CN101678073A - 富组蛋白的环状类似物的应用方法和组合物 - Google Patents
富组蛋白的环状类似物的应用方法和组合物 Download PDFInfo
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Abstract
本发明提供一种用富组蛋白的环状类似物治疗细菌和真菌疾病的新组合物和治疗方法。有益地,所述富组蛋白的环状类似物比目前使用的杀菌剂效力更强但毒性更低。此外,还公开了包括所述环状类似物与其他杀菌剂如唑类化合物的组合物。
Description
技术领域
本发明涉及富组蛋白的环状类似物,以及涉及它们在新组合物和治疗方法中的应用。
背景技术
真菌和细菌感染是不断上升的健康风险,有证据显示在全世界7个主要市场中有900万患者患有这些感染。有风险的患者包括经历外科手术的患者、白血病和HIV/AIDS患者和由于癌症、外科手术或器官移植而导致免疫低下的患者。这部分地是由于微生物中的抗生素耐受性发展的结果。
因此,对于杀菌剂特别是杀真菌和杀细菌剂的需要在不断增长并且未能满足,这昭示了开发对人类具有高效的无毒杀真菌剂的市场机遇。
发明说明
富组蛋白的环状类似物已经被确定可单独或与其他杀菌剂结合用于治疗人类的微生物感染。所述环状类似物比目前使用的杀菌剂效力更强而且毒性更低。此外,包括所述环状类似物与其他杀菌剂的组合物具有协同作用,表现出比预期更强的活性。
因此,本发明的一个方面提供一种治疗人类的微生物感染的方法,包括对所述人类给予治疗有效量的富组蛋白的环状类似物。
本发明的另一方面提供一种治疗人类的微生物感染的杀菌组合物,包括与可药用的载体结合的富组蛋白的环状类似物。
本发明的又一方面提供一种治疗微生物感染的组合物,包括富组蛋白的环状类似物和第二种杀菌剂。
本发明的其他方面提供试剂盒和制品。试剂盒包括富组蛋白的环状类似物以及对应方法如使用说明。一种依照本发明的制品包括其内部是包含富组蛋白的环状类似物的杀菌组合物的包装。所述包装上贴有标签以指示所述组合物适于治疗人类的微生物感染。
本发明的另一方面提供一种治疗哺乳动物中微生物感染的方法,包括对所述哺乳动物给予杀菌剂与靶向于微生物线粒体的载体分子。
本发明的另一方面包括一种抑制微生物菌丝体生长的方法,包括使富组蛋白的环状类似物与微生物接触。
本发明的又一方面提供一种治疗哺乳动物中微生物感染的方法,包括对所述哺乳动物给予治疗有效量的富组蛋白的环状类似物,所述富组蛋白环状类似物靶向于选自下列的一种蛋白:微管相关蛋白(YTM1)、隔蛋白(septin)(CDC3)、纺锤体动态控制蛋白(SLK19)、G蛋白功能调控蛋白(CRP1)、HSP70家族成员(SSA2)、烯醇酶I(ENO1)、HSP成员(SSE1)、26S蛋白酶体亚基(RPT5)、HSP90、线粒体HSP蛋白(SSC1)、ATP酶复合物的β1亚基(ATP2)、线粒体乌头酸酶/水合酶(ACO1)和微粒体ATP酶(CDC48)、RAV1、HSP60、二氢硫辛酰胺脱氢酶(LPD1)、60S核糖体亚基蛋白L3(RPL3)和丝氨酰-tRNA合成酶(SES1)。
本发明的另一方面提供一种筛选候选杀菌化合物的方法。该方法包括以下步骤:
1)使候选化合物接触至少一种选自以下蛋白的靶标:微管相关蛋白(YTM1)、隔蛋白(CDC3)、纺锤体动态控制蛋白(SLK19)、G蛋白功能调控蛋白(CRP1)、HSP70家族成员(SSA2)、烯醇酶I(ENO1)、HSP成员(SSE1)、26S蛋白酶体亚基(RPT5)、HSP90、线粒体HSP蛋白(SSC1)、ATP酶复合物的β1亚基(ATP2)、线粒体乌头酸酶/水合酶(ACO1)和微粒体ATP酶(CDC48)、RAV1、HSP60、二氢硫辛酰胺脱氢酶(LPD1)、60S核糖体亚基蛋白L3(RPL3)和丝氨酰-tRNA合成酶(SES1);和
2)检测所述化合物是否与所述靶标之一缔合或相互作用,其中与靶标的相互作用表明所述化合物可具有杀菌活性。
通过以下详述、权利要求和附图会对本发明的上述和其他方面、特性以及优点更加清楚。
附图说明
图1示出了若干富组蛋白的氨基酸序列;
图2图示了温度对富组蛋白的环状类似物的影响(A)以及5μM和50μM剂量的所述环状类似物的活性(B)。
图3图示了与酮康唑的毒性相比,富组蛋白的环状类似物对人类原代培养细胞无毒性;和
图4是说明与富组蛋白的环状类似物缔合的微生物蛋白的种类的饼状图。
具体实施方式
本发明提供了用于治疗人类的微生物感染的方法和组合物,包括给予富组蛋白的环状类似物或者其变体或衍生物。
可用于本发明组合物的方法的富组蛋白环状类似物在美国专利No.6,555,650中和Brewer,et al.(2002)Biochemistry 41:5526-5536中被描述和表征,这两篇文献都以引用的方式整体纳入本文中。通常,本文所用的术语“富组蛋白的环状类似物”是指由任何其长度适于稳定环化的富组蛋白或者其衍生物或变体构成的具有杀菌活性的环状类似物,包括例如图1所列的富组蛋白1(H-1)到富组蛋白12(H-12),特别是富组蛋白H-1到富组蛋白H-6,更特别地是H-1、H-3和H-5。用于富组蛋白的术语“变体”是指大部分序列与富组蛋白具有同源性的分子,如至少约60%的同源性,优选至少约80%的同源性,和更优选至少约90-95%的同源性。合适的变体的实例包括这样的富组蛋白,即其中将赖氨酸、谷氨酸或半胱氨酸残基引入所述富组蛋白以置换一个或多个现有氨基酸残基,从而得到更易于环化形成环状富组蛋白类似物。本文用于富组蛋白的术语“衍生物”是指在活性位点上(例如游离的羧基或氨基基团或者其他支链基团上)含有一种或多种修饰的富组蛋白分子。可进行这些修饰以赋予所述富组蛋白类似物所需的性质,例如增加的稳定性或提高的细胞吸收。一种符合本发明的环状富组蛋白类似物在本文中称为DB2121,其氨基酸序列为RHHCYKRKFHEKHHCHRGY(SEQ ID NO:1)。
美国专利No.6,555,650描述了这种环状组蛋白类似物的制备,通常包括肽合成的标准方法,然后在需要的地方进行氨基酸置换以利于环化。然后,如本领域技术人员能理解的和如美国专利No.6,555,650中所描述的那样,将线性富组蛋白肽在适于环化的条件下环化,此过程依赖参与所述环化反应的氨基酸残基。
