CN117304317A - Ace2受体特异性结合肽及其应用 - Google Patents
Ace2受体特异性结合肽及其应用 Download PDFInfo
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- CN117304317A CN117304317A CN202210739117.6A CN202210739117A CN117304317A CN 117304317 A CN117304317 A CN 117304317A CN 202210739117 A CN202210739117 A CN 202210739117A CN 117304317 A CN117304317 A CN 117304317A
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Abstract
血管紧张素转化酶II(ACE2)是肾素‑血管紧张素系统(RAS)中的关键性酶,在各种心血管疾病中起着重要作用。ACE2通常定位于上皮细胞的腔面,是新冠病毒(SARS‑CoV‑2)进入宿主细胞的受体。本发明设计了ACE2受体特异性结合肽,其通过与靶细胞上ACE2受体特异性结合,阻断新冠病毒进入细胞,起到预防和治疗新冠病毒感染的作用。体外和体内实验结果证明,本发明的ACE2受体特异性结合肽能够特异性地结合ACE2受体,高效阻断新冠病毒感染靶细胞。
Description
技术领域
本发明属于医药技术领域,涉及ACE2受体特异性结合肽,以及以ACE2为靶点可治疗的各类疾病,尤其是在用于制备预防和/或治疗由SARS-CoV-2感染引起的新型冠状病毒感染(COVID-19)药物中的应用。
背景技术
ACE2在人体心脏、肾脏和睾丸表达水平最高,在肺、肝、肠道和大脑也有广泛分布。ACE2的三个主要功能包括:对RAS进行负调节、肾脏中氨基酸运输的调节以及包括SARS-CoV-2和SARS-CoV在内的病毒受体。ACE2还对人体局部损伤有保护作用,与新型冠状病毒感染的进展和预后有关,因此,基于ACE2的药物可能是新型冠状病毒感染的潜在治疗策略。
已有的研究表明,SARS-CoV-2利用其S蛋白与人细胞表面的血管紧张素转化酶II(ACE2)受体结合,通过受体介导的内吞作用进入宿主细胞中,进行病毒的复制和扩增,达到感染靶细胞和周围组织的目的。
针对此次COVID-19,目前虽然已有多款疫苗批准上市用于预防SARS-CoV-2感染,但是仍然急需抗新冠病毒的治疗性药物。特异性中和抗体兼具预防和治疗的作用,是最具潜力的药物之一,但是这类抗体类药物由于其细胞渗透性低,对于细胞内的病毒难以清除,因此,很难取得较好的疗效,相反,小分子药物往往具有良好的稳定性、口服生物利用度和跨膜能力,所以其一直是细胞内靶标药物开发的首选分子类别。与特异性中和抗体这类大分子药物相比,小分子口服药的抗病毒效果更直接,生产成本和用药成本也更低,另外患者依从性更好,储运也更加方便。
全球首个获批紧急使用的小分子口服新冠药物为美国默沙东的莫努匹韦,同时2021年11月其在英国获得上市批准,2021年12月22日美国辉瑞公司生产的新冠病毒小分子治疗药物帕昔洛韦在美国获批紧急使用。同时,这两款药物随后也获得了以色列、加拿大等多个国家的使用许可。此外,我国原创新冠小分子口服药物VV116已经在乌兹别克斯坦正式获批上市。
2020年10月22日,美国食品药品管理局(FDA)批准了吉利德公司的瑞德西韦(Remdesivir)用于治疗新冠住院患者。也是迄今为止唯一在美国正式获批的小分子新冠治疗药物。但口服瑞德西韦的生物利用度很低,仅为2%左右,很难发挥药效,因此,目前是作为注射液,通过直接静脉输注进入血液来发挥药效,且已有的研究表明,瑞德西韦通过静脉输注以后,其副作用是存在一定的肝肾毒性。并且注射给药对药物的使用便利性也产生了一定的限制,且患者依从性低。吉利德公司也意识到了这一点,开始探索通过雾化的方式给药。即使这样,瑞德西韦对于新冠治疗尚也仍然存在一定的争议。2020年11月WHO考虑四项共7000多名患者的临床试验,表明无证据支持瑞德西韦能够提高患者存活率,反对在住院患者中使用瑞德西韦。
