TWI811724B - 正股核糖核酸病毒之抑制劑 - Google Patents
正股核糖核酸病毒之抑制劑 Download PDFInfo
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- TWI811724B TWI811724B TW110124634A TW110124634A TWI811724B TW I811724 B TWI811724 B TW I811724B TW 110124634 A TW110124634 A TW 110124634A TW 110124634 A TW110124634 A TW 110124634A TW I811724 B TWI811724 B TW I811724B
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Abstract
本發明係關於化合物之用途,其係用於製備治療正股核糖核酸病毒引起的疾病之醫藥組成物,該醫藥組成物包括一有效量的一式I或式II化合物及一醫藥上可接受之載體。
Description
本發明係關於正股核糖核酸病毒之抑制劑。
正股核糖核酸病毒包括病原體,例如茲卡病毒(Zika virus)、登革熱病毒(Dengue virus)、人類冠狀病毒OC43(HCoV-OC43)、人類冠狀病毒229E(HCoV-229E)、及嚴重急性呼吸症候群冠狀病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)。
茲卡病毒引起了2015年及2016年茲卡熱(Zika fever)的廣泛流行。它可以從孕婦傳染給胎兒,導致嬰兒出現小腦症(microcephaly)及其他嚴重的腦部異常。當前沒有針對茲卡病毒的特定藥物或疫苗。
登革熱病毒透過受感染的斑蚊屬(Aedes)蚊子叮咬傳播,導致登革熱(Dengue fever)。它常見於100多個國家,且每年感染全球數百萬人。迄今為止,只有一種疫苗(即Dengvaxia®)被批准用於至少感染過一次登革熱的人。預防蚊子叮咬及控制蚊子數量仍然是對抗登革熱病毒的主要方法。
HCoV-OC43及HCoV-229E是導致普通感冒的病毒,與上呼吸道感染有關。它們還可以引起嚴重的下呼吸道疾病,包括細支氣管炎(bronchiolitis)、支氣管炎(bronchitis)、哮吼(croup)、及肺炎(pneumonia),主要發生在嬰兒及免疫
功能低下的患者身上。藥物只能用於減輕疼痛及發燒。疫苗尚未商業化以保護人們免受這兩種人類冠狀病毒的侵害。
SARS-CoV-2引起了COVID-19大流行,導致全球超過390萬人死亡。為遏制大流行的蔓延,許多國家實施了長達一年的非藥物干預措施,例如居家令、宵禁、及隔離,使全球經濟陷入衰退。美國食品藥物管理局已批准一種藥物-瑞德西韋(remdesivir)用於治療COVID-19。研究顯示,瑞德西韋僅對一小部分患者有效,使他們能夠更快康復。其他潛在的治療方法包括重新利用的藥物,例如巴瑞替尼(baricitinib)、地塞米松(dexamethasone)、環索奈德(ciclesonide)、氯喹(chloroquine)、及羥氯喹(hydroxychloroquine)。未有一種治療具有高的療效。
由於感染SARS-CoV-2、登革熱病毒、茲卡病毒、HCoV-OC43、及HCoV-229E引起疾病的有效治療尚未得到滿足。因此,開發一種有效正股核糖核酸病毒抑制劑,特別是對COVID-19進行有效治療具有迫切需要。
為了滿足上述需求,已確定某些化合物可強效地抑制正股核糖核酸病毒,包括登革熱病毒、茲卡病毒、HCoV-OC43、HCoV-229E、及SARS-CoV-2。
