CN114796264A - 金络合物在制备治疗新型冠状病毒肺炎的药物中的应用 - Google Patents
金络合物在制备治疗新型冠状病毒肺炎的药物中的应用 Download PDFInfo
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Abstract
本发明提供了金络合物在制备治疗新型冠状病毒肺炎的药物中的应用,属于生物医药技术领域。金络合物能够有效的抑制Mpro蛋白的催化活性,抑制细胞中SARS‑CoV‑2活病毒在活细胞中的复制。金络合物能够显著抑制巨噬细胞和肺支气管细胞的NFkB炎性分子通路的活化,从而降低炎性因子IL‑6、IL‑1β和TNF‑α的表达与分泌。金络合物能在COVID‑19模型动物上,抑制肺组织病毒复制和抑制动物肺组织的炎性损伤。金络合物既能够抑制SARS‑CoV‑2在细胞和动物中的复制,也能直接抑制上述病毒感染引发的免疫炎风暴对活体肺组织的损伤。
Description
技术领域
本发明属于生物医药技术领域,尤其涉及金络合物在制备治疗新型冠状病毒肺炎的药物中的应用。
背景技术
新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19),简称“新冠肺炎”。COVID-19以发热、干咳、乏力等为主要表现,少数患者伴有鼻塞、流涕、腹泻等上呼吸道和消化道症状。重症病例多在1周后出现呼吸困难,严重者快速进展为急性呼吸窘迫综合征、脓毒症休克、难以纠正的代谢性酸中毒和出凝血功能障碍及多器官功能衰竭等。目前还没有药物被证明能够有效的治疗COVID-19。
目前的药物设计聚焦在抑制病毒复制的小分子化合物和抑制炎症的抗体/小分子化合物。很多传统药被启用用以治疗COVID-19,比如瑞德西韦能有效的抑制SARS-COV-2复制,但是不能有效的治疗病人因感染而引起的肺部炎症。鲁索替尼和阿卡替尼可以直接的抑制炎症细胞因子,但是不能有效的抑制SARS-COV-2复制。目前缺少一种既能够直接抑制SARS-COV-2复制又能够同时直接抑制机体肺部炎症损伤的药物。
发明内容
本发明的目的在于提供金络合物在制备治疗新型冠状病毒肺炎的药物中的应用,既能够直接抑制SARS-COV-2复制又能够同时直接抑制机体肺部炎症损伤。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了金络合物在制备抑制SARS-COV-2复制和/或抑制SARS-COV-2活性的药物中的应用。
本发明还提供了金络合物在制备抑制病毒感染诱导的机体肺部炎症损伤的药物中的应用。
优选的,所述病毒包括SARS-COV-2。
本发明还提供了金络合物在制备治疗新型冠状病毒肺炎的药物中的应用。
优选的,所述金络合物包括金诺芬、硫代葡萄糖金或金纳米团簇。
优选的,所述金纳米团簇的化学组成为AuxPeptidey;所述Peptide表示肽和/或蛋白分子;所述x表示金原子个数,所述x的数值范围为3~200;所述y表示肽和/或蛋白分子的个数,所述y的的数值范围为2~220。
优选的,所述肽和/或蛋白分子含有自由巯基。
优选的,所述金纳米团簇包括Au29GS27,Au28GS16,Au24C8,Au25H1中的一种或几种;其中,GS代表谷胱甘肽分子,H代表血清蛋白分子,C代表氨基酸序列为CCY的人工合成小肽分子。
优选的,所述药物的剂型包括注射剂、呼吸道雾化剂或透皮剂。
优选的,所述药物中金络合物的含量为1~20mg/ml。
本发明提供了金络合物在制备治疗新型冠状病毒肺炎的药物中的应用。金络合物在溶液或体液中与SARS-CoV-2病毒蛋白的主水解蛋白酶(Mpro)碰撞,金络合物释放出一价金离子,该一价金离子特异结合在SARS-CoV-2病毒的Mpro蛋白的Cys145和Cys156氨基酸上,从而锁住Mpro的活性口袋,有效的抑制Mpro蛋白的催化活性。COVID-19病毒的功能性多蛋白(poly-protein)主要是由主蛋白酶(Mpro)水解后释放发挥作用,Mpro在病毒生命周期中起到了重要作用。Mpro的催化活性被抑制能够有效降低COVID-19病毒的活性。此外,金络合物能够抑制细胞中SARS-CoV-2活病毒在活细胞中的复制。金络合物能够显著抑制巨噬细胞和肺支气管细胞的NFkB炎性分子通路的活化,从而降低炎性因子IL-6、IL-1β和TNF-α的表达与分泌。本发明的实施例结果表明,金络合物能在COVID-19模型动物上,抑制肺组织病毒复制和抑制动物肺组织的炎性损伤。金络合物既能够抑制SARS-CoV-2在细胞和动物中的复制,也能直接抑制上述病毒感染引发的免疫炎风暴对活体肺组织的损伤。
