CN115645396A - 丙基-2-咪唑二硫醚在抗冠状病毒中的应用 - Google Patents
丙基-2-咪唑二硫醚在抗冠状病毒中的应用 Download PDFInfo
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Abstract
本发明公开了多酚类物质等多种化合物在抗冠状病毒中的应用。多酚类物质、质子泵抑制剂、对苯醌及其衍生物、苏木的活性成分、TDZD‑8、硫柳汞、紫草素、Tideglusib、原黄素、雷贝拉唑钠、PX‑12、Dixanthogen、胆酸甲酯、卡莫氟、柯里拉京、二氢杨梅素、氯胺T、汞溴红、没食子儿茶素、秦皮素、甲异靛、乳酸乙吖啶一水合物以及南索拉唑中的一种或多种在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。本发明通过体外酶活实验发现1,4‑萘醌等多种化合物可以很好地抑制冠状病毒中的主蛋白酶的活性,填补了现有技术缺乏治疗冠状病毒引发的疾病的不足。
Description
本专利申请为申请号为:CN202110219570.X,申请日为2021年02月26日,发明名称为《多酚类物质在抗冠状病毒中的应用》的分案申请。
技术领域
本发明属于生物医药技术领域,涉及丙基-2-咪唑二硫醚在抗冠状病毒中的应用,具体涉及丙基-2-咪唑二硫醚在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
背景技术
冠状病毒是一类与人畜密切相关的病毒。冠状病毒HCoV-229E和HCoV-OC43会引起普通感冒(van der Hoek,L.,Pyrc,K.,Jebbink,M.et al.Identification of a newhuman coronavirus.Nat Med 2004,10,368–373)。2002至2003年期间由SARS冠状病毒引起的严重急性呼吸系统综合征(SARS)在全球造成8098人感染,774名患者死亡,致死率达到了10%(Stadler,K.,Masignani,V.,Eickmann,M.et al.SARS—beginning to understand anew virus.Nat Rev Microbiol 2003,1,209–218)。2004年鉴定出的HCoV-NL63同样能引起类似感冒的呼吸道疾病(van der Hoek,L.,Pyrc,K.,Jebbink,M.et al.Identificationof a new human coronavirus.Nat Med 2004,10,368–373)。2012年出现了中东呼吸综合征冠状病毒(MERS-CoV),截至2016年4月26日,在27个国家造成1,728例感染,其中624人死亡(de Wit,E.,van Doremalen,N.,Falzarano,D.et al.SARS and MERS:recent insightsinto emerging coronaviruses.Nat Rev Microbiol 2016,14,523–534.)。最近流行的SARS-CoV-2病毒会引发COVID-19,临床表现为发烧,干咳和呼吸困难,重症会造成死亡(Jeannette Guarner,MD,Three Emerging Coronaviruses in Two Decades:The Storyof SARS,MERS,and Now COVID-19,American Journal of Clinical Pathology,,aqaa029)。冠状病毒对于畜牧业影响巨大:猪流行性腹泻病毒(PEDV)、肠胃炎病毒(TGEV)和猪丁型冠状病毒(Porcine delta coronavirus,PDCoV,也叫德尔塔病毒),可引起猪的严重肠炎、腹泻、呕吐和脱水,给养猪业带来巨大的损失(Akimkin V,Beer M,Blome S,etal.New Chimeric Porcine Coronavirus in Swine Feces,Germany,2012.Emerg InfectDis.2016,22(7):1314–1315)。猫传染性腹膜炎病毒(FIPV)可引起的猫科动物的致死性疾病。禽传染性支气管炎病毒(IBV)感染禽类,是一种分布广泛的家禽疾病,对家禽业造成了巨大的经济影响。
冠状病毒在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae),日前SARS-CoV-2冠状病毒基因组序列已经公布,该序列与SARS-Cov的核苷酸相似度约为90%,蛋白质序列与SARS-CoV有约80%的序列相似性。冠状病毒的基因组为单股正链RNA,长度约28kb,主要编码病毒包装所需的结构蛋白以及与复制转录相关的非结构蛋白。开发治疗冠状病毒相关疾病的药物和疫苗主要针对上述两类蛋白。病毒基因组的三分之二的基因主要编码非结构蛋白。病毒编码了两种多聚酶蛋白pp1a和pp1ab,用于参与病毒的复制过程。pp1a和pp1ab通过两种由病毒编码的木瓜蛋白酶和主蛋白酶(main protease)可以将其切割成16个非结构蛋白nsp1-16,只有当这些功能亚基被病毒编码的蛋白酶切割成独立的蛋白单元,病毒才能完成正常的转录、复制功能,进而组装成复制转录复合物,完成病毒的复制和转录。其中,木瓜蛋白酶有3个酶切位点;主蛋白酶在pp1a和pp1ab上存在11个酶切位点。可见主蛋白酶在病毒的转录、复制过程中发挥关键的调节作用,因此成为研究的焦点(Ziebuhr,J.;Snijder,E.J.;Gorbalenya,A.E.Virus-encoded proteinases and proteolytic processing in theNidovirales.J Gen Virol 2000,81,853-79.;Ziebuhr,J.Molecular biology of severeacute respiratory syndrome coronavirus.Curr Opin Microbiol 2004,7,412-9.)。由于主蛋白酶对冠状病毒扩增复制的重要性,因此寻找针对主蛋白酶催化位点专一性强、安全性高的抑制剂对于药物开发显得尤其重要。
1,4-萘醌(1,4-Naphthoquinone;CAS号:130-15-4)现有技术中被用作单胺氧化酶和DNA拓扑异构酶活性的潜在抑制剂,也被用于抑制乙酰转移酶活性(Coelho-CerqueiraE,Netz P A,Canto V P D,et al.Beyond Topoisomerase Inhibition:Antitumor 1,4-Naphthoquinones as Potential Inhibitors of Human Monoamine Oxidase[J].Chemical Biology&Drug Design,2014,83(4):401-410.;Naphthoquinone-mediatedInhibition of Lysine Acetyltransferase KAT3B/p300,Basis for Non-toxicInhibitor Synthesis*[J].Journal of Biological Chemistry,2014,289.),也可作为某些化合物合成的前体,主要是作为亲二烯体通过Diels-Alder环加成反应用于制备各种芳香环化合物(Dodge,Jeffrey A,Bain,J.D,Chamberlin,A.Richard.Regioselectivesynthesis of substituted rubrenes[J].Journal of Organic Chemistry,55(13):4190-4198.;Manfred,Haber,and,et al.N-benzoylindole-2,3-quinodimethane:Diels-Alder reactivity and synthetic applications for[b]annellated indoles[J].),也可用于蒽醌、非线形苯并多环抗生素等化合物的生产。