於此式中,(1)每一R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、及R15各自獨立為H、鹵素、烷基、芳基、環烷基、雜芳基、雜環烷基、OH、烷氧基、羰氧基(carbonyloxy)、或胺基;(2)每一R16及R17各自獨立為H、鹵素、烷基、芳基、環烷基、雜芳基、雜環烷基、OH、烷氧基、羰氧基、或胺基,或者是R16及R17一起為一單鍵;(3)每一及各自獨立為一單鍵或一雙鍵;以及(4)n為1、2、或3。當X與Y之間的為一單鍵時,X為C=O或CR’R”,且Y為N或N+→O-,其中每一R’及R”各自獨立為H、鹵素、烷基、芳基、環烷基、雜芳基、雜環烷基、OH、烷氧基、或胺基。當X與Y之間的為一雙鍵時,X為CR’,Y為N+,且一相對離子(counterion)共存於該化合物,其中R’如上所定義。
較佳地,每一R1、R5、R8、R9、R10、R11、R12、R13、R14、及R15為H;每一R2、R3、R6、及R7各自獨立為烷氧基(例如,C1-C6烷氧基,甲氧基、及乙氧基);R4為H或烷氧基(例如,C1-C6烷氧基,甲氧基、及乙氧基);R16及R17一起為一單鍵,X為CH2,且Y為N或N+→O-;每一及為一單鍵;以及n為1或2。
正股核糖核酸病毒可為一黃病毒(flavivirus)(例如,茲卡病毒、登革熱病毒)或一冠狀病毒(例如,SARS-CoV-2、HCoV-OC43、及HCoV-229E)。
於此式中,(1)每一R1、R2、R3、R4、R5、R6、R7、R8、R9、及R10各自獨立為H、烷基、烯基、炔基、環烷基、雜環烷基、芳基、雜芳基、鹵素、硝基、氰基、-ORa、-OC(O)Ra、-C(O)ORa、-NRaRb、-NRaC(O)Rb、或-C(O)NRaRb,其中每一Ra及Rb各自獨立為H、烷基、芳基、雜芳基、環烷基、或雜環烷基;(2)XY一起為C(R’)(R”)-N或CR’=N+,其中R’為H、烷基、烯基、炔基、環烷基、
雜環烷基、芳基、雜芳基、鹵素、硝基、或氰基,且R”為H、烷基、烯基、炔基、環烷基、雜環烷基、芳基、雜芳基、鹵素、硝基、氰基、-ORc、或-OC(O)Rc,其中Rc為H、烷基、芳基、雜芳基、環烷基、或雜環烷基;(3)A為H、烷基、烯基、炔基、環烷基、雜環烷基、芳基、或雜芳基;以及(4)為一單鍵或一雙鍵。
較佳地,每一R1、R4、R5、及R8為H;R2為H或烷氧基(例如,C1-C6烷氧基,甲氧基、及乙氧基);每一R3、R6、及R7各自獨立為烷氧基(例如,C1-C6烷氧基,甲氧基、及乙氧基);R9為H或烷基(例如,C1-C6烷基,甲基、乙基、丙基、及異丙基);R10為H或OH;X為CH2,Y為N;A為烷基(例如,C1-C6烷基,甲基、乙基、丙基、及異丙基),且為一單鍵。
於本文中,術語「烷基」是指含有1-20(例如,1-10及1-6)個碳原子的直鏈或支鏈烴基團。實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、及叔丁基。烷基包括其被鹵素取代的衍生物,即鹵代烷基,是指被一或
多個鹵素(氯、氟、溴、或碘)原子取代的烷基。實例包括三氟甲基、溴甲基、及4,4,4-三氟丁基。術語「烷氧基」是指-O-烷基基團。實例包括甲氧基、乙氧基、丙氧基、及異丙氧基。烷氧基包括鹵代烷氧基,是指被一或多個鹵素原子取代的烷氧基。實例包括-O-CH2Cl及-O-CHClCH2Cl。
術語「環烷基」是指具有3至12個碳的飽和及部分不飽和的單環、雙環、三環、或四環烴基團。環烷基的實例包括,但不限於環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基、及環辛基。
術語「雜環烷基」是指具有一或多個雜原子(例如,O、N、P、及S)的非芳香族5-8員單環、8-12員雙環、或11-14員三環系統。雜環烷基的實例包括,但不限於哌嗪基(piperazinyl)、咪唑啶基(imidazolidinyl)、氮雜環庚基(azepanyl)、吡咯啶基(pyrrolidinyl)、二氫噻二唑基(dihydrothiadiazolyl)、二氧環己基(dioxanyl)、嗎啉基(morpholinyl)、四氫吡喃基(tetrahydropuranyl)、及四氫呋喃基(tetrahydrofuranyl)。
術語「芳基」是指6-碳單環、10-碳雙環、14-碳三環之芳香族環系統,其中每一環可具有1至5個取代基。芳基的實例包括苯基、萘基、及蒽基(anthracenyl)。術語「亞芳基」是指二價芳基。術語「芳烷基」是指被芳基取代的烷基。