根据本发明的方法,富组蛋白的环状类似物已被确定可用于治疗微生物感染,包括例如细菌感染和真菌感染。因此,本发明的富组蛋白的环状类似物可用于治疗由下列微生物导致的人类细菌感染:链球菌属(Streptococcus)、葡萄球菌属(Staphylococcus)、博德特氏菌属(Bordetella)、棒状杆菌属(Corynebacterium)、分枝杆菌属(Mycobacterium)、奈瑟氏菌属(Neisseria)、嗜血杆菌属(Haemophilus)、放线菌类(Actinomycetes)、链霉菌属(Streptomycetes)、诺卡菌属(Nocardia)、肠杆菌属(Enterobacter)、耶尔森氏菌属(Yersinia)、弗朗西斯氏菌属(Fancisella)、巴斯德氏菌属(Pasturella)、摩拉克氏菌属(Moraxella)、不动细菌属(Acinetobacter)、丹毒丝菌属(Erysipelothrix)、布兰汉氏球菌属(Branhamella)、放线杆菌属(Actinobacillus)、链杆菌属(Streptobacillus)、李斯特氏杆菌属(Listeria)、荚膜菌属(Calymmatobacterium)、布鲁氏菌属(Brucella)、芽孢杆菌属(Bacillus)、梭菌属(Clostridium)、密螺旋体属(Treponema)、埃希氏菌属(Escherichia)、沙门氏菌属(Salmonella)、克雷白氏杆菌(Kleibsiella)、弧菌属(Vibrio)、变形杆菌属(Proteus)、欧文氏菌属(Erwinia)、包柔氏螺旋体菌(Borrelia)、钩端螺旋体属(Leptospira)、螺旋状菌属(Spirillum)、弯曲杆菌属(Campylobacter)、志贺氏菌属(Shigella)、军团杆菌属(Legionella)、假单胞菌属(Pseudomonas)、气单胞菌属(Aeromonas)、立克次氏体(Rickettsia)、衣原体(Chlamydia)、包柔氏螺旋体属(Borrelia)和支原体(Mycoplasma);还包括但不限于:A群链球菌、B群链球菌、C群链球菌、D群链球菌、G群链球菌、肺炎链球菌(Streptococcuspneumoniae)、酿脓链球菌(Streptococcus pyogenes)、无乳链球菌(Streptococcus agalactiae)、粪链球菌(Streptococcus faecalis)、粪链球菌(Streptococcus faecium)、坚忍链球菌(Streptococcus durans)、淋病奈瑟菌(Neisseria gonorrheae)、脑膜炎奈瑟菌(Neisseria meningitidis)、金黄色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcusepidermidis)、白喉棒杆菌(Corynebacterium diptheriae)、阴道加德纳菌(Gardnerella vaginalis)、结核分枝杆菌(Mycobacterium tuberculosis)、牛分枝杆菌(Mycobacterium bovis)、溃疡分枝杆菌(Mycobacteriumulcerans)、麻风分枝杆菌(Mycobacterium leprae)、以色列放线菌(Actinomyces israelii)、单核细胞增多性李氏菌(Listeria monocytogenes)、百日咳杆菌(Bordetella pertusis)、副百日咳杆菌(Bordatella parapertusis)、支气管败血性博德特氏菌(Bordetella bronchiseptica)、大肠杆菌(Escherichia coli)、痢疾杆菌(Shigella dysenteriae)、流感嗜血杆菌(Haemophilus influenzae)、埃及嗜血杆菌(Haemophilus aegyptius)、副流感嗜血杆菌(Haemophilus parainfluenzae)、杜克雷嗜血杆菌(Haemophilusducreyi)、博德特氏菌(Bordetella)、伤寒杆菌(Salmonella typhi)、弗氏柠檬酸杆菌(Citrobacter freundii)、奇异变形杆菌(Proteus mirabilis)、普通变形杆菌(Proteus vulgaris)、鼠疫耶尔森氏菌(Yersinia pestis)、肺炎克雷白杆菌(Kleibsiella pneumoniae)、粘质沙雷氏菌(Serratia marcessens)、液化沙雷氏菌(Serratia liquefaciens)、霍乱弧菌(Vibrio cholera)、痢疾志贺氏菌(Shigella dysenterii)、痢疾杆菌(Shigella flexneri)、绿脓杆菌(Pseudomonas aeruginosa)、拉热弗郎西丝氏菌(Franscisella tularensis)、流产布鲁氏菌(Brucella abortis)、炭疽杆菌(Bacillus anthracis)、蜡样芽胞杆菌(Bacillus cereus)、产气荚膜梭菌(Clostridium perfringens)、破伤风杆菌(Clostridium tetani)、肉毒杆菌(Clostridium botulinum)、梅毒螺旋体(Treponema pallidum)、立克次氏体(Rickettsia rickettsii)、幽门螺旋杆菌(Helicobacter pylori)或沙眼衣原体(Chlamydia trachomitis)。人类中由细菌感染引起的疾病的非限制性实例包括中耳炎(otitis media)、结膜炎(conjunctivitis)、肺炎(pneumonia)、菌血症(bacteremia)、脑膜炎(meningitis)、鼻窦炎(sinusitis)、脓胸(pleural empyema)和心内膜炎(endocarditis)以及如脑脊液感染的脑膜炎(meningitis)。