TDZD-8(CAS号:327036-89-5)是一种非ATP竞争性的糖原合成酶激酶GSK-3β的抑制剂,IC50为1.4μM,对CDK1、CKII、PKA和PKC具有最低限度的抑制效果(MaximA.Komandirov,Evgeniya A.Knyazeva,Yulia P.Fedorenko,等.On the Role ofPhosphatidylinositol 3-Kinase,Protein Kinase B/Akt,and Glycogen SynthaseKinase-3βin Photodynamic Injury of Crayfish Neurons and Glial Cells[J].45(2):229-235.)。在细胞实验中,TDZD-8被发现可以通过抑制GSK-3β和PKC降低PDT诱导的神经元坏死和胶质细胞凋亡。另外,TDZD-8作用于原代AML细胞样本,通过抑制PKC和FLT3,显示出抗白血病的活性(Guzman M L,Li X,Corbett C A,et al.Rapid and selective death ofleukemia stem and progenitor cells induced by the compound 4-benzyl,2-methyl,1,2,4-thiadiazolidine,3,5dione(TDZD-8).Blood,2007,110(13):4436-4444.)。
巴西木素(Brazilin;CAS号:474-07-7)存在于豆科植物苏木中,是苏木的主要活性成分,也可由合成法得到外消体,再经拆分制得。其应用非常广泛,最早被用作天然的红色生物染色剂(H Puchtler,F Sweat.On the mechanism of sequence iron-hemateinstains[J].Histochemie.histochemistry.histochimie,1964,4(3):197-208.),后续研究进一步发现其具有抗肿瘤、降血糖(Gwi-Seo Hwang,Ji-Young Kim,Tong-Shin Chang,Sun-Duck Jeon,Dhong-Su So,&Chang-Kiu Moon.Effects of brazilin on thephospholipase a2activity and changes of intracellular free calciumconcentration in rat platelets.Archives of Pharmacal Research,21(6),774-778.)、抗炎(Hikino H,Tagushi T,Fujimura H,et al.Antiinflammatory principles ofCaesalpinia sappan wood and of Haematoxylon campechianum wood[J].1977,31(03):214-220.)、抗菌(Hong-Xi Xu,Song F Lee.The antibacterial principle ofCaesalpina sappan[J].Phytotherapy Research Ptr,2004,18(8):647-651.)、抗血小板(H Puchtler,F Sweat.On the mechanism of sequence iron-hematein stains[J].Histochemie.histochemistry.histochimie,1964,4(3):197-208.)、保肝(Chang-Kiu Moon,Kwang-Sik Park,Seong-Gon Kim,Hyeon-Soon Won,&Jin-Ho Chung.(2008).Brazilinprotects cultured rat hepatocytes from brcci3-induced toxicity.Drug&ChemicalToxicology.)等多种生物活性。
硫柳汞(Thimerosal;CAS号:54-64-8)是一种由50%汞构成的有机化合物。具有防腐和杀菌作用,已被认定为是一种完善的防腐剂和抗真菌剂。它已被用作疫苗、免疫球蛋白制剂、皮肤测试抗原、抗蛇毒蛋白、眼科和鼻科产品以及纹身墨水中的防腐剂(DrugBank3.0:a comprehensive resource for'omics'research on drugs.[J].Nucleic acidsresearch,2011.)。
紫草素(Shikonin;CAS号:517-89-5)是中草药紫草的主要成分,是一种天然染料,被用作食用色素和化妆品。紫草素还被发现具有伤口愈合,抗肿瘤和抗血栓形成的特性。紫草素是一种有效的TMEM16A氯化物通道的抑制剂,IC50为6.5μM(Jiang,Yu,Yu,Bo,Yang,Hong,et al.Shikonin Inhibits Intestinal Calcium-Activated Chloride Channelsand Prevents Rotaviral Diarrhea.Front Pharmacol.2016Aug 23;7:270.)。紫草素还是是一种特异的丙酮酸激酶M2(PKM2)的抑制剂,还可以抑制肿瘤坏死因子-α(TNF-α)并阻止核因子-κB(NF-κB)通路的激活(Li Wenjuan,Zhang Chunjing,Ren Amy,et al.ShikoninSuppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.PLoSOne.2015May11;10(5):e0126459.)。相关专利申请为JP2837715B2。
Tideglusib(替徳格塞;CAS号:865854-05-3)是一种不可逆的非ATP竞争性的GSK3小分子抑制剂,已在二期临床试验中被研究为治疗阿尔茨海默症和瘫痪性核上性麻痹的潜在药物。Tideglusib是由噻二唑烷二酮衍生的GSK-3抑制剂,IC50值为105nM(通过人重组GSK-3的方法测定)(Domínguez JM,Fuertes A,et al.Evidence for irreversibleinhibition of glycogen synthase kinase-3βby tideglusib.J Biol Chem.2012Jan 6;287(2):893-904.)。