術語「雜芳基」是指具有一或多個雜原子(例如,O、N、P、及S)的5-8員單環、8-12員雙環、或11-14員三環系統。實例包含三唑基(triazolyl)、噁唑基(oxazolyl)、噻二唑基(thiadiazolyl)、四唑基(tetrazolyl)、吡唑基(pyrazolyl)、吡啶基(pyridyl)、呋喃基(furyl)、咪唑基(imidazolyl)、苯並咪唑基(benzimidazolyl)、嘧啶基(pyrimidinyl)、噻吩基(thienyl)、喹啉基(quinolinyl)、吲
哚基(indolyl)、噻唑基(thiazolyl)、及苯並噻唑基(benzothiazolyl)。術語「雜芳基烷基」是指被雜芳基取代的烷基。
術語「鹵素」是指氟、氯、溴、或碘基團。術語「胺基」是指衍生自胺的基團,其未被取代或被烷基、芳基、環烷基、雜環烷基、或雜芳基單-/二-取代。術語「烷基胺基」是指烷基-NH-。術語「二烷基胺基」是指烷基-N(烷基)-。
本文提及的烷基、環烷基、雜環烷基、芳基、雜芳基、芳烷基、雜芳烷基、烷氧基、及芳氧基皆包括被取代及未被取代的基團。取代基的實例包括,但不限於鹵素、羥基、胺基、氰基、硝基、巰基(mercapto)、烷氧羰基(alkoxycarbonyl)、醯胺基(amido)、羧基、烷磺醯基(alkanesulfonyl)、烷羰基(alkylcarbonyl)、脲基(carbamido)、胺甲醯基(carbamyl)、羧基(carboxyl)、硫脲基、氰硫基(thiocyanato)、磺醯胺基(sulfonamido)、烷基、烯基、炔基、烷氧基、芳基、雜芳基、環烷基、及雜環烷基,其中烷基、烯基、炔基、烷氧基、芳基、雜芳基、環烷基、及雜環烷基可進一步地被取代。
式I或式II化合物可包括陰離子。陰離子的實例包括Cl-、Br-、I-、SO4 2-、PO4 3-、ClO4 -、CH3CO2 -、及CF3CO2 -。
當提及式I或式II化合物時,術語「化合物」還涵蓋其鹽類、溶劑合物、及前驅藥。陰離子與化合物上的帶正電荷的基團(例如,胺基)之間可以形成鹽類;合適的陰離子的實例包括氯離子、溴離子、碘離子、硫酸鹽、硝酸鹽、磷酸鹽、檸檬酸鹽、甲磺酸鹽、三氟乙酸鹽、乙酸鹽、蘋果酸鹽(malate)、甲苯磺酸鹽、酒石酸鹽、延胡索酸鹽(fumurate)、麩胺酸鹽(glutamate)、葡萄糖醛酸鹽(glucuronate)、乳酸鹽(lactate)、戊二酸鹽(glutarate)、及順丁烯二酸鹽(maleate)。
陽離子與帶負電荷的基團之間也可以形成鹽類;合適的陽離子的實例包括鈉離子、鉀離子、鎂離子、鈣離子、及銨陽離子例如四甲基銨離子。此外,鹽類可以包含四級氮原子。溶劑合物是指在活性化合物與藥學上可接受的溶劑之間形成的複合物。藥學上可接受的溶劑的實例包括水、乙醇、異丙醇、乙酸乙酯、乙酸、及乙醇胺。前驅藥是指在給藥後被代謝成藥學活性藥物的化合物。前驅藥的實例包括酯及其他藥學上可接受的衍生物,其在給予主體後能夠提供本發明的活性化合物。
本發明的細節於下述附圖、定義、及詳細描述中闡述。從以下實際的實施例及申請專利範圍中可顯而易知本發明的其他特徵、目的、及優點。
以下描述參考附圖:
圖1顯示三種娃兒藤鹼(tylophorine)化合物在0至300nM的濃度範圍內對HCoV-OC43的抗病毒活性。
圖2顯示化合物1-3在0至50nM的濃度範圍內對HCoV-OC43的抗病毒活性。
如上所述,娃兒藤鹼(tylophorine)(即化合物1)及其衍生物用於治療正股核糖核酸病毒引起的疾病。
娃兒藤鹼,C24H27NO4,為一種主要的生物鹼,富含在娃兒藤(tylophora indica)(原生於印度東部及南部的攀緣植物)的根及葉中。娃兒藤為傳
統醫藥,廣泛用於治療過敏、氣喘(asthma)、癌症、咳嗽、關節疾病(類風濕性關節炎)等病症。