瑞德西韦作用于病毒RNA聚合酶,因此药物必先到达病毒复制的场所才能发挥其作用,但是目前已上市的瑞德西韦是一种β环糊精分散制剂,通过静脉注射进入机体,缺乏靶向性,而SARS-CoV-2在感染的早期主要集中在组织器官的腔面(顶侧),而这些地方,游离的瑞德西韦不易到达,因此很难接触到病毒并干扰其复制,这可能是其抗病毒疗效不佳的主要原因之一。
另一个方面,瑞德西韦仅批准用于住院患者,对于大多数住院患者来说,往往已经发展成了重症患者,病毒已在机体中大面积蔓延,甚至引发组织损伤,进一步加剧病毒的蔓延,这时候才给予瑞德西韦静脉输注治疗,很可能难以很好地控制病毒的蔓延。这可能解释了,在临床使用瑞德西韦治疗住院患者时,其对患者生存率没有显著影响,只能够改善患者住院治疗时间的原因之一。值得注意的是,相较于大多数的抗冠状病毒药物来讲,瑞德西韦在体外细胞水平上的冠状病毒抑制有效浓度在nM级,表明其具有良好的抗病毒活性,然而,其体内的抗病毒活性没有达到很好的预期,这可能归咎于其入血后半衰期短、靶向性差、生物利用度低,很难到达病毒感染的部位,同时,这也是很多抗病毒药物疗效不佳的共同原因。
为此,对于已经入胞的病毒而言,增强活性药物的入胞效率,对提高抗病毒药物的治疗效果具有重要意义。因此,本发明基于病毒感染宿主细胞在时间和空间上的特点,有针对性设计了抗新冠病毒感染的药物。
先从空间上来讲,有研究指出,ACE2分子的完整性及其跨膜区对于SARS-CoV-2的感染至关重要,最初在英国出现的B.1.1.7突变体,其刺突蛋白发生了三个关键突变,这种突变使得病毒的刺突蛋白与人体细胞上的ACE2受体结合得更紧密,从而导致结合的成功率更高,意味着相较以前的变种,这些突变株更容易感染细胞。在SARS-CoV2感染及发病的整个过程中,ACE2发挥了重要作用:
1)作为受体,与病毒S蛋白结合,介导病毒感染;
2)调控肾素-血管紧张素系统(RAS),参与急性肺损伤;
3)参与免疫调控:引起细胞因子风暴,加重炎症。
从时间上来讲,当新冠病毒感染肺深部组织,引发强烈的细胞因子风暴甚至出现肺损伤时,才使得病毒扩散至血液,进而感染其他远端器官。因此,对于新冠病毒的预防和治疗,应早发现早治疗为宜,特别是在确诊了COVID-19感染以后,应尽早地进行治疗,以清除或阻断病毒从上呼吸道的扩增和继续传播,这对于病毒的预防和控制具有重要意义。
为此,特异性阻断SARS-CoV-2-S蛋白与ACE2的结合是预防和治疗COVID-19的有效策略。本发明首次针对SARS-CoV-2-S蛋白受体结合域(RBD)的新突变氨基酸残基序列,设计出能够特异性高效结合ACE2受体的多肽,通过分子水平和细胞水平两个方面筛选出抗病毒感染活性最优多肽,并且多肽药物具备使用量少、选择性强、特异性好、不良反应少等优势,具有良好的市场前景。
因此,为了解决以瑞德西韦为代表的小分子抗病毒药物的靶向性差、生物利用度低、给药剂量大、价格昂贵等问题,本发明设计了ACE2受体特异性结合肽,一方面其可通过结合细胞上的ACE2受体以阻止冠状病毒感染宿主细胞,从而阻止病毒的扩增和蔓延;另一方面将其应用在基于ACE2的治疗药物设计中,以提高治疗药物的靶向性,增加入胞效率,从而降低给药量,以达到增效减毒的目的。
发明内容
本发明的目的是为了克服背景技术中以抗新型冠状病毒感染为代表的小分子药物,例如瑞德西韦,靶向性差、生物利用度低、入胞效率低、给药剂量大的缺点。本发明涉及一种多肽或其药学上可以接受的盐及载体,其中多肽是根据新冠S蛋白和ACE2的复合物结构而设计的,具有与ACE2受体的特异性亲和力,为ACE2受体特异性结合肽。