2017年自然科学杂志(Skrott,Zdenek,et al."Alcohol-abuse drug disulfiramtargets cancer via p97 segregase adaptor NPL4."Nature 552.7684(2017):194-199.]),发表了其抗肿瘤活性,研究发现Disulfiram在体内能被代谢成为一种小分子,从而促进天然蛋白NPL4凝结并与其配偶体p97酶类结合,这个过程就会抑制促进肿瘤生长的NPL4-p97复合体发挥作用,进而诱发癌细胞死亡。此外,Disulfiram还被发现对锌指和环指泛素E3连接酶具有特异性活性,这些连接酶在癌症的发展中起着重要的作用(R Kona,F.,D.A.M.B.Buac,and A.M Burger."Disulfiram,and disulfiram derivatives as novelpotential anticancer drugs targeting the ubiquitin proteasome system in bothpreclinical and clinical studies."Current cancer drug targets 11.3(2011):338-346.)。相关专利申请为WO2017077336A1。
苏木精(Hematoxylin;CAS号:517-28-2):主要用途是诊断癌症恶化,检测嗅癌症进展,宫颈疾病,中枢神经系统故障,以及检测基因,乳腺癌,组织样本中的胶原蛋白,和细胞凋亡,脱髓鞘疾病,抗原。也能够在老年性黄斑变性的治疗,烧伤,前列腺癌,肥胖、病毒性疾病、肿瘤、周围神经和血管疾病、皮肤疾病中应用,生物技术应用,和细胞学、组织学和免疫组织化学的标准对照材料(Fischer,Andrew H.,et al."Hematoxylin and eosinstaining of tissue and cell sections."Cold spring harbor protocols 2008.5(2008):pdb-prot4986)。
对苯醌(p-Benzoquinone;CAS号:106-51-4)用作毒芹碱、吡啶、氮杂茂、酪氨酸和对苯二酚的定性检定,氨基酸测定,脱氢剂,氧化剂和制造染料。对苯醌是一种常用的氧化试剂或脱氢试剂(Natori,Itaru,and Hisaya Sato."Reactivity of quinones for thedehydrogenation of poly(1,3-cyclohexadiene)."Polymer international 56.6(2007):810-815.),因为它很容易被其它化合物还原为对苯二酚,从而能表现出氧化活性,并且其自身的氧化电位决定了1,4-苯醌能够在多种醇化合物共存的情况下选择性地氧化共轭的一级烯丙醇,如在二级醇和苄醇共存情况下选择性地将肉桂醇氧化为肉桂醛(Natori,Itaru,and Hisaya Sato."Reactivity of quinones for the dehydrogenationof poly(1,3-cyclohexadiene)."Polymer international 56.6(2007):810-815.)。此外,采用1,4-苯醌作为脱氢试剂和水合氧化锆作为催化剂还能实现一级醇的氧化反应。相关专利申请GB875948A。
原黄素(Proflavine;CAS号:92-62-6)为外用防腐剂,主要用于伤口敷料。原黄素是一种吖黄素衍生物(Sabolova,Danica,Pavol Kristian,and Mária Kozurkova."Proflavine/acriflavine derivatives with versatile biological activities."Journal of Applied Toxicology 40.1(2020):64-71.),是对多种革兰氏阳性菌的抑菌消毒剂。原黄素在哺乳动物中是有毒和致癌的,所以它只被用作表面消毒剂或治疗表面伤口。原黄素通过插入DNA起作用,从而破坏DNA合成并导致复制DNA链的高水平突变,这可以防止细菌繁殖(Davies,D.S.,C.N.Hinshelwood,and J.M.Pryce."The adaptation ofBact.lactis aerogenes to varying concentrations of an antibacterial drug(proflavine)."Transactions of the Faraday Society 41(1945):163-169.)。
Rebeprazole sodium(雷贝拉唑钠;CAS号:117976-90-6)是一种抗溃疡药物(Carswell,Christopher I.,and Karen L.Goa."Rabeprazole."Drugs 61.15(2001):2327-2356.),属于质子泵抑制剂,是雷贝拉唑的钠盐形式。日本卫材(Eisai)公司首次成功开发了这款产品,其商标为博利特(Bolite)。质子泵抑制剂的作用是减少胃酸的分泌,使病变部位得以稳定,从而达到治疗胃溃疡、十二指肠溃疡和胃食管反流病的效果。临床上主要用于胃溃疡、十二指肠溃疡、消化性溃疡、胃食管反流病、佐林-埃里森综合征等酸性相关疾病的治疗。雷贝拉唑是一种苯并咪唑类取代化合物,它通过与胃壁的细胞质质子泵结合而抑制胃酸的分泌(Kawakami,Yoshiyuki,et al."In Vitro Activities of Rabeprazole,aNovel Proton Pump Inhibitor,and Its Thioether Derivative Alone and inCombination with Other Antimicrobials against Recent Clinical IsolatesofHelicobacter pylori."Antimicrobial agents and chemotherapy44.2(2000):458-461),能特异性抑制胃酸生产过程中的关键酶腺苷三磷酸酶的作用,对基础胃酸及刺激引起的胃酸分泌均有抑制作用。
Myricetin(杨梅黄酮、别名杨梅素;CAS号:529-44-2)是一种黄酮类化合物,能够清除自由基,抗氧化,抗肿瘤,降低神经毒性,影响淋巴细胞的激活和增殖(Ong,Kian C.,and Hoon-Eng Khoo."Biological effects of myricetin."General Pharmacology:TheVascular System 29.2(1997):121-126.)。