娃兒藤鹼最早於1935年從植物中萃取而得。參見Ratnagiriswaran等人,Indian J.Med.Res.22(3),433-441(1935)。近40年後,透過酸萃取及溶劑蒸餾,使用甲醇、乙酸乙酯、及氯仿,從娃兒藤中萃取具有生物有效性的娃兒藤鹼。參見Rao等人,F.J.Pharma.Sci.60(11),1725-26(1971)。透過不同的光譜技術闡明娃兒藤鹼之結構。參見Govindachari等人,Proc.Indian Acad.Sci.3,114(2002)。娃兒藤鹼的分子量為393.48,為一種含有有機氮雜環及有機雜五環化合物之二級代謝產物,其IUPAC名稱為(13aS)-2,3,6,7-四甲氧基-9,11,12,13,13a,14-六氫菲[9,10-f]吲哚嗪((13aS)-2,3,6,7-tetramethoxy-9,11,12,13,13a,14-hexahydrophenanthro[9,10-f]indolizine)。有關其化學結構,請參閱上文摘要段落。
娃兒藤鹼具有多種特性,例如免疫抑制、抗腫瘤、拒食素(antifeedant)、抗菌、抗真菌、抗阿米巴(antiamoebic)、利尿及護肝活性。此外,娃兒藤鹼還對腎上腺皮質提供正向刺激。
娃兒藤鹼的生物技術生產可透過誘導根毛農桿菌(Agrobacterium rhizogenes)(A4株)介導的毛狀根達成。另一方面,娃兒藤鹼的化學合成可以透過腈類穩定的銨中間體使用五步法實現。參見Lahm等人,J.Org.Chem.77,6620-23(2012)。娃兒藤鹼可商購獲得,為黃色固體。供應商包括Alfa Chemistry(美國紐約州Ronkonkoma)、Glixx Laboratories公司(美國馬薩諸塞州霍普金頓)、及MedKoo Bioscience公司(美國北卡羅來納州莫里斯維爾)。
娃兒藤鹼及其衍生物已用於治療癌症及其他病症。參見美國專利第7,652,027、9,216,977及8,486,959號,以及美國專利申請公開案第2011/0201637
號。衍生物通常透過化學合成製備,範例請參見美國專利第8,486,959號、美國專利申請公開案第2011/0201637號、Yang等人,Antiviral Res.88,160-168(2010)、以及Lee等人,J.Med.Chem.55,10363-77(2012)。
式I或式II化合物可以透過常規方法製備,例如,上文引用的參考文獻中所提供的步驟。然後,使用已知方法(例如下文實際的實施例描述的方法)評估它們的抗病毒活性。
本發明的一些化合物含有非芳香族雙鍵或一或多個不對稱中心。其中的每種都作為外消旋物(racemate)或外消旋混合物(racemic mixture)、單一R鏡像異構物(single R enantiomer)、單一S鏡像異構物、單獨的非鏡像異構物(individual diastereomer)、非鏡像異構混合物(diastereometric mixture)、順式異構物、或反式異構物出現。本發明的範圍涵蓋這種異構形式的化合物。它們可以作為混合物存在,也可以使用掌性合成或掌性分離技術進行分離。
為了實施本發明的方法,可以腸胃外、口服、鼻腔、直腸、局部外用、或口頰(buccally)給予含有一或多種上述娃兒藤鹼化合物之組合物。
如本文所用,術語「腸胃外」包括皮下(subcutaneous)、皮內(intracutaneous)、靜脈內(intravenous)、腹腔內(intraperitoneal)、肌肉內(intramuscular)、關節內(intraarticular)、動脈內(intraarterial)、滑膜內(intrasynovial)、胸骨內(intrasternal)、髓鞘內(intrathecal)、病灶內(intralesional)、及顱內注射(intracranial injection)之無菌注射用組合物。事實上,該術語是指任何合適的輸注技術(infusion technique)。
無菌注射用組合物可以是在無毒的腸胃外可接受的稀釋劑或溶劑中的溶液或懸浮液,諸如在1,3-丁二醇(1,3-butanediol)中的溶液。可以使用的
