CN112137994B - 小分子化合物在制备抗丝状病毒药物中的应用 - Google Patents
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Abstract
本发明公开了式I或式II所示结构式的小分子化合物在制备抗丝状病毒药物中的应用,其中首次发现式I的PD 325901和式II的依匹唑派具有优良的抗丝状病毒活性,PD 325901对埃博拉病毒IC50为2.6μM,对马尔堡病毒IC50为5.3μM,依匹唑派对埃博拉病毒IC50为3.8μM,对马尔堡病毒IC50为3.0μM,具有成为抗病毒先导化合物的潜力,且还初步证明了本发明所示的侧链有长碳链取代的苯并杂环化合物能成为快速开发抗丝状病毒抑制剂的基本骨架。
Description
技术领域
本发明属于化合物的新用途领域,具体涉及小分子化合物在制备抗丝状病毒药物中的应用。
背景技术
丝状病毒是一种能够引起人和非人灵长类动物发生严重出血热的单股负链RNA病毒,特别是丝状病毒科属下的埃博拉病毒(Ebola virus),感染者症状与同为纤维病毒科的马尔堡病毒极为相似,包括恶心、呕吐、腹泻、肤色改变、全身酸痛、体内出血、体外出血、发烧等,死亡率高达90%。
目前,现有被批准用于埃博拉病毒的疫情治疗方法主要为接种疫苗。这些疫苗都含有埃博拉病毒的一种蛋白质,一旦进入人体就会引发免疫系统反应。埃博拉病毒疫苗主要用于控制埃博拉病毒的传播或用于辅助性治疗,包括使病毒入侵最小化,平衡电解质,修复损失的血小板以便防止出血,保持血液中氧元素含量,以及对并发症的治疗。但由于其仅具有辅助治疗作用,因此治疗效果并不突出,而且埃博拉疫苗的制备难度相对较大,产量低,对于存储和运输条件都较为苛刻,不适合在医疗环境一般的地区快速推广使用。
因此,亟需一种治疗替代物,能够有效替代疫苗用于丝状病毒的治疗。
发明内容
本发明的目的在于提供式I或式II结构式所示的小分子化合物在制备抗丝状病毒药物中的应用;
本发明的另一目的在于提供一种用于抗丝状病毒的药物组合物。
本发明所采取的技术方案是:
本发明的第一个方面,提供:
式I或式II结构式所示的小分子化合物在制备抗丝状病毒药物中的应用;
式I所示结构式的小分子化合物为N-[(2R)-2,3-二羟基丙氧基]-3,4-二氟-2-[(2-氟-4-碘苯)(英文名PD 325901或(R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide),CAS号为391210-10-9。PD 325901是一种具有口服活性,选择性和非ATP竞争性的MEK抑制剂,IC50为0.33nM。PD 325901抑制p-ERK1/2的表达并诱导细胞凋亡。PD0325901对多种人类肿瘤异种移植物具有抗癌活性。但本发明首次发现了PD 325901还具有抗埃博拉病毒和马尔堡病毒活性,对埃博拉病毒IC50为2.6μM,对马尔堡病毒IC50为5.3μM,效果极好,对控制丝状病毒的传播以及治疗具有极高的研究价值。
式II所示结构式的小分子化合物为依匹唑派(英文名Brexpiprazole),CAS号为913611-97-9。依匹唑派是一种多巴胺、部分5-HT1A受体激动剂以及5-HT2A受体拮抗剂化合物。依匹唑派在多个单胺系统具有广泛的活性,对多巴胺D2受体的部分激动剂活性下降,且对特定5-HT受体(如5-HT1A、5-HT2A、5-HT7)的亲和力提高,具有更好的疗效和耐受性,可减少患者静坐不能、不安和/或失眠等不良反应。依匹唑派目前在III期临床研究中用于精神分裂症的治疗,以及重度抑郁症的辅助治疗。此外,该化合物还针对注意力缺陷多动障碍(ADHD)在展开II期临床研究。但本发明首次发现了依匹唑派还具有抗埃博拉病毒和马尔堡病毒活性,对埃博拉病毒IC50为3.8μM,对马尔堡病毒IC50为3.0μM,效果极好,对控制丝状病毒的传播以及治疗具有极高的研究价值。
进一步地,上述丝状病毒包括埃博拉病毒、马尔堡病毒。
发明人发现,通过化合物筛选,发现具有苯并杂环母核的小分子药物能发挥抑制丝状病毒进入宿主细胞的作用,而进一步研究发现,在骈环上同具有长碳支链的式I化合物和式II都具有较好的抗埃博拉病毒和马尔堡病毒的活性,因此,初步说明侧链有长碳链取代的化合物能成为快速开发抗丝状病毒抑制剂的基本骨架。
本发明的第二个方面,提供:
一种用于抗丝状病毒的药物组合物,该药物组合物中含有药学上有效量的式I或式II结构式的小分子化合物。