附图说明
图1为实施例1中Au-S结合状态的Mpro同型二聚体,链A和链B分别以绿色和紫色显示;
图2为实施例1中Mpro单体的结构域I-III,结构域I-III分别以浅蓝色,浅粉红色和浅青色显示;Au(I)-S结合位点区域分别显示了Au(I)2和Au(I)1的反常傅立叶图(蓝色网格,轮廓为5sigma);残基His41,Cys145和Cys156以棍型表示,两个Au(I)离子以球体表示;
图3为实施例1中Au(I)-S结合态与Mpro原始态结构的比较;AF(金诺芬)处理组(紫色),GA(Au29GS27)处理组(黄色)和未经处理的Mpro组(蓝色)的晶体结构的叠加;天然Mpro的和Au(I)结合的Mpro在表面呈现的催化口袋以及以棍表示的周围氨基酸残基;
图4为实施例1中DFT计算Au1离子与Mpro的Cys145之间的相互作用的结果;其中A显示了由氨基酸和Au1离子组成的蛋白质结合口袋,B表示封装Au1离子的结合袋的几何结构;C,N,O,S和Au原子分别以灰色,蓝色,红色,粉红色和黄色显示;所有以内的Au-N原子距离(以为单位)都用括号中给出的从实验晶体结构获得的相应距离进行标记,以进行比较;
图5为实施例1中DFT计算Au2离子与Mpro的Cys156之间的相互作用的结果;其中A显示了由氨基酸和Au2离子组成的蛋白质结合口袋,B表示封装Au2离子的结合口袋的几何结构;C,N,O,S和Au原子分别以灰色,蓝色,红色,粉红色和黄色显示;所有以内的Au-N原子距离(以为单位)都用括号中给出的从实验晶体结构获得的相应距离进行标记,以进行比较;
图6为实施例2中AF处理组的IC50,即Mpro酶活被抑制50%所需要的AF浓度;
图7为实施例2中GA处理组的IC50,即Mpro酶活被抑制50%所需要的GA浓度;
图8为实施例3中AF处理组的EC50,即在活细胞中,活病毒的复制被抑制50%酶活所需要的的AF浓度;
图9为实施例3中GA处理组的EC50,即在活细胞中,活病毒的复制被抑制50%酶活所需要的的GA浓度;
图10为实施例4中不同浓度AF和GA对巨噬细胞中的IL-6,IL-1β,TNF-α炎性细胞因子表达的抑制情况和NFκB活化的抑制情况;图10中的A为显影观察结果,图10中的B为不同浓度GA统计结果,图10中的C为不同浓度AF统计结果;未配对t检验,***p<0.005,**p<0.01,*p<0.05;
图11为实施例4中不同浓度AF和GA对呼吸道上皮细胞中的IL-6,IL-1β,TNF-α炎性细胞因子表达的抑制影响情况和NFκB活化的抑制情况;图11中的A为显影观察结果,图11中的B为不同浓度GA统计结果,图11中的C为不同浓度AF统计结果;未配对t检验,***p<0.005,**p<0.01,*p<0.05;
图12为实施例5中Mock(正常鼠)组,GA(金簇处理病毒感染鼠)组和NS(生理盐水处理病毒感染鼠)组的给药时间;
图13为实施例5中GA或生理盐水治疗的感染小鼠的体重图;
图14为实施例5中第4天(最后一次GA注射后24h,未配对t检验,***p<0.001)小鼠肺中复制病毒RNA拷贝数;
图15为实施例5中解剖小鼠肺脏的苏木精-曙红(HE)染色的病理评分;
图16为实施例5中SARS-CoV-2感染小鼠肺部炎症的病理图片。
具体实施方式
本发明提供了金络合物在制备抑制SARS-COV-2复制和/或抑制SARS-COV-2活性的药物中的应用。
本发明提供了金络合物在制备抑制病毒感染诱导的机体肺部炎症损伤的药物中的应用。在本发明中,所述病毒优选的包括SARS-COV-2。