可接受的載體(vehicles)及溶劑包括甘露醇(mannitol)、水、林格氏溶液(Ringer’s solution)及等滲透壓的氯化鈉溶液。此外,常規上使用非揮發性油(fixed oils)作為溶劑或懸浮介質(例如合成的甘油單酯或甘油二酯(mono-or di-glycerides))。脂肪酸(諸如油酸(oleic acid)及其甘油酯(glyceride)衍生物)可用於製備注射劑,藥學上可接受的天然油(諸如橄欖油及蓖麻油,特別是其聚氧乙烯化形式)也可用於製備注射劑。這些油性溶液或懸浮液也可以含有長鏈醇類稀釋劑或分散劑、羧甲基纖維素(carboxymethyl cellulose)或類似的分散劑。也可以將其他在製備藥學上可接受的固體、液體或其他劑型所常用的表面活性劑(諸如Tweens及Spans或其他類似的乳劑或生物可利用性增強劑(bioavailability enhancers))用於調製配方。
口服給藥的組合物可以是任何口服可接受的劑型,包括膠囊、錠劑、乳劑及水性懸浮液、分散液及溶液。對於錠劑來說,常用的載體包括乳糖及玉米澱粉。通常也添加諸如硬脂酸鎂(magnesium stearate)的潤滑劑。對於以膠囊形式的口服給藥而言,實用的稀釋劑包括乳糖及乾燥的玉米澱粉。當口服給予水性懸浮液或乳劑時,可以將活性成分懸浮或溶解在與乳劑或懸浮劑結合的油相中。如果需要,可以添加特定甜味劑、調味劑或著色劑。口服固體劑型可以透過噴霧乾燥技術;熱熔擠出策略、微粉化、及奈米研磨技術製備。
可以依據藥物製劑領域中已知的技術來製備鼻用噴霧劑(nasal aerosol)或吸入組合物。例如,可以使用本領域已知的苯甲醇(benzyl alcohol)或其他適合的防腐劑、提升生物可利用性的吸收促進劑、碳氟化合物(fluorocarbons)、及/或其他助溶劑或分散劑,將此種組合物製備為在鹽水中的溶液。具有活性化合物之組合物也可以以栓劑(suppositories)的形式用於直腸給藥。
醫藥組合物中的載體在與組合物的活性成分之相容性上須為「可接受的」(且以能夠穩定活性成分為佳),並且對於治療的主體無害。可以將一或多種增溶劑用作藥物賦形劑以傳遞活性化合物。其他載體的實例包括膠體氧化矽、硬脂酸鎂、纖維素、硫酸月桂酯鈉(sodium lauryl sulfate)、及D&C Yellow#10。
術語「治療(treating)」是指將化合物施用於或給予主體,以治癒、緩解、減輕、改變、矯正(remedy)、改善、或影響疾病、症狀、或其傾向(predisposition)。「有效量」是指對主體達成期望的效果所需的化合物之量。如本領域技術人員所知,有效量取決於給藥途徑、賦形劑用法、以及併用其他治療方法(諸如其他活性藥物的使用)的可能性而變化。式I或式II化合物的劑量濃度為每日劑量為0.1mg/kg體重至500mg/kg體重(例如,0.5mg/kg體重至300mg/kg體重、1mg/kg體重至200mg/kg體重、及10mg/kg體重至100mg/kg體重)。特定患者的具體劑量將取決於許多因素,包括年齡、體重、健康狀況、性別、飲食、給藥時間、排泄率、及病症的嚴重程度。為了提高治療效率,該化合物可以與一或多種其他口服活性抗病毒化合物同時給藥。
無須進一步闡述,相信本領域的技術人員可基於以上描述最充分地利用本發明。以下實施例僅為說明之用,故而其不以任何方式限制本文揭露之其餘部分。
本文所引用的所有出版物(包括專利文件)透過全文併入做為參考。
實施例
測試娃兒藤鹼及8種娃兒藤鹼衍生物(即化合物1-9),強效地顯示出對正股核糖核酸病毒(即SARS-CoV-2、HCoV-OC43、HCoV-229E、茲卡病毒、及登革熱病毒)的抗病毒活性。
實施例1:抑制SARS-CoV-2病毒活性
進行免疫螢光分析法(immunofluorescence assay,IFA)及溶斑分析法(plaque assay)以評估對SARS-CoV-2的抑制作用。
SARS-CoV-2免疫螢光分析法