杨梅素的主要功能:1)抗氧化剂的作用:杨梅素是一种很强的抗氧化剂(Yao,Yashu,et al."Preformulation studies of myricetin:a natural antioxidantflavonoid."Die Pharmazie-An International Journal of Pharmaceutical Sciences69.1(2014):19-26.),氧化应激在缺血、老年痴呆等多种神经系统疾病中起关键作用。Myricetin通过构象变化效应来减少-淀粉酶的产生和毒性。2)抗肿瘤作用(ZHANG,Li-jing,et al."Antitumor activities of the extracts from the bark of Myricarubra Sieb.et Zucc.and myricetin[J]."Journal of Shenyang PharmaceuticalUniversity 4(2009)):杨梅素是一种有效的致癌化学控制剂。3)降低神经毒性(Chang,Yi,et al."Myricetin inhibits the release of glutamate in rat cerebrocorticalnerve terminals."Journal of medicinal food 18.5(2015):516-523.):杨梅素可通过不同途径抑制谷氨酸神经毒性诱导的神经元保护,从而有效预防神经损伤。4)对淋巴细胞活化和增殖的影响:杨梅素可抑制早期T细胞CD69活化指数表达(Han,Rong,et al."Effectof total flavonoids from the seeds of Astragali complanati on natural killercell function."Journal of ethnopharmacology 173(2015):157-165),抑制淋巴细胞增殖反应。5)血小板活化因子(PAF)拮抗:myricetin在体外对PAF诱导的WRP聚集的浓度依赖性和52HT的释放(Zang,B.X.,et al."Antagonistic effect of myricetin on plateletactiving factor."Yao xue xue bao=Acta pharmaceutica Sinica38.11(2003):831-833)。同时能明显抑制血小板Ca2+升高引起的PAF。说明杨梅素具有抗血栓、抗心肌缺血、改善微循环等多种心血管药理作用。降血糖功能:杨梅素对血糖功能有明显的降低作用。7)保肝作用:杨梅色素能明显抑制血清丙氨酸氨基转移酶(ALT)和天冬酰胺氨酶(AST)活性(Seydi,Enayatollah,et al."Myricetin selectively induces apoptosis oncancerous hepatocytes by directly targeting their mitochondria."Basic&clinical pharmacology&toxicology 119.3(2016):249-258),降低血清总胆红素,有明显降酶返黄作用。
PX-12(丙基-2-咪唑二硫醚;CAS号:141400-58-0)是氧化还原蛋白硫氧还蛋白的小分子不可逆抑制剂(Baker,Amanda F.,et al."The antitumor thioredoxin-1inhibitor PX-12(1-methylpropyl 2-imidazolyl disulfide)decreases thioredoxin-1 and VEGF levels in cancer patient plasma."Journal of Laboratory andClinical Medicine 147.2(2006):83-90),刺激细胞凋亡,在动物模型中下调HIF-1α和血管内皮生长因子(VEGF)和抑制肿瘤的生长(Jordan,Bénédicte F.,et al."Thethioredoxin-1inhibitor 1-methylpropyl 2-imidazolyl disulfide(PX-12)decreasesvascular permeability in tumor xenografts monitored by dynamic contrastenhanced magnetic resonance imaging."Clinical cancer research 11.2(2005):529-536)。由于高水平的Trx-1与结直肠癌、胃癌和肺癌相关,因此,对于晚期转移癌患者,PX-12被认为是一种与化疗联合使用的潜在癌症治疗手段(Jordan,Bénédicte F.,et al."Thethioredoxin-1inhibitor 1-methylpropyl 2-imidazolyl disulfide(PX-12)decreasesvascular permeability in tumor xenografts monitored by dynamic contrastenhanced magnetic resonance imaging."Clinical cancer research 11.2(2005):529-536.)。
Dixanthogen(分子式为C6H10O2S4;CAS号:502-55-6)是芽前使用的非持效性触杀型除草剂。防治洋葱、胡萝卜、甜菜、菜豆等、马齿苋、藜、匍匐冰草、野燕麦、马唐、繁缕等一年生阔叶杂草和禾本科杂草。大鼠急性口服半数致死率LD50为603mg/kg,兔为770mg/kg,豚鼠为500mg/kg。
卡莫氟(Carmofur,分子式为C11H16FN3O3;CAS号:61422-45-5)是氟尿嘧啶的衍生物,是一种抗肿瘤药,口服后从肠道迅速吸收,在体内缓缓释出氟尿嘧啶,借氟尿嘧啶的抗代谢作用而发挥抗肿瘤作用。卡莫氟口服后有效血药浓度较氟尿嘧啶静注长久。抗瘤谱广,治疗指数高,对多种实验肿瘤有较好的抗肿瘤作用。临床上对胃癌、结直肠癌及乳腺癌有一定疗效,尤以结直肠癌的有效率较为突出(KAMIKAMA KANEHITO;KIKUCHI MASAHIKO.STABLECARMOFUR-BETA-CYCLODEXTRIN CLATHRATE COMPOUND[P].;JPS60185772,1985-09-21.)。
胆酸甲酯(Methyl Cholate;分子式C25H42O5;CAS号:1448-36-8)用作胆汁酸衍生物,具有抗炎和抗肿瘤作用。不溶于水,溶于中等极性有机溶剂。可作为一种去污剂。
二氢杨梅素(Dihydromyricetin;分子式:C15H12O8;CAS号:27200-12-0)是一种二氢黄酮醇类黄酮化合物,具有抗氧化、抗肿瘤、抗炎、抑制体内血栓形成等多方面的药理作用。二氢杨梅素可以降低细胞内ATP水平激活AMPK通路,从而增加细胞自噬相关基因表达水平和细胞内自噬小体的数量,从而发挥抗衰老的作用。除此之外,二氢杨梅素具有显著的抗甲型流感病毒的活性,它可以特异性地破环PB2cap和宿主细胞帽状结构的相互作用,影响病毒的入侵复制(CUI LANG;FAN XIAOLAN;MAO XUEPING;Anti-aging medicine based ondihydromyricetin[P].中国:CN107496415A 2017-12-22 CHEN FANGZHAO;CHEN FEIMIN;LIU MIAOMIAO;Applications of dihydromyricetin in preparation of anti-influenza virus drugs[P].中国:CN108354923A 2018-08-03)。
柯里拉京(Corilagin分子式:C27H22O18;CAS号:23094-69-1)是一种逆没食子酸鞣质,对许多心血管疾病,包括高血压,动脉粥样硬化、中风、充血性心衰和缺血性心肌病,有很好的作用。柯里拉京以25μg/mL的MIC抑制金黄色葡萄球菌的生长。柯里拉京对肝细胞癌和卵巢癌显示出良好的抗肿瘤活性。柯里拉京是一种天然产物,且具有漫长的药用史,对正常细胞和组织显示出较低水平的毒性。此外,柯里拉京还可以抑制RNA肿瘤病毒的逆转录酶活性以及乙肝病毒DNA聚合酶活性(抗肝炎B病毒DNA-聚合酶的IC50为0.2mM。)(CHENG YUNG-CHI;INHIBITION OF HUMAN RETROVIRUSES.EPO:WO9004968A1 1990-05-17 CHUNG CHONGCHAN;PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF HEPATITIS B COMPRISINGCORILAGIN OR BREVIFOLIN CARBOXYLIC ACID.EPO:WO0027413A1 2000-05-18)。