本发明提供了金络合物在制备治疗新型冠状病毒肺炎的药物中的应用。
在本发明中,所述金络合物优选的包括金诺芬、硫代葡萄糖金或金纳米团簇。
在本发明中,所述金诺芬的化学式为C20H36AuO9PS;所述金诺芬来源于常规市售。
在本发明中,所述硫代葡萄糖金的化学式为C6H11AuO5S;所述硫代葡萄糖金来源于常规市售。
在本发明中,所述金纳米团簇的化学组成为AuxPeptidey;所述Peptide表示肽和/或蛋白分子,所述肽和/或蛋白分子优选的含有自由巯基;所述x表示金原子个数;所述y表示肽和/或蛋白分子的个数;所述x的数值范围为3~200;所述y的数值范围为2~220;该分子式代表多个被肽和/或蛋白分子络合的金簇分子,每个金纳米团簇含有3~200个金原子和2~220个肽和/或蛋白分子。在本发明中,所述金纳米团簇优选的包括Au29GS27、Au28GS16、Au24C8和Au25H1中的一种或几种;其中,GS代表谷胱甘肽分子,H代表血清蛋白分子,C代表氨基酸序列为CCY的人工合成小肽分子。在本发明中,所述Au29GS27、Au28GS16、Au24C8和Au25H1来源于人工合成,所述Au29GS27、Au28GS16、Au24C8和Au25H1的合成方法参见【F.Gao,Q.Yuan,P.Cai,L.Gao,L.Zhao,M.Liu,Y.Yao,Z.Chai,X.Gao,Au clusters treat rheumatoidarthritis with uniquely reversing cartilage/bone destruction,Adv.Sci.6,1801671(2019)】。在本发明中,所述药物的剂型优选的包括注射剂、呼吸道雾化剂或透皮剂;所述药物中金络合物的含量优选为1~20mg/ml,更优选为5~10mg/ml。
下面将结合本发明中的实施例,对本发明中的技术方案进行清楚、完整地描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明实施例中的金诺芬(AF)来源于常规市售,金纳米团簇Au29GS27(GA)来源于人工合成,合成方法参见【F.Gao,Q.Yuan,P.Cai,L.Gao,L.Zhao,M.Liu,Y.Yao,Z.Chai,X.Gao,Au clusters treat rheumatoid arthritis with uniquely reversingcartilage/bone destruction,Adv.Sci.6,1801671(2019)】。纯化的Mpro蛋白的获得方法参见【Z.Jin,X.Du,Y.Xu,et al.Structure of Mpro from SARS-CoV-2 and discovery ofits inhibitors,Nature 582,289–293(2020).】。
实施例1
纯化的Mpro蛋白分子在20~22℃条件下结晶形成小的晶体颗粒,这些Mpro晶体颗粒分别加入金诺芬(AF)分子或者金纳米团簇(GA)分子,分别20~22℃条件下共孵育48h。这些金络合物在溶液中释放出一价金离子结合在Mpro晶体中的蛋白分子上。将这些结合一价金离子的晶体同步辐射做晶体衍射。
测定SARS-COV-2Mpro的三种晶体状态:GA孵育的Mpro,AF孵育Mpro,无金络合物孵育的Mpro。测定结果参见图1~图3。
测定结果显示:AF和GA孵育的Mpro分子结构呈现出高度相似的结构,并且与报道的Mpro晶体结构一致,具体见(【Z.Jin,X.Du,Y.Xu,et al.Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors,Nature 582,289–293(2020)】)。
在Cys145和Cys156两个半胱氨酸上有两个一价金离子的密度。通过反差傅里叶映射确认了这两个一价金离子的位置(参见图2)。这两个一价金离子分别被定义为Au1和Au2。由图2可知,AF和GA提供了一价金离子,通过了迈克尔加成反应加到了Mrpo的Cys145和Cys156上。
