。
本发明所提供的药用化合物为上述C11)、C12)或C13)。
上述药用化合物中，所述药用化合物具有下述U1)-U3)中的至少一种用途：
U1)用于抗病毒；
U2)用于治疗和/或预防和/或辅助治疗病毒感染所致疾病；
U3)用于抑制病毒侵入细胞。
上述药用化合物的U1)-U3)中，所述病毒可为埃博拉病毒(扎伊尔型、苏丹型、塔伊森林型、本迪布焦型和/或莱斯顿型)，或马尔堡病毒。
上文中，所述抑制病毒侵入细胞可为抑制GPcl介导的病毒进入细胞。
本发明的环状多肽药用盐，包括醋酸盐(acetate)、乳糖醛酸盐(lactobionate)、苯磺酸盐(benzenesulfonate)、月桂酸酯(laurate)、安息香酸盐(benzoate)、苹果酸盐(malate)、重碳酸盐(bicarbonate)、马来酸盐(maleate)、硫酸氢盐(bisulfate)、扁桃酸盐(mandelate)、酒石酸氢盐(bitartrate),甲磺酸盐(mesylate),硼酸盐(borate),溴甲烷(methylbromide),溴化物(bromide),硝酸甲酯(methylnitrate),依地酸钙(calciumedetate),甲基硫酸盐(methylsulfate),右旋樟脑磺酸(camsylate),粘酸盐(mucate),碳酸盐(carbonate),萘磺酸盐(napsylate),氯化物(chloride),硝酸盐(nitrate),棒酸盐(clavulanate),N-甲葡糖胺(N-methylglucamine),柠檬酸盐(citrate),铵盐(ammoniumsalt),二氢氯化物(dihydrochloride),油酸盐(oleate),乙二胺四乙酸盐(edetate),草酸盐(oxalate),乙二磺酸盐(edisylate),扑酸盐(pamoate)(双羟萘酸盐embonate),丙酸酯月桂硫酸酯(estolate),棕榈酸盐(palmitate),乙磺酸酯(esylate),泛酸盐(pantothenate),延胡索酸盐(fumarate),磷酸盐/二磷酸(phosphate/diphosphate),葡庚糖酸盐(gluceptate),聚半乳糖醛酸盐(polygalacturonate),葡(萄)糖酸盐(gluconate),水杨酸盐(salicylate),谷氨酸盐(glutamate),硬脂酸盐(stearate),对羟乙酰氨基苯胂酸(glycollylarsanilate),硫酸盐(sulfate),羟基苯甲酸盐(hexylresorcinate),碱式乙酸盐(subacetate),海巴(hydrabamine),琥珀酸盐(succinate),氢溴酸盐(hydrobromide),丹宁酸盐(tannate),氢氯化物(hydrochloride),酒石酸盐(tartrate),羟萘酸盐(hydroxynaphthoate),8-氯茶碱盐(teoclate),碘化物(iodide),甲苯磺酸盐(tosylate),三乙基碘(triethiodide),乳酸(lactate),戊酸盐(valerate)等。取决于用途，药用盐可以由阳离子如钠(sodium)、钾(potassium)、铝(aluminum)、钙(calcium)、锂(lithium)、锰(magnesium)和锌(zinc)、铋(bismuth)等所形成，也可由碱如氨、乙二胺(ethylenediamine)、N-甲基-谷氨酰胺(N-methyl-glutamine)、赖氨酸(lysine)、精氨酸(arginine)、鸟氨酸(ornithine)、胆碱(choline)、N,N'-二苄基乙二胺(N,N'-dibenzylethylene-diamine),氯普鲁卡因(chloroprocaine),二乙醇氨(diethanolamine),普鲁卡因(procaine),二乙胺(diethylamine),哌嗪(piperazine),三羟甲基氨基甲烷(tris(hydroxymethyl)aminomethane)和羟化四甲铵(tetramethylammonium hydroxide)等所形成。这些盐可以采用标准方法制备，例如通过游离酸与有机或无机碱的反应。在一个碱性基团如氨基存在的情况下，酸性盐如氢氯化物(hydrochloride)、氢溴化物(hydrobromide)、醋酸盐(acetate)、扑酸盐(pamoate)等等可用作剂型；在一个酸性基团(如-COOH)或醇基存在的情况下，可药用的酯如醋酸酯(acetate)、马来酸酯(maleate)、三甲基乙酸氯甲酯(pivaloyloxymethyl)等、以及文献中公知的用于改善可溶性和水解性的酯可以用作持续释放和前体药制剂。