本发明提供的ACE2受体特异性结合肽的氨基酸序列通式为:
X1FNCY,X2X3X4QX5,YGFX6X7,TX8GX9G,YQ
上述肽链中单字母符号代表的氨基酸残基定义如下:F为苯丙氨酸,N为天冬酰胺,C为半胱氨酸,Y为酪氨酸,Q为谷氨酰胺,G为甘氨酸,T为苏氨酸,X1-9为可变的氨基酸残基。其中,X1为丙氨酸(A)、甘氨酸(G)、亮氨酸(L)、蛋氨酸(M)、异亮氨酸(I)、缬氨酸(V)、谷氨酰胺(Q)、丝氨酸(S)或苏氨酸(T),其中X2为苯丙氨酸(F)、色氨酸(W)、脯氨酸(P)或酪氨酸(Y),其中X3为亮氨酸(L)、蛋氨酸(M)、异亮氨酸(I)、缬氨酸(V)、谷氨酰胺(Q)、丝氨酸(S)、苏氨酸(T)、丙氨酸(A)或甘氨酸(G),其中X4为亮氨酸(L)、蛋氨酸(M)、异亮氨酸(I)、缬氨酸(V)、谷氨酰胺(Q)、丝氨酸(S)、苏氨酸(T)、丙氨酸(A)或甘氨酸(G),其中X5为丝氨酸(S)、苏氨酸(T)、丙氨酸(A)、甘氨酸(G)、亮氨酸(L)、蛋氨酸(M)、异亮氨酸(I)、缬氨酸(V)或谷氨酰胺(Q),其中X6为谷氨酰胺(Q)、天冬酰胺(N)、半胱氨酸(C)、甘氨酸(G)、苏氨酸(T)、蛋氨酸(M)、丙氨酸(A)、缬氨酸(V)、亮氨酸(L)或异亮氨酸(I),其中X7为脯氨酸(P)、色氨酸(W)、苯丙氨酸(F)或酪氨酸(Y),其中X8为酪氨酸(Y)、苯丙氨酸(F)、色氨酸(W)、脯氨酸(P)、丝氨酸(S)或苏氨酸(T),其中X9为异亮氨酸(I)、亮氨酸(L)、蛋氨酸(M)、缬氨酸(V)、丙氨酸(A)、苯丙氨酸(F)、甘氨酸(G)、半胱氨酸(C)、谷氨酰胺(Q)、丝氨酸(S)或天冬酰胺(N)。同时,ACE2受体特异性结合肽还可以是式(I)所示的氨基酸序列经过替换、增加和/或缺失一个或几个氨基酸且具有相同功能的衍生多肽。优选的,ACE2受体特异性结合肽的序列包括但不局限于如下所示:
优选的本发明的ACE2受体特异性结合肽为:(a)SEQ ID No.1至SEQ ID No.10中任一所示氨基酸序列组成的多肽;(b)SEQ ID No.1至SEQ ID No.10中任一所示氨基酸序列经过替换、增加和/或缺失一个或几个氨基酸且具有与(a)相同功能的衍生多肽。
本发明还提供了根据本发明的式(I)所示的多肽的药学上可以接受的盐,这样的盐包括但不局限于加酸成盐和加碱成盐。本发明中提到的“药学上可以接受的盐”是指保留了式(I)所示的多肽的ACE2的结合活性并且适合用于人或动物的盐。用于制备式(I)所示的多肽的盐的方法在本邻域中是已知的,并且通常涉及将肽与可药用酸或碱混合,可药用酸和碱的实例包括与肽的游离氨基形成铵盐的有机酸和无机酸,例如甲酸、乙酸、丙酸、乳酸、乙醇酸、草酸、丙酮酸、琥珀酸、马来酸、丙二酸、三氟乙酸、肉桂酸、硫酸、盐酸、氢溴酸、硝酸、高氯酸、磷酸和硫氰酸;以及与肽的游离羧基形成羧酸盐的碱,例如乙胺、甲胺、二甲胺、三乙胺、异丙胺、二异丙胺和其他单烷基胺、二烷基胺和三烷基胺、以及芳基胺。
本发明还提供了包含编码式(I)所示的多肽的核酸序列的核酸分子,所述核酸序列包含核苷酸的链,优选DNA和/或RNA。
本发明还提供了包含编码根据本发明的式(I)所示的多肽氨基酸序列的多核苷酸。
在另一个方面中,本发明提供了包含2个及2个以上根据本发明的式(I)所示的多肽的多聚肽或其药学上可以接受的盐,优选包含2个根据本发明的式(I)所示的多肽的二聚肽。
在另一方面,本发明提供一种融合蛋白,其含有式(I)所示多肽或其药学上可以接受的盐。
在另一方面,本发明提供一种融合蛋白,其包含2个及2个以上根据本发明的式(I)所示的肽的多聚肽。