氯胺T(Chloramine-T分子式:C7H7ClNNaO2S;CAS号:127-65-1)为外用消毒药,对细菌、病毒、真菌、芽胞均有杀灭作用。其作用原理是溶液产生次氯酸放出氯,有缓慢而持久的杀菌作用,可溶解坏死组织。适用于饮水食具、食品,各种器具、水果蔬菜消毒,创面、粘膜冲洗。
汞溴红(Merbromin分子式:C20H8O6Br2Na2Hg;CAS号:129-16-8),又名红汞,带有绿色或蓝绿赤褐色的小片或颗粒。无气味。有吸湿性。易溶于水,微溶于乙醇和丙酮,不溶于氯仿和乙醚。其水溶液呈樱红色或暗红色,稀释时显绿色荧光,遇稀无机酸则析出沉淀。医药上是外用消毒剂。其2%的水溶液,俗称红药水,适用于表浅创面皮肤外伤的消毒。它的汞离子解离后与蛋白质结合,从而起到杀菌作用,对细菌芽孢无效,防腐作用较弱,不易穿透完整皮肤。但对皮肤的刺激较小。而且不能与碘酒同时使用。
艾普拉唑钠(Ilaprazole sodium;分子式为C19H18N4NaO2S+;CAS号:172152-50-0)是一种质子泵抑制剂,临床上用以治疗酸性胃肠疾病,减少胃酸分泌。它可以在酸性条件下与氢离子结合产生活性,然后通过二硫键与质子泵蛋白结合抑制质子泵活性,从而减少H+泵出
蟛蜞菊内酯(Wedelolactone;分子式为C16H10O7;CAS号:524-12-9)是一种从中药墨旱莲(Ecliptae herba)中分离出来的多酚类化合物,具有抗蛇毒素、抗炎症以及抗肿瘤的活性,近年来还发现其具有强化骨骼的潜力。它可以抑制5-脂氧合酶、胰蛋白酶、antagonize myotoxins,诱导caspase依赖的细胞凋亡。
表没食子儿茶素没食子酸酯((-)-Epigallocatechin Gallate;分子式为C22H18O11;CAS号:989-51-5)为绿茶提取物,是绿茶多酚的主要成分,诱导破骨细胞的凋亡,调节多种肿瘤细胞的caspase活性具有抗氧化性能,降低自由基引起的脂质过氧化。
茶多酚(Tea polyphenol;CAS号:84650-60-2)是从茶树的干叶中提取,有抗氧化和抗癌活性,还可以抑制衣原体细菌的增殖活性(现有专利申请:EP1005862A1和EP0417385A2)。
百里香醌(Thymoquinone;分子式为C10H12O2;CAS号:490-91-5)是一种植物化学物质,对包括卵巢癌、宫颈癌、膀胱癌和前列腺癌在内的不同类型的恶性肿瘤具有抗癌活性。
甲基儿茶酚(4-Methylcatechol;分子式为C7H8O2;CAS号:452-86-8)是一种多酚类物质,在槲皮素的代谢过程中产生。可用于抗氧化剂合成。
没食子儿茶素((+)-Gallocatechin;分子式为C15H14O7;CAS号:970-73-0)可从植物中提取,基于抗氧化作用。
原苏木素B(Protosappanin B;分子式为C16H16O6;CAS号:102036-29-3)在体内或体外均有明显的抗肿瘤效果(Yang X,Ren L,Zhang S,Zhao L,Wang J.Antitumor Effectsof Purified Protosappanin B Extracted From Lignum Sappan.Integr CancerTher.2016Mar;15(1):87-95.)。Protosappanin B通过干扰细胞周期调节,阻止G(1)向s期的过渡从而抑制T24和5637膀胱癌细胞增殖,促进细胞凋亡(Yang X,Zhao L,Zhang T,XiJ,Liu S,Ren L,Zheng Y,Zhang H.Protosappanin B promotes apoptosis and causesG1cell cycle arrest in human bladder cancer cells.Sci Rep.2019Jan 31;9(1):1048.)。
秦皮素(Fraxetin;分子式为C10H8O5;CAS号:574-84-5)是许多膳食补充剂和草药中的天然化合物,可用于治疗急性细菌性痢疾和2型糖尿病(Qin Z,Zhang B,Yang J,Li S,Xu J,Yao Z,Zhang X,Gonzalez FJ,Yao X,.The Efflux Mechanism of Fraxetin-O-Glucuronides in UGT1A9-Transfected HeLa Cells:Identification of MultidrugResistance-Associated Proteins3and 4(MRP3/4)as the ImportantContributors.Front Pharmacol.2019May 7;10:496)。体外实验表明,Fraxetin对真菌具有较好的抑制作用,能够恢复抗真菌药氟康唑对耐药真菌的作用,因此可以作为抗真菌药和抗真菌药的增效剂(CN108771676A)。
乳酸乙吖啶一水合物(Ethacridine lactate monohydrate;分子式为C18H23N3O5;CAS号:6402-23-9)用于人类和其他动物的破坏有害微生物或抑制其活性的物质。
甲异靛(Meisoindigo;分子式为C17H12N2O2;CAS号:97207-47-1)是一种有效的药物,可用于治疗慢性粒细胞白血病(CML)(Wang Y,Zhu XF,Xiao ZJ,Wang HH,Zhou JM,MeiYP,Deng R,Jiang WQ,Liu ZC.Inducement effect of Meisoindigo on apoptosis ofleukemia cell line HL-60and its mechanism.Ai Zheng.2005Dec;24(12):1464-8)。
迷迭香酸(Rosmarinic acid;分子式为C18H16O8;CAS号:20283-92-5)是一种天然的酚类抗氧化剂羧酸,具有多种生物活性,包括抗炎和抗肿瘤作用,这是其抑制炎症过程和活性氧清除的结果(Sotnikova R,Okruhlicova L,Vlkovicova J,Navarova J,Gajdacova B,Pivackova L,Fialova S,Krenek P.Rosmarinic acid administration attenuatesdiabetes-induced vascular dysfunction of the rat aorta.J PharmPharmacol.2013May;65(5):713-23.)。
南索拉唑(Lansoprazole;分子式为C16H14F3N3O2S;CAS号:103577-45-3)是一种胃酸分泌抑制剂,在体外对幽门螺杆菌有抗菌作用(Matheson AJ,Jarvis B.Lansoprazole:an update of its place in the management of acid-relateddisorders.Drugs.2001;61(12):1801-33.)。可用于治疗胃溃疡。