Mpro-Au复合物整体呈现一个二聚体的状态(图1),每个单体包括3个结构域(图2)。这些结构与之前报道的SARS-COV-2Mpro结构相同,详见(【Z.Jin,X.Du,Y.Xu,etal.Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors,Nature582,289–293(2020).】)。Mpro的结构域1和2是由β-桶型结构组成,组成的结构和糜蛋白酶相似,均是形成了一条狭缝的酶活中心,然而结构域3则主要是由Alpha螺旋组成的。而Au1正是与酶活中心的Cys145的巯基相互作用,这个遗传保守的半胱氨酸残基正是Mpro催化的核心(参见图2和图3)。Au2的结合位点在Cys156上(参见图2),位于在Mpro的更表层。
通过比较空白的Mpro和Au结合的Mpro的结构发现,Au的结合并没有引起蛋白构象的变化(图3)。Au1离子特定的结合在Cys145上并嵌在活性口袋里,说明Au1离子阻挡住了活性口袋并抑制了其催化的功能(图3)。Cys145的S和Au1离子在结构上的距离是2.3A,从距离上来看,S和Au1离子是共价连接的。Au1离子不仅仅跟Cys145结合,这一结合还使得催化中心的Cys145和His41的距离从3.7A变成了3.9A(图3)。尽管每一个Mpro蛋白单体包含了12个半胱氨酸残基(Cys16,Cys22,Cys38,Cys44,Cys85,Cys117,Cys128,Cys145,Cys156,Cys160,Cys265,Cys300),但是只有Cys145和Cys156特定的结合了一价金离子。
通过密度泛函理论模型(DFT)计算Au和Mpro之间的能量关系。通过计算表明,Au1离子与Cys145的结合能(EBD’s)为46kcal/mol(图4)。Au2离子与Cys156的结合能(EBD’s)为26kcal/mol(图5)。由此可以看出,Au1离子与Cys145以及Au2离子与Cys156的结合能的能量数值较高,相互作用较强,表明了一价金离子锁住了Mpro的活性口袋,从而有效的抑制了Mpro的催化活性。
实施例2
检测AF和GA抑制Mpro活性的指标IC50,具体检测方法参见(【V.Grum-Tokars,K.Ratia,A.Begaye,S.C.Baker,A.D.Mesecar,Evaluating the 3C-like proteaseactivity of SARS-Coronavirus:Recommendations for standardized assays for drugdiscovery,Virus Research 133,63–73(2008).】),Mpro的活性通过荧光能量共振脑转移的方法来测定,测定过程中应用了人工合成的荧光标记的肽段((EDNAS-Glu)-Ser-Ala-Thr-Leu-Gln-Ser-Gly-Leu-Ala-(Lys-DABCYL)-Ser)作为病毒蛋白的酶切底物。
测定结果如下:
如图6所示,AF的IC50约等于0.46μM,现有药物Ebselen的IC50值为0.67μM(参见【Z.Jin,X.Du,Y.Xu,et al.H.Yang,Structure of Mpro from SARS-CoV-2 and discoveryof its inhibitors,Nature 582,289–293(2020)】),与Ebselen相比AF的IC50值更低,可见在试管实验层面AF能够有效的抑制Mpro的酶活。
如图7所示,GA的IC50约为3.3μM,在试管实验层面GA能够有效的抑制Mpro的酶活。接下来,我们测试了GA能否有效的在细胞里抑制Mpro的酶活。
将带strep-tag的SARS-COV-2Mpro质粒瞬转进入HEK293细胞。在Mpro基因表达的24h之后,GA以500μM的浓度加入到了细胞培养的培养基当中,并继续培养24h。从培养的细胞中提取和纯化Mpro蛋白,对Mpro蛋白酶活进行测定。测定结果显示,被GA处理前的细胞中的SARS-Cov-2Mpro的活性为100%,被GA处理的细胞中的SARS-Cov-2 Mpro的活性被压制,保留了约为60%的活性。