本发明所提供的环状多肽、其衍生物、或其药用盐，所述多聚体，所述组合物或所述药用化合物，可以用于EBOV和/或MARV感染的治疗。本发明所提供的脂肽或多肽、其衍生物、或其药用盐，所述多聚体，所述组合物或所述药用化合物，也可以用于EBOV和/或MARV感染的预防，包括暴露前或可疑暴露后，例如输血、器官移植、体液交换、咬伤、意外针刺或手术中暴露于病人血液等。
在实际应用中，可以将本发明的环状多肽、其衍生物、或其可药用盐，所述多聚体，所述组合物或所述药用化合物作为药物直接给予病人、或者与适宜的载体或赋形剂混合后给予病人，以达到治疗和/或预防EBOV和/或MARV感染感染的目的。这里的载体材料包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如醋酸纤维素酞酸酯和羧甲乙纤维素等)。其中优选的是水溶性载体材料。使用这些材料可以制成多种剂型，包括但不限于片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。其中，栓剂可为阴道栓剂，也可以是阴道环，也可以是适于阴道应用的药膏、乳霜或凝胶。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。为了将单位给药剂型制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将单位给药剂型制成栓剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将单位给药剂型制成注射用制剂，如溶液剂、乳剂、冻干粉针剂和混悬剂，可以使用本领域常用的所有稀释剂，例如，水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
使用上述剂型可以经注射给药，包括皮下注射、静脉注射、肌肉注射和腹腔注射、脑池内注射或灌输等；腔道给药，如经直肠、阴道和舌下；呼吸道给药，如经鼻腔；粘膜给药。上述给药途径优选的是注射给药，优选的注射途径是皮下注射。
本发明的环状多肽、其衍生物、可药用盐，所述多聚体，所述组合物或所述药用化合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重及个体反应，所用的具体活性成分，给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药。
对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定，所述因素包括所治疗的障碍和该障碍的严重程度；所采用的具体活性成分的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、性别和饮食；所采用的具体活性成分的给药时间、给药途径和排泄率；治疗持续时间；与所采用的具体活性成分组合使用或同时使用的药物；及医疗领域公知的类似因素。例如，本领域的做法是，活性成分的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。
本发明的环状多肽、其衍生物、或其可药用盐，所述多聚体，所述组合物或所述药用化合物可以直接单独用于EBOV和/或MARV感染者的治疗和预防，也可以与一种或多种抗EBOV和/或MARV感染药物联合使用，可以同时使用，也可以间隔使用，以达到提高整体治疗效果的目的。
本发明中，所述抗病毒活性也可称为抑制病毒活性，具体可为抑制病毒侵入细胞。
实验证明，本发明的环状多肽可特异性抑制埃博拉病毒进入细胞。本发明的环状多肽能够通过与靶蛋白EBOV-GPcl结合从而特异性抑制埃博拉病毒进入细胞，达到抗EBOV感染的效应。本发明的环状多肽或其药用盐及其衍生物可以作为新的EBOV进入抑制剂，并可应用于开发抗EBOV的疫苗或药物。
附图说明