在另一个方面中,本发明提供了一种组合物,其含有式(I)所示的多肽、核酸分子、多聚肽、多核苷酸和/或包含2个及2个以上根据本发明的式(I)所示的多肽的多聚肽的融合蛋白或其药学上可接受的盐。该组合物包含载荷组合物,其中所述肽和所述载荷组合物彼此共价偶联或非共价缔合,任选地,其中所述载荷组合物包含治疗剂、可检测剂、载体、表面分子或其组合,优选地,其中所述治疗剂是抗血管生成剂、抗菌剂、抗癌剂、抗炎剂、化疗剂、降血压剂、细胞毒性剂、免疫刺激剂、免疫抑制剂、核酸分子、多肽、促血管生成剂、促凋亡剂、促炎剂或毒素,优选地,其中所述可检测剂是标记剂、造影剂、显像剂,任选地,其中所述肽与所述载荷组合物缀合,优选地,其中所述缀合肽中的一种或更多种通过接头与所述载荷组合物间接缀合,任选地,其中所述载荷组合物还包含多种接头,优选地,其中所述接头中至少一种包含聚乙二醇或马来酰亚胺偶联、氨基官能化的右旋糖酐化学性质来偶联,以及组分可通过任何官能团,例如,胺、羰基、羧基、醛、醇直接或间接地与表面分子或彼此共价结合。
在另一个方面,本发明提供式(I)所示的多肽,或前述所述的核酸分子、多聚肽、多核苷酸或/和融合蛋白的药物递送系统,所述药物递送系统包括:胶束、脂质体、纳米粒、纳米乳、微乳、纳米囊、磷脂复合物、聚合物复合物、碳纳米管、量子点、微囊、水凝胶、微球、噬菌体、噬菌体衣壳、噬菌体颗粒、病毒、病毒衣壳、病毒颗粒、细胞外囊泡、外泌体的一种或多种。
在另一方面,本发明还涉及式(I)所示的多肽,或前述所述的核酸分子、多聚肽、多核苷酸或/和融合蛋白的组合物,其包含连接剂,所述连接剂包括:蛋白、多肽、脂肪酸及其衍生物、抗体、抗体片段、环糊精及其衍生物、小分子药物、PEG,PEG及其衍生物、脂肪酸、介孔无机材料、线性聚合物、交联聚合物、或支化共聚物的一种或几种。
在另一个方面中,根据本发明的式(I)所示的多肽,或如前所述的核酸分子、多聚肽、多核苷酸、融合蛋白或其药学上可以接受的盐,提供其在制备预防和/或治疗新型冠状病毒感染病毒的药物中的应用。同时,在另一方面,本发明还涉及式(I)所示的多肽,或前述所述的核酸分子、多聚肽、多核苷酸或/和融合蛋白的组合物,可将该组合物用于制备治疗剂、靶向剂、预防剂、诊断剂或成像剂中的应用,或是将该组合物用于在制备治疗肿瘤和冠状病毒感染性疾病的诊断和/或治疗、图像引导手术、药物递送、成像剂的靶向递送中的药物中的应用。所述组合物优选用于制备治疗或预防冠状病毒感染、炎性疾病或癌症的药物中的应用。
在另一方面,本发明还涉及将式(I)所示多肽、或前所述的核酸分子、多聚肽、多核苷酸或/和融合蛋白在制备治疗基于ACE2受体相关疾病的药物中的应用。
本发明在分子水平、细胞水平和动物水平的相关实验结果显示,本发明的多肽对ACE2受体具有靶向性和高效的亲和性,不论是游离给予多肽还是将上述多肽连接于递药载体上,均可以实现对ACE2高效的亲和性。本发明所述的这种ACE2受体特异性结合肽可以解决现有技术中抗新冠病毒药物对于治疗新型冠状病毒感染疾病的疗效不佳的技术问题,并为治疗基于ACE2的各类疾病,尤其是防治病毒感染提供新的思路和科学依据。
本发明针对SAR-CoV-2蛋白RBD的新突变氨基酸残基序列,设计了ACE2受体特异性结合肽。相比于现有的技术,本发明具有以下优点:
1、提供了ACE2受体特异性的结合肽,所设计的ACE2受体特异性结合肽通过体内外实验验证表明靶向性高、特异性强、稳定性高,与ACE2亲和力能力强:(1)本发明的多肽片段能够特异性结合细胞上ACE2,而不识别正常细胞。因此,该ACE2受体特异性结合肽及其衍生物在基于ACE2的分子诊断,筛查和靶向治疗中具有重要应用价值。
2、本发明的多肽分子通过与细胞上ACE2结合,阻断病毒进入靶细胞,为包括治疗新型冠状病毒感染在内的以ACE2为治疗靶点的药物递送提供新的思路和科学依据,同时拓宽了该多肽的应用范围。