实施例3
检测AF和GA在Vero细胞模型上抑制SARS-COV-2病毒复制能力的指标EC50,具体检测方法参见(【Z.Jin,X.Du,Y.Xu,Y.Deng,M.Liu,Y.Zhao,B.Zhang,X.Li,L.Zhang,C.Peng,Y.Duan,J.Yu,L.Wang,K.Yang,F.Liu,R.Jiang,X.Yang,T.You,X.Liu,X.Yang,F.Bai,H.Liu,X.Liu,L.W.Guddat,W.Xu,G.Xiao,C.Qin,Z.Shi,H.Jiang,Z.Rao,H.Yang,Structureof Mpro from SARS-CoV-2 and discovery of its inhibitors,Nature 582,289–293(2020)】)。
测定结果如下:
如图8所示,AF的EC50接近0.83μM,如图9所示,GA的EC50接近7.32μM。二种金络合物都能很好抑制病毒在哺乳细胞中的复制。
实施例4
培养RAW264.7细胞并与不同浓度的GA和AF孵育24h,其中GA的浓度分别为0μM、0.3μM、0.6μM、1.2μM、10μM、20μM和40μM;AF的浓度分别为0μM、0.3μM、0.6μM和1.2μM。然后将细胞裂解,跑胶(westernblot),用抗体标记和显影观察以下各个蛋白含量,通过显影的灰度值分析蛋白表达的高低(参见【F.Gao,Q.Yuan,P.Cai,L.Gao,L.Zhao,M.Liu,Y.Yao,Z.Chai,X.Gao,Au clusters treat rheumatoid arthritis with uniquely reversingcartilage/bone destruction,Adv.Sci.6,1801671(2019)】)。
如图10所示,AF在0.6μM的低浓度能显著的抑制IL-6,IL-1β,TNF-α的在巨噬细胞当中表达水平。在20μM的浓度下,GA可以抑制IL-6,IL-1β,TNF-α的在巨噬细胞当中表达水平。图10的数据,也显示AF和GA可以有效的抑制IKK的磷酸化水平,从而抑制下游的IkB和p65的磷酸化,从而抑制NFkB的激活。COVID-19病毒感染细胞群体就是支气管上皮细胞,最终通过NFkB通路激活炎性因子基因的表达。这些细胞因子会反过来激活巨噬细胞,造成炎性环境。我们评价了GA和AF是否可以抑制NFkB通路从而抑制人类支气管上皮细胞的炎性因子表达。如图11所示,在0.08μM的AF和10μM的GA浓度下可以显著的抑制IKK,IkB,p65的磷酸化,从而显著的抑制炎性因子IL-6,IL-1beta,TNF-alpha的表达。AF和GA均能够压制NFκB通路进而抑制人支气管上皮细胞中炎性细胞因子的表达。
实施例5
12只BALB/c小鼠被分为三组,分别为Mock组(正常小鼠),GA组(以BALB/c小鼠为基础,构建COVID-19模型后GA治疗新冠肺炎小鼠)和NS组(以BALB/c小鼠为基础,构建COVID-19模型后生理盐水治疗新冠肺炎小鼠),COVID-19模型的构建参照(【J.Sun,Z.Zhuang,J.Zheng,K.Li,R.L.Wong,D.Liu,J.Huang,J.He,A.Zhu,J.Zhao,X.Li,Y.Xi,R.Chen,A.N.Alshukairi,Z.Chen,Z.Zhang,C.Chen,X.Huang,F.Li,X.Lai,D.Chen,L.Wen,J.Zhuo,Y.Zhang,Y.Wang,S.Huang,J.Dai,Y.Shi,K.Zheng,M.R.Leidinger,J.Chen,Y.Li,N.Zhong,D.K.Meyerholz,P.B.McCray,Jr.,S.Perlman,J.Zhao,Generation of a broadly usefulmodel for COVID-19 pathogenesis,vaccination,and treatment,Cell 182,734-743(2020).】):小鼠麻醉后被鼻内给予50μl的2.5×108FFU的Ad5-hACE2,在转染5天之后,SARS-Cov-2感染前1h,GA组小鼠腹腔注射15mg/kg.bw的GA,NS组被给予生理盐水。