图1为Pep-3.1，Pep-3.2，Pep-3.3和Pep-3.10能够特异性抑制EBOV-Zaire GP/HIV-luc重组病毒活性。图1中，VSVG表示VSV-G/HIV-luc，Ebola-GP表示EBOV-GP/HIV-luc，病毒感染率＝1-抑制率。
图2为细胞生长实验验证多肽对293T细胞生长的影响。
图3为Pep-3.1,Pep-3.2,Pep-3.3和Pep-3.10对EBOV-Zaire GP/HIV-luc重组病毒的抑制作用具有良好的剂量依赖性。
图4为药物作用时间点实验表明多肽Pep-3.3作用于病毒的进入阶段。
图5为生物膜层光学干涉技术体外测定不同浓度的多肽Pep-3.1,Pep-3.2,Pep-3.3和Pep-3.10与靶蛋白GPcl的动力学结合曲线。图中，箭头示各个样品的浓度。
具体实施方式
本发明通过以下技术方案实现：
首先以NPC1结构域C末端的环状结构(氨基酸序列DDFFVY)为模板进行基于结构的多肽药物设计。为了提高多肽稳定性，保护其免受磷酸酶攻击，在氨基酸序列的首尾末端各引入一个半胱氨酸，借此引入一个二硫键。然后通过对碳末端进行酰胺化修饰，对氮末端进行乙酰化修饰进一步提高多肽稳定性。此时多肽结构是Ac-cyclo(CDDFFVYC)-NH2。为了提高多肽与靶蛋白EBOV-GPcl的结合能力，通过构建单点、双点以及三点氨基酸突变对多肽结构进行进一步优化，获得多肽最佳组合序列。然后将设计得到的多肽对接到靶蛋白GPcl中，选择自由能较优的多肽(表1)进行固相合成。
EBOV被列为危险性四级病毒，因此使用假病毒技术这种安全有效的研究手段对多肽进行体外水平的生物学活性评价。利用毒性最强的扎伊尔型EBOV的GP蛋白包裹HIV核心制备复制缺陷型假病毒EBOV-GP/HIV-luc，通过荧光报告基因检测技术来判断样品的抗病毒活性。与此同时，采用VSVG/HIV-luc重组病毒模型分析多肽的特异性。在排除细胞毒性后，采用药物作用时间点实验进一步验证多肽的作用机制。最后利用基于光纤生物传感器的生物膜层光学干涉技术体外测定多肽与靶蛋白GPcl的结合能力，验证多肽的靶向性。
表1中所有多肽的氨基末端均乙酰化修饰(Ac-)、羧基末端均酰胺化修饰(-NH2)。“cyclo”表示括号内的氨基酸序列通过第1位的氨基酸残基与最后1位的氨基酸残基形成环状多肽。Pep-1中，括号内的氨基酸序列通过第1位的氨基酸残基与最后1位的氨基酸残基通过形成酰胺键连接形成环状多肽；Pep-3、Pep-3.1、Pep-3.2、Pep-3.3、Pep-3.6、Pep-3.7和Pep-3.10中，括号内的氨基酸序列通过第1位的氨基酸残基与最后1位的氨基酸残基通过形成二硫键连接形成环状多肽。
表1.多肽的序列结构
| 名称 | 序列结构 |
| Pep-1 | Ac-cyclo(DDFFVY)-NH<sub>2</sub> |
| Pep-2 | Ac-DDFFVY-NH<sub>2</sub> |
| Pep-3 | Ac-cyclo(CDDFFVYC)-NH<sub>2</sub> |
| Pep-3.1 | Ac-cyclo(CHYFFVYC)-NH<sub>2</sub> |
| Pep-3.2 | Ac-cyclo(CDYFFWYC)-NH<sub>2</sub> |
| Pep-3.3 | Ac-cyclo(CEYFFWYC)-NH<sub>2</sub> |
| Pep-3.6 | Ac-cyclo(CDRFFVYC)-NH<sub>2</sub> |
| Pep-3.7 | Ac-cyclo(CDYFFRYC)-NH<sub>2</sub> |
| Pep-3.10 | Ac-cyclo(CYYFFVHC)-NH<sub>2</sub> |
表1的多肽全部由北京赛百盛基因技术有限公司合成，纯度>98％。具体的获取手段为现有技术，本发明对此不作特别限定。
下面结合具体实施方式对本发明进行进一步的详细描述，给出的实施例仅为了阐明本发明，而不是为了限制本发明的保护范围。虽然下文以扎伊尔型EBVO为例具体说明本发明技术方案的抗病毒机理，但本发明对多肽用途的保护范围并不限于EBOV。任何适用上述抗病毒机理的病毒均在本发明所述病毒的范围之内，例如可以是EBOV的其他四种亚型以及MARV等。
另外，需要注意的是，除非特别指明，下面实施例中所用的各种材料和试剂都是本领域中常用的材料和试剂，可以通过常规的商业途径获得；所用方法均为本领域技术人员公知的常规方法或按照厂商所建议的条件。