所述富组蛋白的环状类似物也可用于治疗由例如下列真菌引起的人类真菌感染:隐球菌属(Cryptococcus spp.)、念珠菌属(Candida spp.)、曲霉属(Aspergillus spp.)、组织胞浆菌属(Histoplasma spp.)、球孢子菌属(Coccidioides spp.)、副球孢子菌属(Paracoccidioides spp.)、芽生菌属(Blastomyces spp.)、镰刀菌属(Fusarium spp.)、孢子丝菌属(Sporothrixspp.)、毛孢子菌属(Trichosporon spp.)、球拟酵母属(Torulopsis spp.)、根霉属(Rhizopus spp.)、假阿利什菌属(Pseudallescheria spp.)、皮肤癣菌属(Dermatophytes spp.)、拟青霉属(Paeciliomyces spp.)、交链孢属(Alternaria spp.)、弯孢菌属(Curvularia spp.)、外瓶霉属(Exophiala spp.)、万吉拉菌属(Wangiella spp.)、青霉菌属(Penicillium spp.)、酵母属(Saccharomyces spp.)、暗色真菌(Dematiaceous fungi)和卡氏肺囊虫(Pneumocystis carinii)。由真菌感染引起的疾病的非限制性实例包括隐球菌性脑膜炎(cryptococcal meningitis)、脚癣(athlete′s foot)、酵母感染、霉菌和霉病相关疾病、鹅口疮(thrush)、组织胞浆菌病(histoplasmosis)、酿母菌病(blastomycosis)、甲癣(onychomyosis)和癣感染,如头癣(Tineacapitis)、花斑癣(Tinea versicolor)和足癣(Tinea pedis)。
对人类给予治疗有效量的富组蛋白环状类似物以治疗微生物感染。本文所用的术语“治疗有效的”剂量是指对治疗给定微生物感染有效而不导致不可接受的有害副作用的剂量。术语“给予”是指任何合适的向接受者提供所述环状富组蛋白药剂的方式,所述方式倚赖如下所述的所用的给药形式。例如,如下文所详述的,所述药剂可通过口服、注射、经黏膜和局部方式给予。术语“治疗”是指对引起感染的微生物的至少部分抑制,所述抑制可使所述感染的一种或多种症状改善。
因此,本方法的治疗有效剂量为每公斤体重0.01ng到约10g,优选地为每公斤约1ng到约0.1g,更优选地为每公斤约100ng到约10mg。然而,如本领域技术人员可理解的,所述富组蛋白的环状类似物的治疗有效剂量会根据被治疗患者的症状、年龄和体重,要治疗或预防的感染的性质和严重程度以及给药途径而变化。本发明的富组蛋白类似物可单次或分次给药。
在人类的微生物感染的治疗中,可单独或者以与可药用的佐剂或载体结合的组合物的形式给予所述富组蛋白的环状类似物。表述“可药用的”是指在药学领域的应用是可接受的,即没有不可接受的毒性或其他不适于对人给药的的性质。可药用的佐剂的实例包括但不限于稀释剂、赋形剂等。可参考″Remington′s:The Science and Practice of Pharmacy″,21st Ed.,Lippincott Williams & Wilkins,2005作为一般药物制剂的指南。佐剂的选择依赖于拟采用的给予所述组合物的方式。在本发明的一个实施方案中,将所述化合物配制成用于通过输注或者皮下或静脉注射给药,并因此以无菌和无热原的并任选地被缓冲或等渗的水溶液形式使用。因此,所述化合物可在蒸馏水中或更优选地在盐水、磷酸缓冲盐水或5%葡萄糖溶液中被给药。制备用于通过片剂、胶囊、糖锭、水或非水液体中的溶液或悬浮液、水包油或油包水乳液、酏剂或糖浆来口服的组合物,使用的佐剂包括糖类例如乳糖、葡萄糖和蔗糖;淀粉例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物包括羟甲基纤维素钠、乙基纤维素和醋酸纤维素;西黄蓍胶粉;麦芽;明胶;滑石粉;硬脂酸;硬脂酸镁;硫酸钙;植物油如花生油、棉籽油、芝麻油、橄榄油和玉米油;多元醇如丙二醇、甘油、山梨糖醇、甘露醇和聚乙二醇;琼脂;海藻酸;水;等渗盐水和磷酸缓冲溶液。也可存在润湿剂、润滑剂例如十二烷基硫酸钠、稳定剂、制锭剂、崩解剂、抗氧化剂、防腐剂、着色剂和调味剂。在另一个实施方案中,所述环状类似物可被配制为用于局部涂敷的霜剂、洗剂或软膏。对于这种局部涂敷,所述环状类似物与一种合适的基质如甘油三酯基质结合。这些霜剂、洗剂和软膏还可包含表面活性剂和其他化妆品添加剂例如柔肤水等以及香水。也可使用合适的推进剂佐剂制备用于例如鼻腔给药的气雾制剂。本发明组合物也可作为丸剂、药糖剂或贴剂给药。还包括粘膜给药的组合物,包括口服、鼻内、直肠或阴道给药以治疗影响这些区域的感染。这些组合物通常包括一种或多种合适的非刺激性赋形剂或载体,包括例如可可脂、聚乙二醇、栓剂蜡、水杨酸盐或其他合适的载体。不管所述组合物是如何被给药的,也可将例如有助于延长所述组合物保质期的其他佐剂加入到所述组合物中。
因此,在优选地具有杀菌性质的组合物中可包括本发明的富组蛋白的环状类似物,所述组合物例如治疗上述特定感染的药物;其他卫生保健产品如外伤处理、滴眼剂、牙膏、漱口水或漱口剂、肥皂、沐浴液、香波、润肤液;以及美容产品如粉底或其他化妆品。
在本发明的另一方面,可对需要微生物感染治疗的哺乳动物结合给予所述富组蛋白的环状类似物与另一种活性成分,例如第二种杀菌剂如一种杀真菌剂或杀细菌剂。可在本发明的组合物和方法中用作第二种杀菌剂的杀细菌剂包括但不限于:头孢菌素类抗菌素(cephalosporins)包括第一代头孢菌素如头孢羟氨苄(Cefadroxil)、头孢唑啉(Cefazolin)、头孢氨苄(Cephalexin)、头孢噻吩(Cephalothin)、头孢吡硫(Cephapirin)和头孢拉定(Cephradine);第二代头孢菌素如头孢克洛(Cefaclor)、头孢孟多(Cefamandol)、头孢尼西(Cefonicid)、头孢替坦(Cefotetan)、头孢西丁(Cefoxitin)、头孢丙烯(Cefprozil)、头孢美唑(Ceftmetazole)、头孢呋辛(Cefuroxime)、头孢呋辛酯(Cefuroxime