3、与传统药物相比,在生产上,应用生物工程技术,多肽类药物合成和纯化简便,容易实现规模化生产,而且兼有相对分子质量较小、免疫原性弱、活性高等优点,选出的多肽有望成为效果好、效益高的新时代药物带来更多希望。
附图说明
图1.根据新冠病毒S蛋白和ACE2的复合结构设计多肽氨基酸序列。
图2.MST方法检测多肽SEQ ID No.1亲和力实验结果。
图3.MST方法检测多肽SEQ ID No.2亲和力实验结果。
图4.MST方法检测多肽SEQ ID No.3亲和力实验结果。
图5.MST方法检测多肽SEQ ID No.4亲和力实验结果。
图6.MST方法检测多肽SEQ ID No.5亲和力实验结果。
图7.MST方法检测多肽SEQ ID No.6亲和力实验结果。
图8.MST方法检测多肽SEQ ID No.7亲和力实验结果。
图9.MST方法检测多肽SEQ ID No.8亲和力实验结果。
图10.MST方法检测多肽SEQ ID No.9亲和力实验结果。
图11.MST方法检测多肽SEQ ID No.10亲和力实验结果。
图12.MST方法检测多肽与ACE2亲和力的统计结果。
图13.考察ACE2在不同细胞系的表达水平。
图14.代表性多肽抑制新冠假病毒感染能力考察。
具体实施方式
为使本发明实例的目的、技术方案和优点更加清楚,下面将结合本发明实施例,对本发明实施例中的技术方案进行更加清楚、完整地描述、所描述的实施例是本发明的一部分实施例,而不是全部的实施例。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰,但这些都将包括在本发明的范围内。
本发明通过微量热泳动(MST)技术在体外分子水平上检测所合成的不同多肽与人源ACE2蛋白的结合效果,进而筛选出结合能力最优的多肽。进一步,在hACE2-293T细胞上,采用新冠假病毒,考察代表性多肽抑制新冠假病毒感染hACE2-293T细胞能力,筛选出抑制病毒感染效果最优的多肽。
本发明的ACE2受体特异性结合肽和现有技术相比,其技术效果是显著的,可以特异性抑制新冠病毒的进入,解决了新型冠状病毒感染传染性强,新冠治疗药物靶向性差的缺点,同时拓宽了以ACE2为靶点的治疗药物的应用范围。
实施例1本发明根据新冠病毒S蛋白与ACE2的复合结构,来设计出具有特异性结合ACE2的多肽,如附图1所示。本发明的ACE2受体特异性结合肽的氨基酸序列结构为:X1FNCY,X2X3X4QX5,YGFX6X7,TX8GX9G,YQ;其中X1选自A,G,L,M,I,V,Q,S,T中的任一种,X2选自:F,W,P,Y中的任一种,X3选自L,M,I,V,Q,S,T,A,G中的任一种,X4选自L,M,I,V,Q,S,T,A,G任一种,X5选自S,T,A,G,L,M,I,V,Q中的任一种,X6为选自Q,N,C,G,T,M,A,V,L,I中的任一种,X7选自P,W,F,Y中的任一种,X8选自Y,F,W,P,S,T中的任一种,X9选自I,L,M,V,A,F,G,C,Q,S,N的任一种。优选的,本发明ACE2受体特异性结合肽氨基酸序列包括但不局限于如下表所示。
表1:优选的ACE2受体特异性结合肽氨基酸序列
多肽编号 | 多肽名称 | 多肽氨基酸序列 |
SEQ ID No.1 | FQ | FNCYFPLQSYGFQPTNGVGYQ |
SEQ ID No.2 | YQ | YGFQPTNGVGYQ |
SEQ ID No.3 | GQ | GVEGF,NCYFP,LQSYG,FQPTN,GIGYQ |
SEQ ID No.4 | AY | AFNCY,FLLQS,YGFQP,TNGIG,Y |
SEQ ID No.5 | FY | FNCYF,PLQSY,GFQPT,NGVGY |
SEQ ID No.6 | AYQ(12224) | AFNCY,FLLQS,YGFQP,TYGIG,YQ |