埃索美拉唑镁(Esomeprazole Magnesium;分子式为C34H36MgN6O6S2;CAS号:161973-10-0)具有胃质子泵抑制剂活性,被用作抗溃疡药,有时代替组胺H2拮抗剂用于胃食管反流。
现有技术中尚无以上药物可用于治疗冠状病毒引发的相关疾病。
发明内容
本发明所要解决的技术问题是针对现有技术中尚无有效治疗和/或预防冠状病毒所引发的疾病的药物的缺陷,提供多酚类物质在抗冠状病毒中的应用,具体涉及多酚类物质等化合物在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
本发明主要通过以下技术方案解决上述技术问题。
本发明提供多酚类物质、质子泵抑制剂、对苯醌(CAS号:106-51-4)及其衍生物、苏木的活性成分、TDZD-8(CAS号:327036-89-5)、硫柳汞(CAS号:54-64-8)、紫草素(CAS号:517-89-5)、Tideglusib(CAS号:865854-05-3)、原黄素(CAS号:92-62-6)、杨梅黄酮(CAS号:529-44-2)、PX-12(CAS号:141400-58-0)、Dixanthogen(CAS号:502-55-6)、胆酸甲酯(CAS号:1448-36-8)、卡莫氟(CAS号:61422-45-5)、柯里拉京(CAS号:23094-69-1)、二氢杨梅素(CAS号:27200-12-0)、氯胺T(CAS号:127-65-1)、汞溴红(CAS号:129-16-8)、没食子儿茶素(CAS号:970-73-0)、秦皮素(CAS号:574-84-5)、甲异靛(CAS号:97207-47-1)、乳酸乙吖啶一水合物(CAS号:6402-23-9)以及南索拉唑(CAS号:103577-45-3)中的一种或多种在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
具体地为:多酚类物质、质子泵抑制剂、对苯醌及其衍生物、苏木的活性成分、TDZD-8(CAS号:327036-89-5)、硫柳汞(CAS号:54-64-8)、紫草素(CAS号:517-89-5)、Tideglusib(CAS号:865854-05-3)、原黄素(CAS号:92-62-6)、杨梅黄酮(CAS号:529-44-2)、PX-12(CAS号:141400-58-0)、Dixanthogen(CAS号:502-55-6)、胆酸甲酯(CAS号:1448-36-8)、卡莫氟(CAS号:61422-45-5)、柯里拉京(CAS号:23094-69-1)、二氢杨梅素(CAS号:27200-12-0)、氯胺T(CAS号:127-65-1)、汞溴红(CAS号:129-16-8)、没食子儿茶素(CAS号:970-73-0)、秦皮素(CAS号:574-84-5)、甲异靛(CAS号:97207-47-1)、乳酸乙吖啶一水合物(CAS号:6402-23-9)或者南索拉唑(CAS号:103577-45-3)在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
较佳地,所述的苏木的活性成分选自苏木精(CAS号:517-28-2)、原苏木素B(CAS号:102036-29-3)或者巴西木素(CAS号:474-07-7)。
较佳地,所述的对苯醌衍生物选自百里香醌(CAS号:490-91-5)或者1,4-萘醌(CAS号:130-15-4)。
较佳地,所述的质子泵抑制剂选自雷贝拉唑钠(CAS号:117976-90-6)、艾普拉唑钠(CAS号:172152-50-0)或者埃索美拉唑镁(CAS号:161973-10-0)。
较佳地,所述的多酚类物质选自蟛蜞菊内酯(CAS号:524-12-9)、表没食子儿茶素没食子酸酯(CAS号:989-51-5)、甲基儿茶酚(CAS号:452-86-8)、茶多酚(CAS号:84650-60-2)或者迷迭香酸(CAS号:20283-92-5)。
较佳地,所述的疾病为哺乳动物或者禽类疾病。
较佳地,所述的哺乳动物包括人、猪和猫。
本发明所述的冠状病毒,其定义为本领域熟知,在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae)。冠状病毒是具有囊膜(envelope)、基因组为单股正链的RNA病毒,是自然界广泛存在的一大类病毒。
本发明的目的是提供冠状病毒感染引起的疾病的潜在治疗方案。本发明所述的冠状病毒较佳地属于正冠状病毒亚科(Orthocoronavirinae),更佳地属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属。
在本发明一较佳实施例中,所述的化合物除可用于治疗SARS-CoV-2(Beta冠状病毒属)引发的疾病以外,还应可治疗其他冠状病毒SARS-CoV(Beta冠状病毒属)和MERS-CoV等引起的重大传染病,亦可作为普通感冒药,治疗HCoV-HKU1(Human coronavirus HKU1;Beta冠状病毒属)、HCoV-NL63(Human coronavirus NL63;Alpha冠状病毒属)、HCoV-OC43(Human coronavirus OC43)以及HCoV-229E(Human coronavirus 22E;Alpha冠状病毒属)等冠状病毒引起的疾病;还可作为兽药,治疗猪传染性胃肠炎病毒(Transmissiblegastroenteritis virus,TGEV;Alpha冠状病毒属)、猪流行性腹泻病毒(Porcine epidemicdiarrhea virus,PEDV;Alpha冠状病毒属)、猪丁型冠状病毒(Porcine deltacoronavirus,PDCoV;Delta冠状病毒属)、猫传染性腹膜炎病毒(Feline infectiousperitonitis virus,FIPV;Alpha冠状病毒属)、禽传染性支气管炎病毒(Infectiousbronchitis virus,IBV;Gamma冠状病毒属)等动物疾病。
因此,本发明所述冠状病毒的较佳地选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
在某一方案中,本发明的以上化合物或其药学上可接受的盐以包含其的药物组合物的形式存在;较佳地,所述药物组合物以本发明所述化合物和/或其药学上可接受的盐作为所述药物组合物的唯一活性成份;和/或,所述药物组合物还包含药学上可接受的载体,例如药学上可接受的药用辅料。
在某一方案中,本发明的以上多种化合物或其药学上可接受的盐以包含其的套装药盒的形式存在,所述套装药盒还包括治疗与冠状病毒相关的疾病的药物和/或治疗其他病毒引起的疾病的药物。
本发明提供了丙基-2-咪唑二硫醚在制备抑制冠状病毒的药物中的应用。
在某一方案中,所述冠状病毒为SARS-CoV-2。
本发明中涉及的以本发明多种化合物作为活性成份的药物组合物,均可根据本领域公知的方法制备。可通过将本发明化合物制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的重量含量通常为0.1-99.0%。
所述的药学可接受的载体可为本领域常规的载体,所述的载体可以为任意合适的生理学或药学上可接受的药物辅料。所述的药物辅料为本领域常规的药物辅料,较佳地包括药学上可接受的赋形剂、填充剂或稀释剂等。更佳地,所述的药物组合物包括0.01~99.99%的上述蛋白质和/或上述的抗体药物偶联物,和0.01~99.99%的药用载体,所述百分比为占所述药物组合物的质量百分比。