axetil)和氯碳头孢(Loracarbef);第三代头孢菌素如头孢地尼(Cefdinir)、头孢布烯(Ceftibuten)、头孢妥仑(Cefditoren)、头孢他美(Cefetamet)、头孢泊肟(Cefpodoxime)、头孢丙烯(Cefprozil)、头孢呋辛(酯)(Cefuroxime(axetil))、头孢呋辛(钠)(Cefuroxime(sodium))、头孢哌酮(Cefoperazone)、头孢克肟(Cefixime)、头孢噻肟(Cefotaxime)、头孢泊肟酯(Cefpodoxime proxetil)、头孢他啶(Ceftazidime)、头孢唑肟(Ceftizoxime)和头孢曲松(Ceftizoxime);和第四代头孢菌素如头孢吡肟(Cefepime);喹诺酮类(quinolones)和氟喹诺酮类(fluoroquinolonesands)如西诺沙星(Cinoxacin)、环丙沙星(Ciprofloxacin)、依诺沙星(Enoxacin)、加替沙星(Gatifloxacin)、咪莫特(Grepafloxacin)、左氧氟沙星(Levofloxacin)、洛美沙星(Lomefloxacin)、莫西沙星(Moxifloxacin)、萘啶酸(Nalidixic acid)、诺氟沙星(Norfloxacin)、氧氟沙星(Ofloxacin)、司帕沙星(Sparfloxacin)、曲伐沙星(Trovafloxacin)、恶喹酸(Oxolinic acid)、氟喹诺酮类吉米沙星(Gemifloxacin),和甲氟哌酸(Perfloxacin);青霉素类(penicillins)如阿莫西林(Amoxicillin)、氨苄青霉素(Ampicillin)、巴氨西林(Bacampicillin)、卡茚西林(CarbenicillinIndanyl)、美洛西林(Mezlocillin)、哌拉西林(Piperacillin)和替卡西林(Ticarcillin);青霉素/β内酰胺酶抑制剂如阿莫西林克拉维酸(Amoxicillin-Clavulanic Acid)、氨苄西林/舒巴坦(Ampicillin-Sulbactam)、氨苄青霉(Benzylpenicillin)、邻氯青霉素(Cloxacillin)、双氯西林(Dicloxacillin)、甲氧苯青霉素(Methicillin)、苯甲异恶唑青霉素(Oxacillin)、青霉素G(苄星(Benzathine)、钾、普鲁卡因)、青霉素V、哌拉西林(Piperacillin)+他唑巴坦(Tazobactam)、替卡西林+克拉维酸和萘夫西林;碳青霉烯类(carbapenems)如亚胺培南西司他丁(Imipenem-Cilastatin)及美罗培南(Meropenem);单酰胺菌素(monobactam)如氨曲南(Aztreonam);大环内酯类(macrolides)和林可胺类(lincosamines)如阿奇霉素(Azithromycin)、克拉霉素(Clarithromycin)、克林霉素(Clindamycin)、地红霉素(Dirithromycin)、红霉素(Erythromycin)、林可霉素(Lincomycin)和醋竹桃霉素(Troleandomycin);糖肽类如替考拉宁(Teicoplanin)和万古霉素(Vancomycin);利福平类(rifampins)如利福布丁(Rifabutin)、利福平(Rifampin)和利福喷丁(Rifapentine);噁唑烷酮类(oxazolidonones)如利奈唑酮(Linezolid);四环素类(tetracyclines)如美环素(Demeclocycline)、强力霉素(Doxycycline)、甲烯土霉素(Methacycline)、二甲胺四环素(Minocycline)、土霉素(Oxytetracycline)、四环素和金霉素(Chlortetracycline);氨基糖苷类如丁胺卡那霉素(Amikacin)、庆大霉素(Gentamicin)、卡那霉素(Kanamycin)、新霉素(Neomycin)、奈替米星(Netilmicin)、链霉素(Streptomycin)、妥布霉素(Tobramycin)和巴龙(Paromomycin);链阳菌素类(streptogramin)如(Quinopristin)+达福普汀(Dalfopristin);磺胺类药如(Mafehide)、银磺胺嘧啶(SilverSulfadiazine)、磺胺醋酰(Sulfacetamide)、磺胺嘧啶(Sulfadiazine)、磺胺甲基异恶唑(Sulfamethoxazole)、柳氮磺胺吡啶(Sulfasalazine)、硫代异恶唑(Sulfisoxazole)、甲氧苄氨嘧啶(Trimethoprim)-磺胺甲基异恶唑(Sulfamethoxazole)和磺胺甲噻二唑(Sulfamethizole);以及其他抗生素如杆菌肽(Bacitracin)、氯霉素(Chloramphenicol)、肠粘菌素(Colistemetate)、磷霉素(Fosfomycin)、异烟肼(Isoniazid)、乌洛托品(Methenamine)、灭滴灵(Metronidazol)、莫匹罗星(Mupirocin)、呋喃妥因(Nitrofurantoin)、呋喃西林(Nitrofurazone)、新生霉素(Novobiocin)、多粘菌素B(PolymyxinB)、大观霉素(Spectinomycin)、甲氧苄氨嘧啶(Trimethoprim)、粘杆菌素(Colistin)、丝氨酸(Cycloserine)、卷曲霉素(Capreomycin)、吡嗪酰胺(Pyrazinamide)、对氨基水杨酸(Para-aminosalicyclic acid)和琥乙红霉素(Erythromycin ethylsuccinate)+磺胺异恶唑(sulfisoxazole)。
可在本发明的组合物和方法中用作第二种杀菌剂的杀真菌剂的实例包括但不限于:唑类(azoles)如氟康唑(fluconazoles)、伏立康唑(voriconazoles)、克霉唑(clotrimazoles)、伊曲康唑(itraconazoles)、酮康唑(ketoconazoles)、咪康唑(miconazoles)、ER 30346、SCH 56592;多烯类如两性霉素(amphotericin B)、制霉菌素(nystatins)或者其脂质体及其脂质形式如Abelcet、AmBisome和Amphocil;嘌呤或嘧啶核苷酸酶抑制剂如氟胞嘧啶(flucytosines);或多氧菌素(polyoxin)如尼柯霉素(nikkomycinss),特别是尼柯霉素Z或其他几丁质抑制剂、延伸因子抑制剂如粪壳菌素(sordarin)及其类似物、甘露聚糖酶抑制剂如predamycin、杀菌/通透性诱导(BPI)的蛋白质产品如XMP.97或XMP.127。