將Vero E6細胞(BCRC#60476,源自臺灣新竹生物資源保存及研究中心)以指定濃度的每種化合物在37℃下處理1小時。細胞以0.01的感染複數(Multiplicity of infection,MOI)在37℃下被SARS-CoV-2病毒(TCDC#4,中華民國臺灣臺北國立臺灣大學)吸附1小時。病毒吸附後,用磷酸鹽緩衝鹽水(PBS)洗滌細胞。以指定濃度加入含有化合物的新鮮培養基,將含混合物的細胞培養2天。兩天後,細胞用4%聚甲醛(paraformaldehyde)固定,並用0.5% TritonTM X-100洗劑溶液(Thermo Fisher Scientific,美國麻薩諸塞州沃爾瑟姆)透化(permeabilized)細胞。隨後,使用抗SARS-CoV-2 N核鞘蛋白(N protein)抗體及抗人IgG-488(綠色)進行免疫螢光染色。使用4’,6-二脒基-2-苯基吲哚(4’,6-diamidino-2-phenylindole,DAPI,Thermo Fisher Scientific,美國麻薩諸塞州)進行細胞核染色。使用高通量影像分析系統(high-content image analysis system)(Molecular Devices,美國加利福尼亞州聖荷西)測量病毒核鞘蛋白表達。以細胞增殖及細胞毒性檢測套組(Cell Counting Kit-8,Sigma-Aldrich,美國密蘇里州聖路易斯)測定細胞存活率(cell viability),由Prism軟體計算EC50及CC50值。術語EC50是指病毒被抑制50%時化合物的半數最大有效濃度。術語CC50是指化合物的50%細胞毒性濃度,在該濃度下
細胞生存力降低50%。EC50及CC50兩者以摩爾單位測量,例如mol/L(M)、μmol/L(μM)、及nmol/L(nM)。
結果顯示於下表1中。化合物1、化合物2、及化合物3均對SARS-CoV-2具有高效抑制活性,EC50非常低,在9nM至77nM的範圍內。
SARS-CoV-2病毒溶斑(plaque)分析法
該分析法在24孔組織培養盤中以三重複(triplicate)進行。在感染前一天,將Vero E6細胞接種在含有10%胎牛血清(FBS,Biological Industries,吉布茲,以色列)及抗生素的Dulbecco改良Eagle培養基(Dulbecco’s modified Eagle’s medium,DMEM)中。將SARS-CoV-2病毒添加到細胞中,並在37℃下靜置1小時。去除病毒後,細胞用PBS洗滌一次,然後用含有洋菜膠(agarose)或甲基纖維素的培養基覆蓋5-7天。細胞用3.7%甲醛固定過夜,接著去除覆蓋培養基,然後用結晶紫(crystal violet)對它們進行染色以計算病毒溶斑形成單位(plaque-forming units,PFU)。抑制百分比以[1-(VD/VC)]×100%計算,其中VD及VC分別是指存在及不存在測試化合物時的病毒效價(virus titer)。
抑制SARS-CoV-2病毒活性
在Vero E6細胞中檢測了化合物1-3對SARS-CoV-2的抑制活性。對被SARS-CoV-2感染的Vero E6細胞的細胞病變效應(Cytopathic effects,CPE)進行可視化,其中以2倍稀釋的12種濃度的化合物進行處理。計算EC50及CC50值。參見下表1。
CPE:可視化之細胞病變效應
如CPE結果所示,化合物1-3均具有強效的抗SARS-CoV-2活性。此外,IFA分析法顯示的結果與CPE結果相當。化合物1-3均具有強效的抑制SARS-CoV-2效力。其中,化合物2的抗病毒活性最高。進行四次病毒溶斑分析以測量化合物2在受感染的Vero E6細胞中對抗SARS-CoV-2的效力。在所有的四次測量中,化合物2的EC50值在11~14nM的範圍內,這與從上表1所示的細胞病變效應分析法及IFA分析法所獲得的一致。
實施例2:抑制HCoV-OC43病毒活性
使用針對HCoV-OC43核鞘(nucleocapsid,N)蛋白的IFA分析法測試了化合物1-6對人類冠狀病毒HCoV-OC43(β冠狀病毒)的抑制活性。
人類結腸腺癌細胞系(Human colon adenocarcinoma cell line)HCT-8(ATCC® CCL-244TM,美國維吉尼亞州馬納薩斯美國菌種保存中心)自美國菌種保存中心(ATCC)獲得。HCoV-OC43病毒(ATCC® VR1558TM,美國維吉尼亞州馬納薩斯美國菌種保存中心)在使用DMEM及2%FBS(Biological Industries,吉布茲,以色列)培養的HCT-8細胞中生長及繁殖。將細胞接種在96孔盤中,然後培養在含有2%FBS的DMEM培養基中。隨後,在HCoV-OC43病毒以0.05的MOI感染之前,以5倍稀釋的五種預定濃度的化合物1-6中之一者預處理1小時。在病毒感染72小時後(hours post-infection,h.p.i.)所得的上清液,進行終點稀釋分析法(end-point dilution assay)並在6天後測定TCID50(Median Tissue