实施例1、EBOV进入抑制剂筛选模型验证Pep-3.1，Pep-3.2，Pep-3.3和Pep-3.10能够特异性抑制EBOV活性。
利用细胞水平重组病毒技术，将Zaire-EBOV的GP与HIV核心质粒(pNL4-3.Luc)共表达，制备重组病毒(EBOV-GP/HIV-luc)，应用靶向GP蛋白的EBOV进入抑制剂的高通量筛选模型评价多肽的抗病毒活性。具体步骤为：
取293T细胞进行培养，待细胞长满培养瓶后，弃旧培养基，用含0.25％胰酶和0.02％EDTA的消化液消化。待细胞变圆，弃消化液，立即加入含10％FBS(购自GIBCO)的高糖DMEM培养基(GIBICO)，用吸管轻轻吹打瓶底，使细胞完全脱离瓶底且使之分散为单细胞悬液。计数后，用培养基将细胞浓度调整为2.2×105个/ml，接种于6孔板，2mL/孔。24h后(细胞丰度约为70％)转染，质粒用量：2μg pZEBOV-GP与3μg携带荧光素酶报告基因的HIV-luc质粒pNL4-3.Luc.R-E-，转染试剂为Lipofectamine2000(Invitrogen公司),根据使用说明书进行转染，产生埃博拉假型病毒，将该埃博拉假型病毒命名为EBOV-GP/HIV-luc或EBOV-Zaire GP/HIV-luc。在转染后48小时收集含有假型病毒的上清液，合并，通过低速离心从漂浮的细胞和细胞碎片中澄清，并通过0.45μm孔径的过滤器过滤。通过使用ELISA测定法测量病毒相关的HIV p24水平来定量假病毒颗粒。
其中，pZEBOV-GP是将Zaire ebolavirus isolateH.sapiens-wt/GIN/2014/Makona-Gueckedou-C07的GP基因(GenBank Accession No.KJ660347(Update Date Dec18,2014 01:25PM)的第5900-8305位插入到载体pcDNA3.1(+)得到的表达Zaire-EBOV的糖蛋白(GP)的重组表达质粒。
将EBOV-GP/HIV-luc假病毒颗粒与293T细胞一起温育到96孔板中。48小时后，收集细胞并裂解以测量萤火虫萤光素酶活性。萤光素酶活性的值代表病毒感染。
将表1的多肽分别用DMSO溶解后分别与EBOV-GP/HIV-luc假病毒混合加入到293T细胞中，使表1的多肽含量为10μM。48小时后，裂解293T细胞，通过测量荧光素酶活性评估多肽对病毒的抑制率。以溶剂DMSO为空白对照(DMSO)，同时引入EBOV进入抑制剂粉防己碱(tetrandrine，TET)和HIV-1逆转录酶抑制剂依法韦仑(efavirenz，EFV)作为对照。粉防己碱和依法韦仑分别用DMSO溶解后分别与EBOV-GP/HIV-luc假病毒混合加入到293T细胞中，粉防己碱和依法韦仑的含量均为1μM。48小时后，裂解293T细胞，通过测量荧光素酶活性评估多肽对病毒的抑制率。
目前已知的EBOV抑制剂大多是广谱性抗病毒药物，为了寻找针对EBOV的窄谱抑制剂，需要对筛到的活性多肽进行特异性分析。由于水泡性口膜炎病毒外壳糖蛋白(vesicular stomatitis virus glycoprotein,VSVG)和EBOV-GPcl作用相似，在病毒和受体的识别中发挥重要作用，因此使用表达VSV-GP的假病毒对所筛到的活性多肽进行特异性分析。在排除细胞毒性因素后，同样利用荧光素酶原理检测活性多肽对VSV-G/HIV-luc假病毒的抑制活性，方法同上。若多肽只对EBOV-GPcl介导的病毒进入有明显抑制作用，而对VSV没有抑制或抑制率很低，则说明此多肽对EBOV具有特异性。
结果如图1所示，Pep-3.1,Pep-3.2，Pep-3.3和Pep-3.10对EBOV-GP/HIV-luc假病毒的抑制率高于80％，相同浓度下对VSV-G/HIV-luc假病毒的抑制率却低于50％。这说明Pep-3.1，Pep-3.2，Pep-3.3和Pep-3.10对EBOV-GP/HIV-luc假病毒具有特异性抑制作用。其中，Pep-3.3的特异性抑制作用最为明显。作为阳性对照的EBOV进入抑制剂粉防己碱(TET)具有与活性多肽相似的选择性抑制作用，而HIV-1逆转录酶抑制剂依法韦仑(EFV)对两种假病毒均有抑制作用。