所述环状富组蛋白抑制剂和第二种杀菌剂在感染的治疗中可单独或结合给予哺乳动物。本文所用的术语“哺乳动物”包括人类和非人哺乳动物。
此外,所述富组蛋白的环状类似物可与第二种杀菌剂结合得到一种有效的杀菌组合物。所述组合物还可包括可药用的佐剂以有利于以上述选定的剂型给药。如本领域技术人员可理解的,富组蛋白环状类似物与第二种杀菌剂结合的量要随着所用的富组蛋白环状类似物以及所用的第二种杀菌剂而变动。通常,每种的量都是——通过合适的试验确定的——适于对哺乳动物给药而无毒性及其他不可接受的作用的量。因此,所述组合物中环状富组蛋白的剂量可为每公斤体重0.01ng到约10g,而第二种杀菌剂的剂量为由具体试剂确定的合适剂量。在一个优选实施方案中,富组蛋白环状类似物与另一种杀菌剂的结合得到一种这样的组合物,即所述组合物所产生的杀菌活性大于其预期的杀菌作用,即大于所述结合的预期的累加作用,因此是一种具有协同效应的组合物。因此,所述结合组合物中所述环状富组蛋白和第二种杀菌剂每种的剂量都有益地小于单独使用所述环状富组蛋白和第二种杀菌剂时的通常给药剂量。这对降低使用杀菌剂的全强度剂量时可能存在的毒性和其他不良作用都是特别理想的。
本发明的另一方面提供一种包括杀菌组合物的试剂盒,所述组合物包括与可药用的佐剂或载体结合的富组蛋白环状类似物,以及顺应性手段,例如其用于治疗人类中微生物感染的应用说明。所述说明还可包括建议使用剂量的指示。这种试剂盒也可包括任何有利于所述组合物的正确给药的其他顺应性手段。这些顺应性手段可包括补充说明、配药方法等。或者,还提供了一种包括其中含有所述杀菌组合物的包装的制品。在此情况下,所述包装的标签至少指明所述组合物适于治疗人类的微生物感染,并还可指明建议剂量和其他使用条件。依照本发明的前述方面,所述试剂盒和产用用品还可包括与所述富组蛋白环状类似物结合或单独存在的第二种杀菌组合物。
本发明的另一方面提供用作杀菌试剂的化合物的筛选方法,所述方法基于以下认定,即某些微生物蛋白是富组蛋白的环状类似物的靶标。这些蛋白包括微管相关蛋白(YTM1)、隔蛋白(CDC3)、纺锤体动态控制蛋白(SLK19)、G蛋白功能调控蛋白(CRP1)、HSP70家族成员(SSA2)、烯醇酶I(ENO1)、HSP成员(SSE1)、26S蛋白酶体亚基(RPT5)、HSP90、线粒体HSP蛋白(SSC1)、ATP酶复合物的β1亚基(ATP2)、线粒体乌头酸酶/水合酶(ACO1)和微粒体ATP酶(CDC48)、RAV1、HSP60、二氢硫辛酰胺脱氢酶(LPD1)、60S核糖体亚基蛋白L3(RPL3)和丝氨酰-tRNA合成酶(SES1)。这些蛋白中的某些在念珠菌基因组数据库(http://www.candidagenome.org)中的系统化名称如下:YTM1-orf19.4815、cdc3-orf19.1055、SLK19-orf19.6763、CRP1-orf19.4784、SSA2-orf19.1065、ENO1-orf19.395、SSE1-orf19.2435、SSC1-orf19.1896、ATP2-orf19.5653、ACO1-orf19.6385和CDC48-orf19.2340。
筛选候选杀菌剂的方法包括将所述候选化合物与一种或多种所述靶标蛋白直接或在整个细胞环境中一起孵育,并测定所述候选化合物是否以例如包括经由共价、静电、疏水、芳香、离子和极性缔合作用,通过氢的供给和接受力而与所述靶标蛋白缔合。候选化合物与靶标蛋白的缔合的确定指示所述候选化合物可具有杀菌活性,并成为进行进一步检测如微生物细胞抑制研究的候选化合物。或者,如本领域技术人员可理解的,可用合适的测定法确定所述候选化合物是否调节所述靶标蛋白的活性。所述候选化合物通过抑制或激活调节靶标蛋白的确定指示所述候选化合物可具有杀菌活性,并因此应当进行进一步研究。尽管适于筛选的候选杀菌剂可为任何选定化合物,然而富组蛋白环状类似物特别适于以上述方式进行筛选。
对前述富组蛋白环状类似物的靶标蛋白的识别也提供了另一种治疗哺乳动物中微生物感染的方法。所述方法包括给予与靶向于选自以下的蛋白的载体结合的杀菌剂:微管相关蛋白(YTM1)、隔蛋白(CDC3)、纺锤体动态控制蛋白(SLK19)、G蛋白功能调控蛋白(CRP1)、HSP70家族成员(SSA2)、烯醇酶I(ENO1)、HSP成员(SSE1)、26S蛋白酶体亚基(RPT5)、HSP90、线粒体HSP蛋白(SSC1)、ATP酶复合物的β1亚基(ATP2)、线粒体乌头酸酶/水合酶(ACO1)和微粒体ATP酶(CDC48)、RAV1、HSP60、二氢硫辛酰胺脱氢酶(LPD1)、ATP酶复合物的β1亚基(ATP2)、60S核糖体亚基蛋白L3(RPL3)和丝氨酰-tRNA合成酶(SES1)。尽管所述载体分子可为任何适于与一种或多种所述靶标蛋白缔合的分子,然而富组蛋白的环状类似物特别适于这一目的。
本领域的技术人员将认识到或者可通过使用不超过常规的实验确定本文所述的具体实施方案的许多等价方式。尽管已经讨论了本发明的具体实施方案,然而上面说明是为了阐释而非限制。本领域技术人员可在阅读本说明书的基础上清楚地理解本发明的许多变化方案。本发明的全部范围应依照本权利要求及其全部等价范围,以及本说明书与这些变化方案而确定。后面的权利要求意欲包括这些等价方式。
以下具体实施例是为了描述本发明的实施方案,而不应被认为是限制。
实施例
实施例1:DB2121抗真菌和细菌的活性。
在多种真菌和细菌生物体中测量了所述环状类似物DB2121抑制细胞生长的效果并将所述结果与若干已知的抗真菌化合物如酮康唑比较(表1)。DB2121在真菌或酵母菌株中的MIC比富组蛋白H5或以前开发的专利类似物P-113强至少100倍。发现DB2121抑制革兰氏阳性杆菌枯草芽孢杆菌(Bacillus subtilis)的能力比富组蛋白H5强约40倍。
表1
实施例2:与另一种杀菌剂结合的活性
在与上面的实施例1所述相似的细胞抑制研究中,DB2121在与其他杀菌剂(包括酮康唑、依曲康唑和氟康唑)结合使用时也显示可杀死白色念珠菌菌株。