Culture Infectious Dose)以分析病毒量之抑制效果。而移除上清液之細胞(72h.p.i.)再用80%丙酮固定,並使用抗HCoV-OC43核鞘蛋白的抗體透過IFA分析法進行分析,以確定EC50。亦使用CellTiter 96® AQueous非放射性細胞增殖分析套組(Non-Radioactive Cell Proliferation Assay kit,MTS)(Promega,美國威斯康辛州麥迪遜)測量HCT-8細胞的存活率,計算CC50值。此外,為了探討以0.05的MOI被HCoV-OC43感染的HCT-8的細胞病變效應,上述條件之化合物處理後的細胞在病毒感染後6天(day post-infection,d.p.i.).固定後以結晶紫染色進行分析。參見Yang等人,Front.Pharmacol.11,Article 606097(2020)。
化合物1-6對HCoV-OC43病毒表現出高效的抗病毒活性,對HCoV-OC43的EC50值範圍為16nM至1.8μM,選擇指數(Selectivity index)為610至5.3(表2)。
aData表示來自三個獨立實驗的±S.D.,每個實驗為二重複(HCoV-OC43)。
bEC50:50%最大有效濃度的值。
cCC50:50%最大細胞毒性濃度的值。
值得注意的是,化合物1-3均具有非常高的抑制HCoV-OC43病毒效力。然後在6d.p.i.評估這三種化合物的細胞病變效應,並在3d.p.i.評估IFA,接著是隨後的終點稀釋分析法及TCID50測定,以劑量依賴方式顯示抑制活性。於終點稀釋分析法中,HTC-8細胞用HCoV-OC43病毒以0.05的MOI感染72小時,以達到107p.f.u./ml的病毒量,然後使用化合物1-3中之一者以預定濃度進行處理。每種化合物1-3顯著阻斷病毒複製並降低病毒量,導致在30nM與300nM之間的濃度下病毒量減少7個數量級。參見圖1。
實施例3:抑制HCoV-229E病毒活性
化合物1-3用於抑制HCoV-229E病毒,這是另一種屬於α-冠狀病毒屬的人類冠狀病毒。
透過RT-PCR與針對其開放閱讀框1(open reading frame 1,ORF1)及ORF核鞘(ORFN)的特異性引子(primers)檢測HCoV-229E病毒基因組複製。參見Yang等人,Front.Pharmacol.11,Article 606097(2020)。
胎兒肺成纖維細胞MRC5細胞以1的MOI接種HCoV-229E病毒。如此感染的MRC5細胞用化合物1-3中之一者處理。未處理的MRC5細胞用作對照樣本。進行RT-PCR分析。每種化合物1-3在10nM與300nM之間的濃度下抑制HCoV-229E病毒基因組複製及亞基因組病毒核糖核酸合成。
在用化合物1-3中之一者處理感染的細胞後研究並觀察細胞病變效應。使用結晶紫對活細胞進行染色以確定每種化合物的EC50。參見表3。此外,計算CC50及選擇指數。
Data表示來自三個獨立實驗的±S.D.,每個實驗為二重複(HCoV-229E)。
EC50:50%最大有效濃度的值。
CC50:50%最大細胞毒性濃度的值。
透過TCID50進行終點分析法。按照上述步驟研究了HCoV-229E病毒量。每種化合物1-3顯著阻斷病毒複製並消除病毒量,導致被HCoV-229E感染的MRC5細胞在30nM至600nM濃度範圍內的病毒量降低6~7個數量級。參見Yang等人,Front.Pharmacol.11,Article 606097(2020)。
實施例4:抑制茲卡病毒活性
使用針對茲卡病毒外膜(E)蛋白的IFA分析法,評估化合物1-9對茲卡病毒的抑制活性。