其中，表达VSV-GP的假病毒VSV-G/HIV-luc的制备方法与EBOV-GP/HIV-luc的制备方法的区别仅在于将EBOV-GP/HIV-luc的制备方法中的pZEBOV-GP替换为pVSV-GP，其它操作完全相同。pVSV-GP是将水泡性口膜炎病毒外壳糖蛋白GP基因(GenBank AccessionNo.V01214(Update Date Feb 4,2011)的第14-1567位插入到载体pcDNA3.1(+)得到的表达水泡性口膜炎病毒外壳糖蛋白的重组表达质粒。
实施例2、Pep-3.1,Pep-3.2,Pep-3.3和Pep-3.10的抗病毒活性与其细胞毒性无关。
为了排除由于多肽毒性而产生的非特异性差异，采用细胞计数试剂盒-8(ellCounting Kit-8，CCK-8)评估多肽对293T细胞生长的影响。
CCK-8试剂盒是检测细胞增殖、细胞存活和细胞毒性的试剂盒，是一种基于WST-8(水溶性四唑盐，化学名：2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐)的广泛应用快速高灵敏度检测试剂盒，为MTT法的替代方法，试剂盒中采用水溶性四唑盐-WST-8，在电子耦合试剂存在的情况下，可以被线粒体内的一些脱氢酶还原生成橙黄色的formazan。细胞增殖越多越快，则颜色越深；细胞毒性越大，则颜色越浅。对于同样的细胞，颜色的深浅和细胞数目呈良好线性关系。具体步骤为：
将293T细胞在96孔板中培养并与表1的多肽(用DMSO溶解)分别孵育，多肽在培养基中的含量为25μM。48小时后，细胞上清更换为含有10％CCK-8试剂的细胞培养液，细胞在37℃、5％CO2孵箱中继续培养1h。在微孔板读数器(Thermo，Varioskan Flash)上记录450nm处每孔的光密度(OD)值。以溶剂DMSO为空白对照(DMSO)，粉防己碱(TET)作为对照，粉防己碱在培养基中的含量为3.125μM(粉防己碱在该浓度下不具有细胞毒性，以此为阳性对照)。
如图2所示，在25μM(远远高于测得的IC50值)浓度下，多肽对细胞活性均无明显影响。由此说明，多肽的抗病毒活性与其细胞毒性无关。
实施例3、Pep-3.1,Pep-3.2,Pep-3.3和Pep-3.10对EBOV的抑制作用具有良好的剂量依赖性。
参照实施例1中的方法，将不同浓度的表1的Pep-3.1,Pep-3.2,Pep-3.3和Pep-3.10分别用DMSO溶解后分别与EBOV-GP/HIV-luc假病毒混合加入到293T细胞中。48小时后，裂解293T细胞，通过测量荧光素酶活性评估肽的抗EBOV活性。以溶剂DMSO为空白对照(DMSO)，将空白对照的荧光素酶活性作为细胞存活力为100％。从图3可以看出，Pep-3.1,Pep-3.2,Pep-3.3和Pep-3.10呈剂量依赖性地显著抑制EBOV-GP/HIV-luc假病毒活性。
实施例4、通过药物作用时间点实验确定Pep-3.3作用于病毒的进入阶段。
多肽Pep-3.1,Pep-3.2,Pep-3.3和Pep-3.10对EBOV-GP/HIV-luc假病毒的特异性抑制作用表明它们可能充当EBVO进入抑制剂。为了验证这点，通过药物作用时间点实验(Time of addition，TOA)实验研究多肽在病毒感染周期中的作用阶段。由于在实施例1中，Pep-3.3对EBOV-GP/HIV-luc假病毒的特异性抑制作用最强，因此主要研究Pep-3.3的作用机制。具体步骤为：
感染前一天,将293T细胞按细胞数6×104个/孔接种到96孔板中,分别加入实施例1的EBOV-GP/HIV-luc 50μL感染细胞。在感染(-1小时)，感染期间(0小时)以及感染后于0、2、4、6、8、10、12、14和16h时间点加入表1的Pep-3.3(用DMSO溶解，在培养基中的含量(终浓度)为1×10-5mol·L-1),以EBOV进入抑制剂粉防己碱(tetrandrine，TET)(用DMSO溶解，在培养基中的含量为1×10-7mol·L-1)、非核苷类逆转录酶抑制剂依法韦仑(efavirenz，EFV)(用DMSO溶解，在培养基中的含量为1×10-9mol·L-1)为对照，DMSO为溶剂对照；感染48h后，检测报告基因荧光素酶活性反映重组病毒复制水平。