通常,将白色念珠菌的对数生长培养物在含有20mM的Tris-Cl、pH7.2和20mM NaCl的溶液中洗涤2次,然后悬浮在此溶液中。然后将多种浓度的环状富组蛋白类似物和氟康唑、依曲康唑或酮康唑立即加入此培养物中并在37℃下剧烈振荡1小时。取等分试样以1∶100的稀释度加入在24孔盘中预热的YPD培养基中。将所述盘在37℃培养箱中孵育24小时以监测生长,并确定每种化合物单独作为对照和结合使用的最小抑制浓度。
表2指出在使用富组蛋白环状类似物和所述三种测试杀菌化合物之一的结合治疗中,富组蛋白环状类似物的浓度最多可降低12倍并且所需的另一杀菌化合物也较单独给药时为少。
表2
处理 | MIC(DB2121a)μM | MIC(唑b)μM |
DB2121 | 11 | N/A |
DB2121+氟康唑 | 0.375 | 8.15 |
DB2121+酮康唑 | 0.375 | 0.078 |
DB2121+伊曲康唑 | 0.375 | 0.059 |
氟康唑 | N/A | 97.8 |
酮康唑 | N/A | 0.94 |
伊曲康唑 | N/A | 0.71 |
a)指环状富组蛋白类似物
b)指氟康唑、酮康唑或伊曲康唑
对于这些具体结合,所述环状富组蛋白类似物和第二杀菌剂的合适的工作范围如下:
i)环状富组蛋白类似物的量等于或大于0.37μM,酮康唑的量等于或大于0.078μM
ii)环状富组蛋白类似物的量等于或大于0.37μM,氟康唑的量等于或大于8.15μM
iii)环状富组蛋白类似物的量等于或大于0.37μM,伊曲康唑的量等于或大于0.059μM
实施例3:微生物菌丝体生长的抑制
根据标准方法培养白色念珠菌(SC5314)真菌。进入对数期后,将所述真菌细胞重悬浮于10mM磷酸钠中并在A)50μM酮康唑、(B)载体、(C)50μM富组蛋白H5或(D)50μM DB2121的存在下在37℃下培育1小时。取所述混合物的等分试样加入含有10%FBS的YPD中并在37℃下培养。在多个时间点,用相差显微镜在40倍放大倍数下对所述细胞成像。所述实验进行至少三次。
当白色念珠菌用DB2121预先孵育过时,可观察到对菌丝体生长的明显抑制。此外,DB2121对抑制菌丝诱导之前和之后的菌丝体生长都有效(数据未显示)。连续稀释表明在DB2121的存在下菌丝体生长比对照和其他处理(如接触酮康唑或富组蛋白H5)降低约500-1000倍。
实施例4:用DB2121的抑制条件
根据标准方法培养白色念珠菌(SC5314)真菌。进入对数期后,将所述真菌细胞重悬浮于10mM磷酸钠中并检测DB2121肽在多种条件下抗白色念珠菌的效果。将DB2121加入所述真菌细胞中并在4℃或37℃下振荡孵育1.5小时。在一个独立实验中,在37℃下用5或50μM DB2121(f.c.)孵育白色念珠菌共1.5小时。在特定时间点,取样以检测细胞存活率。在相关组的实验中,将(1)载体或(2,3)丹磺酰化DB2121在上述指定条件下引入白色念珠菌中。接触后,用SYTOX Green试剂将所述真菌细胞反染色以监测细胞存活率。所述实验进行至少三次,结果相似。误差条代表标准差。
DB2121的活性被测定为温度依赖的,特别地在生理温度下活性更强(图2A),并且在某种浓度(例如50μM)下在少至5分钟的接触时间内迅速作用以杀死念珠菌(图2B)。
实施例5:DB2121的毒性
还在人类细胞中进行了DB2121的毒性研究。依照Min et al.2004.Nat Biotechnol 22:717-23中所述的方法,使用原代人类新生儿包皮上皮细胞检测DB2121的毒性,所述文献的内容以引用的方式纳入本文中。简言之,当所述细胞处于对数生长期时,将(A)50μM DB2121、B)50μM富组蛋白H5、(C)50μM酮康唑或(D)DMSO加入所述培养基中。在加入化合物18和36小时后,用相差显微镜在20倍的放大倍数下对所述包皮上皮细胞成像。(E)图像分析后,立即通过SDS-PAGE凝胶提取、分离蛋白,进行蛋白质印迹并检测磷酸化和非磷酸化的ERK 1、2以监测所述包皮角化细胞的增殖。所述实验重复三次。
前述处理之后,除用酮康唑处理以外,人类原代细胞显示形态学正常。酮康唑对哺乳动物细胞的毒性是已知的。
然后研究这些表型是否在上分子水平有所反映。将所述原代细胞裂解并监测一种称为磷酸化ERK1、2的增殖标记。与对照相比,在用酮康唑处理的细胞中可观察到ERK 1,2活化的明显抑制。相反,与对照相比,在用DB2121处理的细胞中活化的ERK 1,2未被抑制。
两种研究都表明DB2121在50μM的工作(例如杀菌)浓度下对人类原代细胞是无毒的。
为测定DB2121的无毒性浓度,将多种浓度的DB2121和作为对照的50μM的酮康唑或DMSO分别加入原代人类包皮上皮细胞培养物中。在加入0、36和72小时后,从培养皿中取出所述上皮细胞并测定存活细胞数。所述试验重复三次。在第72小时时,用相差显微镜在20倍放大倍数下对与各种化合物接触的包皮上皮细胞成像。为进行细胞计数,用台盼蓝拒染法将所述上皮细胞染色以监测细胞存活率。
这些结果显示DB2121在原代培养细胞中具有极低的毒性和比酮康唑良好的毒性特征(图3)。
此外,当通过腹膜内途径注射时,小鼠能够耐受15mg/kg的DB2121。当对成年大鼠进行静脉内注射时,最高达且包括1.5mg/kg的浓度是无害的。
实施例6:DB2121的体外靶标
通过使用荧光标记的DB2121共聚焦显微术测得DB2121确实进入白色念珠菌(SC5314)并且其特异地定位在所述生物体的线粒体中(通过对酵母特异的荧光探针测得)。
在一个为阐明DB2121的作用方式的研究中,用标准方法将白色念珠菌在液体培养基中培养至OD600值为约0.40-0.80。在此时收获细胞并收集全部细胞提取物。使等量的蛋白通过含有纯化的GST或GST-DB2121的谷胱甘肽-琼脂糖柱。充分洗涤该柱并用游离谷胱甘肽梯度洗脱所结合的蛋白。收集洗脱成分并通过12%SDS-PAGE凝胶分开这些级分中的蛋白。将所述凝胶染色。为识别目的蛋白,将所述蛋白提取、干燥并溶解于0.2%的甲酸中。然后在Micromass上用LC/MS/MS分析从每条蛋白带获得的肽。图4显示了在白色念珠菌中识别的蛋白的分类的饼状图。