Vero E6細胞(BCRC#60476,臺灣新竹生物資源保存及研究中心)用化合物1-9中之一者以預定濃度在37℃下處理1小時。細胞以0.02的MOI在37℃下被茲卡病毒(ATCC VR-1843,美國菌種保存中心,美國維吉尼亞州馬納薩斯)吸附49小時。細胞用10%福馬林(formalin)固定,以甲醇透化。細胞用抗黃病毒E抗體(ATCC HB-112,美國菌種保存中心,美國維吉尼亞州馬納薩斯)及抗小鼠IgG-FITC(MP Biomedicals,美國加利福尼亞州爾灣)進行染色。細胞核用DAPI(藍色)(Thermo Fisher Scientific,美國麻薩諸塞州)進行反染色。使用高通量影像分析系統(Molecular Devices)測量E蛋白表達。透過MTS套組測定細胞存活率。由Prism軟體計算EC50及CC50兩者。
它們的細胞毒性作用也透過上述使用Vero E6細胞的MTS套組分析法測定。每種化合物1-9均有效抑制茲卡病毒。另一方面,它們的50%細胞毒性濃度遠高於其EC50,表明抑制茲卡病毒的選擇性很高。結果如下表4所示。
實施例5:抑制登革熱病毒
使用針對登革熱病毒外膜(E)蛋白的IFA分析法,評估化合物1-9對登革病毒(另一種屬於黃病毒屬的單正股核糖核酸病毒)的抑制活性。
Vero E6細胞(BCRC#60476,臺灣新竹生物資源保存及研究中心)用化合物1-9中之一者以預定濃度在37℃下處理1小時。細胞以0.02的MOI感染登革熱病毒1型(DV1,ATCC VR-1856,美國維吉尼亞州馬納薩斯美國菌種保存中心)或以0.02的MOI感染登革熱病毒2型(DV2,ATCC VR-1584,美國維吉尼亞州馬納薩斯美國菌種保存中心),兩者在33℃下培養5天。然後,用10%福馬林固定並用甲醇透化。隨後,將細胞用抗黃病毒E抗體(ATCC HB-112,美國維吉尼亞州馬納薩斯美國菌種保存中心)及抗小鼠IgG-FITC(MP Biomedicals,美國加利福
尼亞州爾灣)進行染色。細胞核用DAPI(藍色)(Thermo Fisher Scientific,美國麻薩諸塞州)進行反染色。透過使用高通量影像分析系統(Molecular Devices)測量E蛋白表達。透過MTS套組測定細胞存活率。由Prism軟體計算EC50及CC50。
每種化合物1-9在抑制登革熱病毒方面非常有效。參見下表5。
其他實施例
在本說明書揭露之所有特徵可以以任何組合進行結合,本說明書揭露之每一特徵可以由具有相同、等同或類似目的之替代特徵來替換,因此,除非另有明確說明,本揭露之每一特徵僅為等同或類似特徵的一般系列之實例。
此外,從以上描述中,本領域技術人員可以容易的確定本發明之基本特徵,且在不背離本發明之精神及範圍下,可以對本發明進行各種改變及修飾以適應各種用途及條件。因此,其他實施例也在所附申請專利範圍內。
Claims (14)
- 一種式I化合物之用途,其係用於製備治療一正股核糖核酸病毒引起的疾病之醫藥組成物,該醫藥組成物包括:一有效量的該式I化合物及一醫藥上可接受之載體:
- 如請求項1所述之用途,其中該正股核糖核酸病毒為一茲卡病毒或一登革熱病毒。
- 如請求項1所述之用途,其中該正股核糖核酸病毒為一SARS-CoV-2病毒或一HCoV-OC43病毒。
- 如請求項5所述之用途,其中該正股核糖核酸病毒為一茲卡病毒或一登革熱病毒。
- 如請求項5所述之用途,其中該正股核糖核酸病毒為一SARS-CoV-2病毒或一HCoV-OC43病毒。
- 一種式II化合物之用途,其係用於製備治療一正股核糖核酸病毒引起的疾病之醫藥組成物,該醫藥組成物包括:一有效量的該式II化合物及一醫藥上可接受之載體:
- 如請求項8所述之用途,其中該正股核糖核酸病毒為一茲卡病毒或一登革熱病毒。
- 如請求項8所述之用途,其中該正股核糖核酸病毒為一SARS-CoV-2病毒或一HCoV-OC43病毒。
- 如請求項12所述之用途,其中該正股核糖核酸病毒為一茲卡病毒或一登革熱病毒。
- 如請求項12所述之用途,其中該正股核糖核酸病毒為一SARS-CoV-2病毒或一HCoV-OC43病毒。
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