本发明化合物或含其的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全,并且适合于患者使用。所述的“患者”优选哺乳动物,更优选为人类。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时,可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of PharmaceuticalSalts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
本发明通过体外酶活实验发现1,4-萘醌等33个化合物可以很好地抑制冠状病毒中的主蛋白酶的活性,填补了现有技术缺乏治疗冠状病毒引发的疾病的不足。可对该化合物进行进一步研究、改造以进行应用。
附图说明
图1:1,4-萘醌对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图2:TDZD-8对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图3:苏枋精对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图4:硫柳汞对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图5:紫草素对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图6:Tideglusib对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图7:埃索美拉唑镁对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图8:苏木精对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图9:对苯醌对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图10:原黄素对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图11:雷贝拉唑钠对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图12:杨梅黄酮对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图13:PX-12对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图14:Dixanthogen对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图15:卡莫氟对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图16:胆酸甲酯对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图17:二氢杨梅素对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图18:柯里拉京对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图19:氯胺T对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图20:红汞对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图21:艾普拉唑钠对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图22:蟛蜞菊内酯对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图23:(-)-Epigallocatechin Gallate对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图24:茶多酚对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图25:百里香醌对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图26:甲基儿茶酚对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图27:没食子儿茶素对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图28:原苏木素B对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图29:秦皮素对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图30:乳酸乙吖啶一水合物对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图31:甲异靛对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图32:迷迭香酸对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图33:南索拉唑对新型冠状病毒主蛋白酶的抑制活性;1:DMSO(阴性对照),2:化合物分子;3:阳性对照(N3抑制剂)。
图1~图33中纵坐标单位为RFU(Relative Fluorescence Units;相对荧光的单位)。
图34:卡莫氟对新冠病毒主蛋白酶的酶活抑制曲线。
图35:卡莫氟在细胞水平上的抗病毒效果,数据通过qRT-PCR方法测得。
图36:卡莫氟在细胞水平上的抗病毒效果,数据通过免疫荧光法测得,以氯喹作为阳性对照。
图37:体外细胞毒性实验,测定细胞存活率。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
以下所用Vero E6细胞购自ATCC。
实施例1
从不同的化合物库中进行高通量筛选,成功筛选的33种化合物对新型冠状病毒主蛋白酶均有较好的抑制效果。酶活实验条件具体为:
酶活实验荧光底物:MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2,此荧光底物的激发波长和发射波长分别为320nm和405nm。
酶活反应buffer为50mM Tris–HCl(pH 7.3),1mM EDTA;酶活反应温度:30℃。反应起始通过添加蛋白酶,蛋白酶反应终浓度为0.2μM,底物浓度为20μM,抑制剂(33种小分子化合物)浓度1.5μM。(Xue X,Yang H,Shen W,et al.Production of authentic SARS-CoVMpro with enhanced activity:application as a novel tag-cleavage endopeptidasefor protein overproduction[J].Journal of molecular biology,2007,366(3):965-975.)。