在白色念珠菌(SC5314)中识别的DB2121蛋白靶标为:微管相关蛋白(YTM1)、隔蛋白(CDC3)、纺锤体动态控制蛋白(SLK19)、G蛋白功能调控蛋白(CRP1)、HSP70家族成员(SSA2)、烯醇酶I(ENO1)、HSP成员(SSE1)、26S蛋白酶体亚基(RPT5)、HSP90、线粒体HSP蛋白(SSC1)、ATP酶复合物的β1亚基(ATP2)、线粒体乌头酸酶/水合酶(ACO1)和微粒体ATP酶(CDC48)、RAV1、HSP60、二氢硫辛酰胺脱氢酶(LPD1)、60S核糖体亚基蛋白L3(RPL3)和丝氨酰-tRNA合成酶(SES1)。通常,上面所列的蛋白属于不同的功能组:与形态发生/细胞周期/细胞纺锤体/胞质分裂有关的蛋白、与线粒体有关的蛋白、与细胞应激和代谢有关的蛋白和与翻译调控有关的蛋白。这些数据与从共焦显微术获得的数据很好地吻合。
实施例7-DB2121的稳定性
质谱测定显示DB2121环状类似物可在人类唾液中可体外稳定至少72小时。将所述环状类似物在1μM浓度和37℃下在人类唾液中体外孵育。在从0到72小时的多个时间点,取1.0μl的等分试样直接注射到Micromass Quattro Micro质谱仪中。收集总计3分钟的数据。然后用Mass Lynx 4.0 Analysis软件处理所述数据。
以活性形式存在的环状类似物的预期平均质量为2557.93。显示环状富组蛋白类似物在人类唾液中可存在至少72小时的孵育。对应于环状富组蛋白类似物的在约1质量单位的可接受误差范围内的峰值为在0小时2556.95、在24小时2557.65和在72小时2557.10。
Claims (35)
1.一种治疗人类的微生物感染的方法,包括对所述人类给予治疗有效量的富组蛋白环状类似物。
2.权利要求1的方法,其中所述富组蛋白环状类似物是富组蛋白H5的环状类似物。
3.权利要求1的方法,其中所述环状类似物是用富组蛋白制备的,其中所述富组蛋白的至少一个氨基酸被选自谷氨酸、赖氨酸、半胱氨酸和其他含巯基氨基酸的氨基酸置换以使得所述富组蛋白环化。
4.权利要求2的方法,其中所述环状类似物的序列为RHHCYKRKFHEKHHCHRGY(SEQ ID NO.1)。
5.权利要求1的方法,其中所述微生物感染是细菌感染。
6.权利要求1的方法,其中所述微生物感染是真菌感染。
7.权利要求1的方法,还包括给予有效剂量的第二种杀菌剂。
8.权利要求7的方法,其中所述杀菌剂选自杀真菌剂和杀细菌剂。
9.权利要求7的方法,其中所述杀菌剂是一种唑类化合物。
10.权利要求9的方法,其中所述唑类化合物选自氟康唑、伏立康唑、克霉唑、伊曲康唑、酮康唑和咪康唑。
11.一种适于治疗由微生物感染引起的人类疾病的杀菌组合物,包括富组蛋白的环状类似物和至少一种可药用的载体。
12.权利要求11定义的组合物,其中所述感染选自细菌感染和真菌感染。
13.权利要求11定义的组合物,还包括第二种杀菌剂。
14.权利要求13的组合物,其中所述杀菌剂是一种唑类化合物。
15.根据权利要求14的方法,其中所述唑类化合物选自氟康唑、伏立康唑、克霉唑、伊曲康唑、酮康唑和咪康唑。
16.权利要求11定义的组合物,其中所述富组蛋白的环状类似物选自H1、H3和H5的环状类似物。
17.权利要求16定义的组合物,其中所述环状类似物是富组蛋白H5的环状类似物。
18.权利要求17定义的组合物,其中所述环状类似物的序列为RHHCYKRKFHEKHHCHRGY(SEQ ID NO.1)。
19.一种杀菌组合物,包括富组蛋白的环状类似物与第二种杀菌剂。
20.权利要求19定义的组合物,其中所述富组蛋白环状类似物选自H1、H3和H5的环状类似物。
21.权利要求20定义的组合物,其中所述环状类似物是富组蛋白H5的环状类似物。
22.权利要求21定义的组合物,其中所述环状类似物的序列为RHHCYKRKFHEKHHCHRGY(SEQ ID NO.1)。
23.权利要求16定义的组合物,其中所述杀菌剂是一种唑类化合物。
24.权利要求23定义的组合物,其中所述唑类化合物选自氟康唑、伏立康唑、克霉唑、伊曲康唑、酮康唑和咪康唑。
25.一种制品,包括其中装有一种包含富组蛋白的环状类似物的杀菌组合物的包装,所述包装的标签指明所述组合物适于治疗人类的微生物感染。
26.一种治疗哺乳动物的微生物感染的方法,包括对所述哺乳动物给予哺乳动物杀菌剂与靶向于微生物线粒体的载体分子。
27.权利要求26定义的方法,其中所述载体分子是富组蛋白的环状类似物。
28.权利要求27定义的方法,其中所述环状类似物是富组蛋白H1、H3和H5之一的环状类似物。
29.权利要求28定义的方法,其中所述环状类似物是H5的类似物。
30.权利要求29定义的方法,其中所述环状类似物的序列为RHHCYKRKFHEKHHCHRGY。
31.一种抑制哺乳动物中微生物菌丝体生长的方法,包括对所述哺乳动物给予富组蛋白的环状类似物。
32.一种治疗哺乳动物的微生物感染的方法,包括对所述哺乳动物给予靶向于选自下列的一种蛋白的富组蛋白的环状类似物:微管相关蛋白(YTM1)、隔蛋白(CDC3)、纺锤体动态控制蛋白(SLK19)、G蛋白功能调控蛋白(CRP1)、HSP70家族成员(SSA2)、烯醇酶I(ENO1)、HSP成员(SSE1)、26S蛋白酶体亚基(RPT5)、HSP90、线粒体HSP蛋白(SSC1)、ATP酶复合物的β1亚基(ATP2)、线粒体乌头酸酶/水合酶(ACO1)和微粒体ATP酶(CDC48)、RAV1、HSP60、二氢硫辛酰胺脱氢酶(LPD1)、60S核糖体亚基蛋白L3(RPL3)和丝氨酰-tRNA合成酶(SES1)。
33.一种筛选候选杀菌化合物的方法,包括以下步骤:
(a)使候选化合物接触至少一种靶标蛋白,所述靶标蛋白选自:微管相关蛋白(YTM1)、隔蛋白(CDC3)、纺锤体动态控制蛋白(SLK19)、G蛋白功能调控蛋白(CRP1)、HSP70家族成员(SSA2)、烯醇酶I(ENO1)、HSP成员(SSE1)、线粒体HSP蛋白(SSC1)、ATP酶复合物的β1亚基(ATP2)、线粒体乌头酸酶/水合酶(ACO1)和微粒体ATP酶(CDC48);和
(b)检测所述化合物是否与所述靶标蛋白缔合,其中检测到所述化合物和所述靶标蛋白之间的缔合指示所述化合物可具有杀菌活性。
34.权利要求33定义的方法,其中所述候选化合物是富组蛋白的环状类似物。