上述药物组合物还含有如式I或式II化合物的同分异构体、衍生物、氘代物中的一种或其组合。
本发明的有益效果是:
1.本发明首次发现了PD 325901和依匹唑派具有优良的抗丝状病毒活性,具有成为抗病毒先导化合物的潜力。
2.结合实施例中的数据,本发明初步证明了侧链有长碳链取代的苯并杂环类化合物能成为快速开发抗丝状病毒抑制剂的基本骨架。
3.本发明所用的小分子化合物(PD 325901和依匹唑派)具有很好的水溶性,代谢稳定性和吸收率。
具体实施方式
为了使本发明的发明目的、技术方案及其技术效果更加清晰,以下结合具体实施方式,对本发明进行进一步详细说明。应当理解的是,本说明书中描述的具体实施方式仅仅是为了解释本发明,并非为了限定本发明。
所使用的实验材料和试剂,若无特别说明,均为常规可从商业途径所获得的耗材和试剂。
试验材料
PD 325901(化合物1)、依匹唑派(化合物2)、RO5126766(CH5126766)(化合物3)、西洛他胺(Butanamide,N-cyclohexyl-4-[(1,2-dihydro-2-oxo-6-quinolinyl)oxy]-N-methyl-Cilostamide,别名OPC 3689)(化合物4)均购自上海远祚医药科技有限公司。
抗丝状病毒活性实验
RO5126766和西洛他胺被选择作为对照组,RO5126766和西洛他胺是与PD 325901和依匹唑派结构相似(都含有苯并杂环母核)的化合物,RO5126766的结构式为:
西洛他胺的结构式为:
抗丝状病毒活性实验的具体步骤为:
1)细胞培养
实验所用的细胞为人肾上皮细胞(239T,ATCC编号为CRL-1573)和人肺上皮细胞(A549,ATCC编号为CCL185)。细胞培养基采用高糖DMEM培养液(Cellgro,Manassas,VA,USA),内含10%的胎牛血清(FBS,Sigma,St.Louis,MO,USA)及100μg/mL的链霉素和100units的青霉素(Invitrogen,Carlsbad,CA,USA),上述细胞于5%CO2、37℃培养箱中孵育。
2)假病毒粒子感染试验和细胞活力试验
根据聚乙烯亚胺(polyethylenimine,PEI)转染试剂说明书分别将编码埃博拉病毒(EBOV)GP基因或马尔堡病毒(MARV)GP基因的质粒与复制缺陷型的HIV载体(pNL4-3.Luc.R-E-)质粒共转染至293T细胞中。转染6小时后,去除旧的培养基,PBS洗涤细胞一次,每孔再加入20mL新鲜的培养基进行换液。培养24小时后收集上清病毒液,经0.45μm滤膜(Nalgene,Rochester,NY,USA)过滤,去除细胞碎片,即获得HIV/EBOV和HIV/MARV假病毒粒子,于4℃条件下保存。
感染前24小时,在96孔板中接种低传代的A549细胞(1×105/孔)。将化合物1-4(化合物1:PD 325901、化合物2:依匹唑派、化合物3:RO512676、化合物4:西洛他胺)连续稀释3倍后与HIV/MARV或HIV/EBOV伪病毒液或与新鲜培养基混合,每孔接入100uL上述混合液共孵育。细胞培养48小时后,用NeoLite萤火虫荧光素酶报告基因(PerkinElmer,Waltham,MA,USA)测定细胞荧光素酶活性,用CellTiter-Glo试剂盒(Promega,Madison,WI,USA)检测细胞活力。将上述病毒液与细胞共培养或者培养液与细胞共培养作为阴性对照,将细胞信号用作数据归一化。用GraphPad逻辑回归法拟合剂量-反应曲线来确定化合物的IC50和CC50值。
检测结果如下。
表1化合物1-4的抗丝状病毒活性实验结果
SI表示治疗指数,治疗指数越高,表示对该病毒的治疗效果越好。
结果显示,PD 325901和依匹唑派具有优良的抗丝状病毒活性,具有成为抗病毒先导化合物的潜力。而根据与结构相似的RO5126766和西洛他胺比较发现,并非具有相似结构的化合物均会显示出抗丝状病毒活性,但该数据却能初步证明侧链有长碳链取代的苯并杂环化合物(可具有碳链,含氧碳链(即PEG链),甘油链等支链)能成为快速开发抗丝状病毒抑制剂的基本骨架。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
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