SEQ ID No.7 | AFQ | AFNYY,FLLQY,YGFQP,TNGIG,YQ |
SEQ ID No.8 | Pep-1222-1 | GVEAF,NCYFL,LQSYG,FQPTY,GIGYQ |
SEQ ID No.9 | Pep-1222-2 | GVEAF,NYYFL,LQYYG,FQPTY,GIGYQ |
SEQ ID No.10 | Pep-GQ2 | GVEAF,NYYFL,LQYYG,FQPTN,GIGYQ |
同时,通过在分子水平、细胞水平和动物水平上评价了上述多肽对ACE2的靶向亲和性,并筛选出更高稳定性和更高活性的ACE2受体特异性结合肽,期望获得具有更好成药性的,更高稳定性和更高活性的ACE2受体特异性结合肽,为以ACE2为靶点的药物设计提供更多的方向。
实施例2ACE2受体特异性结合肽与ACE2亲和力的测定
在本发明中,采用微量热泳动(MST)检测ACE2受体特异性结合肽与ACE2的亲和力,MST是一种定量分析生物分子间相互作用的有效方法。检测分子在微观温度梯度场中的运动,探测其水化层、电荷以及分子大小的变化。MST将荧光检测的精准性与热泳动的灵活性及灵敏度结合起来,其可快速、可信地检测分子间相互作用。在本发明在分子水平检测了ACE2受体特异性结合肽与ACE2的亲和力,阳性对照为RBD,通过测试ACE2受体特异性结合肽、RBD与ACE2蛋白的亲和力,得到结合解离常数Kd值,实验结果如附图2~11所示,附图12为SEQ ID 1-10的多肽进行MST检测的统计结果。可见,本发明所涉及的多肽与ACE2具有较高的亲和力,其中多肽SEQ ID No.4、SEQ ID No.9、SEQ ID No.10与ACE2的亲和力较其它多肽更优。
实施例3对不同细胞ACE2表达水平的考察
在本发明中,为进一步在细胞水平上对所设计合成的多肽进行抑制新冠假病毒感染靶细胞的能力进行考查,首先采用蛋白质印迹(Western blotting)实验验证了ACE2在各种细胞上的表达情况,具体操作步骤为:
在本发明中考察了Caco-2、hACE2-293T、293T、4T1、RAW这5种细胞中ACE2表达水平。将上述细胞接种于6孔板,每孔2.0×105个细胞,经过24h后,收集各种细胞,RIPA裂解液裂解细胞,加入蛋白酶抑制剂,冰浴裂解细胞30min,收集细胞裂解物,12000rpm,离心15min,收集裂解液上清,进行BCA蛋白质浓度定量检测,将各种细胞裂解液样品蛋白浓度调整一致,加入Loading buffer,沸水煮样10min,接着进行SDS-PAGE电泳分离,ACE2一抗4℃孵育过夜,二抗室温孵育1h,接着进行凝胶成像显色观察。实验结果如附图13所示。在所选择的细胞中,hACE2-293T细胞中ACE2的表达量远远高于其它各种细胞,因此,在后续的病毒感染实验中,选择hACE2-293T细胞为模型细胞。
实施例4考察ACE2受体特异性结合肽抑制新冠假病毒感染hACE22-293T的能力
在本发明中所用到的新冠假病毒购自金唯智COVID-19假病毒,具体操作步骤:将1.5×104个hACE2-293T细胞接种于96孔板中,并与不同浓度的ACE2受体特异性结合肽在37℃孵育2h,接着向孔中加入130倍的TCID50值的新冠假病毒。继续培养48h,按照荧光素酶活性检测试剂盒说明书进行后续操作,裂解细胞,采用酶标仪检测,测定结果如附图14所示,实验结果表明,与对照组(即0ug/ml)相比,本发明中所设计的ACE2受体特异性结合肽具有抑制新冠假病毒的感染hACE22-293T的能力,由于SEQ ID No.6的水溶性较差,在培养基中浓度低于5μg/ml时,能够充分溶解,相较于其余多肽表现出较强的抗新冠病毒感染活性,SEQ ID No.6多肽在培养基中浓度高于5μg/ml时,因溶解度降低,抗病毒活性不理想。因此,在浓度范围为0~5μg/ml时,SEQ ID No.6和SEQ ID No.9体现出更优的抗新冠病毒感染能力。