通过测定EBOV单次感染时药物的失效时间可初步判断药物的作用环节。如图4所示，Pep-3.3在病毒进入的早期表现出非常强的抑制作用，在4h(病毒完成吸附过程)之后对病毒感染无抑制作用。这与EBOV进入抑制剂粉防己碱的作用时间一致。非核苷类逆转录酶抑制剂依法韦仑在6h时依然对病毒有抑制作用。这些结果表明Pep-3.3是在病毒与宿主结合之后，病毒与宿主发生膜融合之前发挥作用。
实施例5、采用生物膜层光学干涉技术体外测定多肽与靶蛋白GPcl的结合能力
埃博拉病毒囊膜表面糖蛋白GP在内吞体里经过宿主蛋白酶Cathepsin的酶切处理，变成激活态糖蛋白GPcl，暴露出受体结合位点。为了验证多肽是通过与靶蛋白GPcl结合从而特异性抑制病毒的进入，利用基于光纤生物传感器的生物膜层光学干涉(BioLayerInterferometry,BLI)技术体外测定多肽与靶蛋白GPcl的结合能力。BLI技术能够实时跟踪生物分子间的相互作用，是研究蛋白质和其它生物分子相互作用的理想选择。具体步骤为：
实验选用Ni-NTA(NTA)生物传感器，通过Octet RED96(ForteBio,Inc.)仪器进行。主要采用以下步骤进行实验：1)检测基线将NAT传感器浸没在缓冲溶液中静置120s以达平衡；2)将蛋白孵育到传感器上将传感器探针移动到纯化后带有His标签的GPcl蛋白溶液(50μg/ml)中静置600s，使蛋白固定在NTA传感器上；3)第二次检测基线将传感器移动到缓冲溶液中静置120s以达平衡；4)结合将传感器移动到多肽溶液中静置60s测量Kon值；5)解离将传感器移动到缓冲溶液中静置60s以获得Koff值。在此过程中使用四种不同浓度的多肽获得最终的动力学曲线。使用ForteBio数据分析软件Data Analysis 9.0分析实验数据。解离速率常数KD＝Koff/Kon。
图5中的横坐标为反应时间，单位为秒。纵坐标为GPcl与多肽的相互作用的信号强度，单位为nm。结果表明表1的Pep-3.1,Pep-3.2,Pep-3.3,和Pep-3.10均能够与GPcl蛋白结合，拟合出的解离速率常数KD分别为119.8μM,97.4μM，69.7μM，和31μM。
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<110> 中国医学科学院医药生物技术研究所
<120> 多肽及其在抗埃博拉病毒中的应用
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Claims (5)
1. 环状多肽或其药用盐，其特征在于：所述环状多肽为Pep-3.2；所述Pep-3.2的氨基酸序列为序列表中的SEQ ID No.2。
2.权利要求1所述的环状多肽的衍生物，所述衍生物为在所述环状多肽的氨基末端连接氨基端保护基和/或在所述环状多肽的羧基末端连接羧基端保护基得到的连接物。
3.多聚体，其特征在于：所述多聚体为由权利要求1所述的环状多肽或其药用盐形成的多聚体，或为由权利要求2所述的衍生物形成的多聚体。
4.一种组合物，其包含C1）和C2）：C1）为C11）、C12）或/和C13）；所述C11）为权利要求1所述的环状多肽或其药用盐；所述C12）为权利要求2所述的衍生物；所述C13）为权利要求3所述的多聚体；
所述C2）为药学上可接受的载体或辅料；
所述组合物具有下述F1）- F3）中的至少一种功能：
F1）抗病毒；
F2）治疗和/或预防和/或辅助治疗病毒感染所致疾病；
F3）抑制病毒侵入细胞；
所述F1）- F3）中，所述病毒为埃博拉病毒。
5.C11）、C12）、C13）或/和C14）在制备E1）- E3）中至少一种产品中的应用：
所述C11）为权利要求1所述的环状多肽或其药用盐；所述C12）为权利要求2所述的衍生物；所述C13）为权利要求3所述的多聚体；所述C14）为权利要求4所述的组合物；
所述E1）为抗病毒的产品；所述E2）为治疗和/或预防和/或辅助治疗病毒感染所致疾病的产品；所述E3）为抑制病毒侵入细胞的产品；
所述E1）-E3）中，所述病毒为埃博拉病毒。
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| CN108314706A (zh) | 2018-07-24 |
| CN108314706B (zh) | 2020-06-16 |
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