35.一种试剂盒,包括含富组蛋白的环状类似物的组合物和治疗人类感染的使用说明。
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CN102766197A (zh) * | 2011-05-06 | 2012-11-07 | 上海医药工业研究院 | 一组新型的hrp5类似物及其制备方法 |
CN108602852A (zh) * | 2015-11-30 | 2018-09-28 | 伊利诺伊大学理事会 | 组胺素及其使用方法 |
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ES2543254T3 (es) | 2008-01-07 | 2015-08-17 | Rapid Pathogen Screening, Inc. | Uso de péptidos para estimular la cicatrización de heridas |
US9115180B2 (en) * | 2008-01-07 | 2015-08-25 | Rapid Pathogen Screening, Inc. | Use of peptides for promoting wound healing |
US8980876B2 (en) | 2010-10-28 | 2015-03-17 | The Procter & Gamble Company | Inhibition of microbial growth by aconitase inhibition |
EP2637682A4 (en) * | 2010-11-10 | 2014-05-14 | Univ Western Ontario | METHOD AND COMPOSITIONS WITH CYCLIC ANALOGUE OF HISTATIN-5 FOR THE TREATMENT OF WOUNDS |
US20130310327A1 (en) * | 2012-05-18 | 2013-11-21 | Rapid Pathogen Screening, Inc. | Histatin for Corneal Wound Healing and Ocular Surface Disease |
US9556226B2 (en) | 2013-03-15 | 2017-01-31 | The Board Of Trustees Of The University Of Arkansas | Peptides with antifungal activity and methods of using the peptides |
US20220257593A1 (en) * | 2019-06-10 | 2022-08-18 | Visus Therapeutics, Inc. | Carabachol-bromonidine formulation to enhance anti-presbyopia effects |
CN113905715A (zh) | 2019-06-28 | 2022-01-07 | 宝洁公司 | 光增强处理方法 |
JP2023504074A (ja) | 2019-11-27 | 2023-02-01 | ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティ オブ イリノイ | ペンタペプチドおよびその使用方法 |
EP4153209A1 (en) | 2020-05-20 | 2023-03-29 | The Board of Trustees of the University of Illinois | Method for treating lysosomal storage diseases with histatin peptides |
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US6309669B1 (en) * | 1984-03-16 | 2001-10-30 | The United States Of America As Represented By The Secretary Of The Army | Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix |
US5486503A (en) * | 1991-11-01 | 1996-01-23 | The Trustees Of Boston University | Anti-fungal histatin-based peptides |
US5912230A (en) * | 1991-11-01 | 1999-06-15 | Periodontix, Inc. | Anti-fungal and anti-bacterial histatin-based peptides |
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US6528488B2 (en) * | 1999-01-08 | 2003-03-04 | Demegen, Inc. | Method for treating cystic fibrosis |
CA2285673C (en) * | 1999-10-21 | 2008-07-29 | Gilles Andre Lajoie | Cyclic analogs of histatins |
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CN102766197B (zh) * | 2011-05-06 | 2014-10-15 | 上海医药工业研究院 | 一组新型的hrp5类似物及其制备方法 |
CN108602852A (zh) * | 2015-11-30 | 2018-09-28 | 伊利诺伊大学理事会 | 组胺素及其使用方法 |
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