序列表
<110> 四川大学
<120> ACE2受体特异性结合肽及其应用
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Claims (13)
1.一种多肽或其药学上可以接受的盐,其特征在于氨基酸序列如下式(I)所示,
式(I)为X1FNCYX2X3X4QX5YGFX6X7TX8GX9GYQ,
其中X1为:A,G,L,M,I,V,Q,S或T;
X2为:F,W,P或Y;
X3为:L,M,I,V,Q,S,T,A或G;
X4为:L,M,I,V,Q,S,T,A或G;
X5为:S,T,A,G,L,M,I,V或Q;
X6为:Q,N,C,G,T,M,A,V,L或I;
X7为:P,W,F或Y;
X8为:Y,F,W,P,S或T;
X9为:I,L,M,V,A,F,G,C,Q,S或N;或式(I)所示的氨基酸序列经过替换、增加和/或缺失一个或几个氨基酸且具有相同功能的衍生多肽。
2.一种核酸分子,其包含编码根据权利要求1所述肽的核酸序列。
3.一种多聚肽,其包含2个或2个以上根据权利要求1所述的任一项所述的多肽、或其药学上可以接受的盐。
4.一种多核苷酸,其包含编码权利要求1所述多肽氨基酸序列的多核苷酸。
5.一种融合蛋白,含有权利要求1所述的多肽或其药学上可以接受的盐。
6.一种融合蛋白,含有权利要求3所述的多聚肽。
7.一种组合物,其包含权利要求1所述的多肽或其药学上可以接受的盐,和/或包含权利要求2所述的核酸分子,和/或包含权利要求3所述的多聚肽,和/或包含权利要求4所述的多核苷酸,和/或包含如权利要求5-6任一所述的融合蛋白。
8.权利要求7所述的组合物在制备治疗剂、靶向剂、预防剂、诊断剂或成像剂中的应用。
9.如权利要求8所述的组合物,其包含载荷组合物,其中所述肽和所述载荷组合物彼此共价偶联或非共价缔合,任选地,其中所述载荷组合物包含治疗剂、可检测剂、载体、表面分子或其组合,优选地,其中所述治疗剂是抗血管生成剂、抗菌剂、抗癌剂、抗炎剂、化疗剂、降血压剂、细胞毒性剂、免疫刺激剂、免疫抑制剂、核酸分子、多肽、促血管生成剂、促凋亡剂、促炎剂或毒素,优选地,其中所述可检测剂是标记剂、造影剂、显像剂,任选地,其中所述肽与所述表面分子缀合,优选地,其中所述缀合肽中的一种或更多种通过接头与所述表面分子间接缀合,任选地,其中所述组合物还包含多种接头,优选地,其中所述接头中的至少一种包含聚乙二醇或马来酰亚胺偶联、氨基官能化的右旋糖酐来偶联以及组分可通过任何官能团,所述官能团为胺、羰基、羧基、醛、醇直接或间接地与表面分子或彼此共价结合。
10.包含权利要求1-6任一所述的多肽、核酸分子、多聚肽、多核苷酸或/和融合蛋白的药物递送系统,所述药物递送系统包括:胶束、脂质体、纳米粒、纳米囊、纳米乳、微乳、磷脂复合物、聚合物复合物、碳纳米管、量子点、微囊、水凝胶、微球、噬菌体、噬菌体衣壳、噬菌体颗粒、病毒、病毒衣壳、病毒颗粒、细胞外囊泡、外泌体的一种或多种。
11.包含权利要求1-6任一所述的多肽、核酸分子、多聚肽、多核苷酸或/和融合蛋白的组合物,其包含连接剂,所述连接剂包括:蛋白、多肽、脂肪酸及其衍生物、抗体、抗体片段、环糊精及其衍生物、小分子药物、PEG及其衍生物、脂肪酸、介孔无机材料、线性聚合物、交联聚合物、或支化共聚物的一种或几种。
12.权利要求1-6任一所述的多肽、核酸分子、多聚肽、多核苷酸或融合蛋白在制备预防和/或治疗新型冠状病毒的药物中的应用。
13.权利要求1-6任一所述的多肽、核酸分子、多聚肽、多核苷酸或融合蛋白在制备治疗基于ACE2受体相关疾病的药物中的应用。
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