所用阳性对照为N3抑制剂,已知其能够有效灭活冠状病毒主蛋白酶(杨海涛,谢卫青,Xiaoyu X,et al.Design of wide-spectrum inhibitors targeting coronavirusmain proteases[J].生命有机化学,2005,3(10):1742-1752.),结构式如下所示:
根据图1~图33可知:33个化合物的酶活实验曲线,明显区别于阴性对照,对冠状病毒主蛋白酶有明显抑制活性。
实施例2
酶活抑制曲线测定使用的荧光底物:MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2,此荧光底物的激发波长和发射波长分别为320nm和405nm。
酶活抑制曲线测定buffer为50mM Tris–HCl(pH 7.3),1mM EDTA;反应温度:30℃。反应起始通过添加蛋白酶,蛋白酶反应终浓度为0.2μM,底物浓度为20μM,使用11个不同浓度的卡莫氟进行测量,测试结果显示IC50值为1.82μM(图34)(Jin Z,Du X,Xu Y,etal.Structure of Mpro from COVID-19 virus and discovery of its inhibitors[J].Nature,2020,582(7811):1-9.)。
体外细胞抗病毒实验使用6个不同浓度的卡莫氟处理感染SARS-CoV-2的Vero E6细胞1小时,病毒MOI(multiplicity of infection)为0.05。然后去除病毒和药物和混合物,清洗后继续使用含不同浓度卡莫氟的培养基培养。经过24小时培养后取上清进行qRT-PCR分析,同时将细胞固定通过免疫荧光法检测细胞内N蛋白水平进一步确定实验结果。实验发现卡莫氟可防止新型冠状病毒感染引起的细胞病变,EC50值为24.3μM(图35、图36),因此卡莫氟可用于治疗冠状病毒引发的相关疾病(Jin,Z.,Zhao,Y.,Sun,Y.etal.Structural basis for the inhibition of SARS-CoV-2main protease byantineoplastic drug carmofur.Nat Struct Mol Biol 27,529–532(2020).)。
体外的细胞毒性实验使用8个不同浓度的卡莫氟处理Vero E6细胞。Vero E6细胞在96孔板中悬浮培养。第二天,在培养基中加入不同浓度的卡莫氟。24小时后,使用细胞计数试剂盒-8(CCK8,Beyotime)测定存活细胞的相对数量。如图37所示,卡莫氟的CC50值为133.37μM(Jin,Z.,Zhao,Y.,Sun,Y.et al.Structural basis for the inhibition ofSARS-CoV-2main protease by antineoplastic drug carmofur.Nat Struct Mol Biol27,529–532(2020).)。
Claims (11)
1.丙基-2-咪唑二硫醚在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述的疾病为哺乳动物或者禽类疾病。
3.如权利要求2所述的应用,其特征在于,所述的哺乳动物包括人、猪和猫。
4.如权利要求1所述的应用,其特征在于,所述的冠状病毒属于正冠状病毒亚科(Orthocoronavirinae)。
5.如权利要求4所述的应用,其特征在于,所述的冠状病毒属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属。
6.如权利要求5所述的应用,其特征在于,所述的冠状病毒选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
7.如权利要求1所述的应用,其特征在于,所述丙基-2-咪唑二硫醚以包含其的药物组合物的形式存在,所述丙基-2-咪唑二硫醚作为所述药物组合物的唯一活性成分。
8.如权利要求1所述的应用,其特征在于,所述的药物还包含药学上可接受的载体。
9.如权利要求8所述的应用,其特征在于,所述的药学上可接受的载体为药学上可接受的药用辅料。
10.如权利要求1~9任一项所述的应用,其特征在于,所述丙基-2-咪唑二硫醚以包含其的套装药盒的形式存在,所述套装药盒还包括治疗与冠状病毒相关的疾病的药物和/或治疗其他病毒引起的疾病的药物。
11.丙基-2-咪唑二硫醚在制备抑制冠状病毒的药物中的应用;
所述冠状病毒优选为SARS-CoV-2。
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CN114668751A (zh) * | 2022-03-22 | 2022-06-28 | 天津国际生物医药联合研究院 | 双硫仑在抗人冠状病毒nl63感染中的应用 |
CN115089564A (zh) * | 2022-05-18 | 2022-09-23 | 南方科技大学 | 紫草素和左旋紫草素在制备抗冠状病毒药物中的应用 |
CN115025165A (zh) * | 2022-06-09 | 2022-09-09 | 南京农业大学 | 莓茶提取物在制备抗猪流行性腹泻病毒的药物中的应用 |
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CN115569133A (zh) | 2023-01-06 |
CN115252610A (zh) | 2022-11-01 |
CN115581692A (zh) | 2023-01-10 |
CN115998718A (zh) | 2023-04-25 |
CN115175673A (zh) | 2022-10-11 |
EP4115880A1 (en) | 2023-01-11 |
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CN115252610B (zh) | 2024-03-26 |
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CN115998718B (zh) | 2023-12-12 |
CN115770246B (zh) | 2024-01-23 |
CN115581692B (zh) | 2023-10-17 |
CN115569135A (zh) | 2023-01-06 |
CN115778943B (zh) | 2023-11-10 |
US20230293457A1 (en) | 2023-09-21 |
CN115569196B (zh) | 2024-06-18 |
CN115671119B (zh) | 2023-11-10 |
CN113304131B (zh) | 2022-10-18 |
CN115569196A (zh) | 2023-01-06 |
BR112022017060A2 (pt) | 2022-11-16 |
CN113304131A (zh) | 2021-08-27 |
CN115770246A (zh) | 2023-03-10 |
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CN115645393A (zh) | 2023-01-31 |
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