小鼠鼻腔感染所用的50μl含SARS-Cov-2(1×105PFU)的DMEM。在感染病毒后,小鼠共接受3次GA或者生理盐水的治疗,给药时间如图12所示。所有的小鼠在第四天被处死,测量小鼠体重,肺部SARS-COV-2RNA拷贝数,肺部的病理损伤变化和炎症因子。
如图13所示,感染SARS-COV-2的小鼠模型呈现出体重降低,高的病毒RNA拷贝,严重的支气管肺炎和间质性肺炎,肺泡的淋巴细胞浸润。GA组的小鼠体重丢失要小于NS组。
如图14所示,GA治疗组的病毒的RNA拷贝是4×log 104,要显著性小于NS组小鼠的5×log 105。
肺部组织的病理评价如图15所示,NS组小鼠肺部损伤的病理评分约为3,感染SARS-CoV-2的小鼠显示出严重的肺部炎症。GA的治疗COVID-19小鼠肺部损伤的病理评分约为1.8。GA的治疗显著消除了SARS-CoV-2感染小鼠的肺部炎症。
如图16所示,感染SARS-CoV-2的小鼠肺泡间隔,支气管,细支气管和血管周间质明显增宽,同时有大量淋巴细胞浸润和少量中性粒细胞浸润。此外,少数淋巴细胞和脱落的上皮细胞位于局部细支气管腔内。GA的治疗小鼠局部肺泡间隔,支气管,细支气管和血管周间质增宽明显减少,支气管和细支气管的粘膜上皮完好无损,并且未观察到管腔中有异物。GA治疗结果与未感病毒小鼠的肺病理结果较为类似。
综上所述,GA抑制病毒复制,同时也直接抑制了炎症细胞因子的表达,从而保护受感染小鼠的肺免受炎症损伤。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.金络合物在制备抑制SARS-COV-2复制和/或抑制SARS-COV-2活性的药物中的应用。
2.金络合物在制备抑制病毒感染诱导的机体肺部炎症损伤的药物中的应用。
3.根据权利要求2所述的应用,其特征在于,所述病毒包括SARS-COV-2。
4.金络合物在制备治疗新型冠状病毒肺炎的药物中的应用。
5.根据权利要求1~4任意一项所述的应用,其特征在于,所述金络合物包括金诺芬、硫代葡萄糖金或金纳米团簇。
6.根据权利要求5所述的应用,其特征在于,所述金纳米团簇的化学组成为AuxPeptidey;所述Peptide表示肽和/或蛋白分子;所述x表示金原子个数,所述x的数值范围为3~200;所述y表示肽和/或蛋白分子的个数,所述y的的数值范围为2~220。
7.根据权利要求6所述的应用,其特征在于,所述肽和/或蛋白分子含有自由巯基。
8.根据权利要求6所述的应用,其特征在于,所述金纳米团簇包括Au29GS27,Au28GS16,Au24C8,Au25H1中的一种或几种;其中,GS代表谷胱甘肽分子,H代表血清蛋白分子,C代表氨基酸序列为CCY的人工合成小肽分子。
9.根据权利要求1~4任意一项所述的应用,其特征在于,所述药物的剂型包括注射剂、呼吸道雾化剂或透皮剂。
10.根据权利要求9所述的应用,其特征在于,所述药物中金络合物的含量为1~20mg/ml。
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PCT/CN2021/074607 WO2022160327A1 (zh) | 2021-01-27 | 2021-02-01 | 金络合物在制备治疗新型冠状病毒肺炎的药物中的应用 |
US17/927,390 US20230241101A1 (en) | 2020-05-27 | 2021-05-20 | Therapeutic composition and method for treating coronavirus infection |
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