CN110621655B - Mitoriboscin:靶向癌细胞、细菌和致病性酵母的基于线粒体的治疗剂 - Google Patents
Mitoriboscin:靶向癌细胞、细菌和致病性酵母的基于线粒体的治疗剂 Download PDFInfo
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- CN110621655B CN110621655B CN201880031954.5A CN201880031954A CN110621655B CN 110621655 B CN110621655 B CN 110621655B CN 201880031954 A CN201880031954 A CN 201880031954A CN 110621655 B CN110621655 B CN 110621655B
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Abstract
本公开内容涉及线粒体功能的抑制剂。公开了筛选抑制线粒体的化合物的方法。还公开了使用称为mitoriboscin的线粒体抑制剂‑具有抗癌和抗生素性质的基于线粒体的治疗性化合物以预防或治疗癌症、细菌感染和致病性酵母的方法,以及使用线粒体抑制剂以提供抗衰老益处的方法。还公开了具体的mitoriboscin化合物和mitoriboscin的组。
Description
相关申请的交叉引用
本申请要求2017年3月15日递交的美国临时专利申请第62/471,688号的权益,其被通过引用全部并入本文。
领域
本公开内容涉及靶向线粒体核糖体的新型线粒体功能抑制剂(本文称其为“mitoriboscin”)、用于鉴定mitoriboscin的方法、使用所述抑制剂靶向癌症干细胞的方法、使用所述抑制剂靶向细菌和致病性酵母的方法、以及使用所述抑制剂提供抗衰老益处的方法,以及用于治疗癌症、细菌感染、酵母感染和衰老的药物组合物,其含有一种或更多种mitoriboscins作为活性成分。
背景
研究人员已努力开发新的抗癌治疗方法。常规癌症疗法(例如放射、烷化剂如环磷酰胺和抗代谢物如5-氟尿嘧啶)试图通过干扰参与细胞生长和DNA复制的细胞机制来选择性地检测并根除快速生长的癌细胞。其他癌症疗法已经使用选择性结合快速生长的癌细胞上的突变肿瘤抗原的免疫疗法(例如,单克隆抗体)。不幸的是,在这些疗法后,肿瘤经常在相同或不同部位复发,表明并非所有癌细胞都已被根除。复发可能是由于化疗剂量不足和/或出现对治疗有抗性的癌症克隆。因此,需要新的癌症治疗策略。同样,研究人员已努力开发新的抗生素治疗方法。由于微生物中随机突变的逐渐累积和抗生素的滥用,抗生素耐药性已经发展。在抗生素研究和开发方面贫乏的资金投入使情况恶化。因此,需要新的抗生素治疗策略。
突变分析的进展允许深入研究癌症发展期间发生的基因突变。尽管已经知晓基因组图谱(genomic landscape),但现代肿瘤学在鉴定跨多种癌症亚型的主要驱动突变方面存在困难。严酷的现实似乎是,每个患者的肿瘤是独特的,并且单个肿瘤可能包含多种不同的克隆细胞。那么,需要的是一种注重不同癌症类型之间的共性的新方法。靶向肿瘤和正常细胞之间的代谢差异有望作为一种新的癌症治疗策略。对来自人乳腺癌样品的转录特征分析数据的分析揭示了超过95个与线粒体生物发生和/或线粒体翻译相关的升高的mRNA转录物。Sotgia等,Cell Cycle,11(23):4390-4401(2012)。另外,95种上调的mRNA中的超过35种编码线粒体核糖体蛋白(MRP)。对人乳腺癌干细胞的蛋白质组学分析同样揭示了几种线粒体核糖体(mitoribosomal)蛋白以及与线粒体生物发生相关的其他蛋白的过表达。Lamb等,Oncotarget,5(22):11029-11037(2014)。使用某些抑菌抗生素或OXPHOS抑制剂的脱靶效应对线粒体生物发生的功能抑制提供了额外的证据,即功能性线粒体是癌症干细胞增殖所必需的。
本领域存在对新的抗癌策略、具有广谱抗生素活性的新化合物和减少衰老效应的化合物的需要。“线粒体进化的内共生理论”可以用作开发应对肿瘤复发和传染病的特征性耐药性的疗法的基础,并且此类疗法可能具有减缓衰老过程的额外益处。
概述
因此鉴于前述背景,本公开的目的是证明线粒体生物发生在许多癌症的繁殖和维持中起关键作用。本公开的目的还在于提出用于鉴定结合线粒体核糖体(大亚基或小亚基)并具有抗癌和抗生素特性的线粒体抑制剂的方法。本公开的目的还在于鉴定具有抗癌和抗生素特性的线粒体抑制剂及它们的组。本公开的目的还在于鉴定具有抗衰老特性的多个种类的线粒体抑制剂。本公开的目的还在于鉴定多个种类的起放射致敏剂和光敏剂作用的线粒体抑制剂。
本公开涉及具有抗癌和抗微生物活性、放射致敏和光敏作用以及抗衰老作用的线粒体抑制剂化合物。术语“mitoriboscin”广义上指具有抗癌和抗生素特性的靶向线粒体核糖体(mitoribosome)的治疗剂。这些化合物结合线粒体核糖体的大亚基或小亚基(或在某些情况下,结合两者)并抑制线粒体生物发生。本公开还涉及鉴定mitoriboscin的方法,制备此类mitoriboscin的方法,以及使用mitoriboscin用于治疗目的的方法。
本发明人分析了可以跨多种多样的癌症类型被靶向的癌症干细胞(CSC)的表型特性,并且鉴定了CSC为了CSC的克隆扩增和存活而对线粒体生物发生的严格依赖性。本发明人先前的工作证明,不同种类的FDA批准的抗生素,且特别是四环素例如强力霉素和红霉素,具有抑制线粒体生物发生的脱靶效应。因此,这些化合物能够具有根除CSC的功效。然而,这些常见的抗生素并未被设计成靶向线粒体核糖体,且因此具有有限的抗癌特性。在本策略中,本发明人已经鉴定了靶向线粒体核糖体(mitochondrial ribosome)或线粒体核糖体(mitoribosome)并抑制线粒体生物发生的化合物。因此,除了其他有利特性之外,这些靶向线粒体核糖体的化合物-mitoriboscin-具有极为强有力的抗癌特性。
鉴于线粒体生物发生在细胞增殖中的作用,根据本策略鉴定的线粒体抑制剂提供了全新的一类癌症疗法。mitoriboscin除了作为癌症疗法的潜在用途外,它们还用作有用的广谱抗生素。线粒体进化的内共生理论推论,线粒体细胞器由被吞食的好氧细菌在数百万年的共生和适应后进化而来。线粒体细胞器的进化史表明,靶向癌细胞中线粒体蛋白质翻译的化合物也具有抗微生物活性。实际上,如下文所讨论的,mitoriboscin已经展示了抗生素特性。
另外,关于线粒体蛋白质翻译的遗传抑制的研究已经显示出有益的“副作用”,例如衰老过程的减慢和模型生物体的寿命增加。这些结果表明线粒体抑制剂也可用于抗衰老疗法,这是正在进行的研究的主题。
新的线粒体抑制剂可以通过虚拟高通量计算机筛选的收敛方法,然后体外验证线粒体抑制来鉴定。通过将计算机药物设计与表型药物筛选相结合,可以快速开发新的线粒体抑制剂。
附图简要说明
图1图示了线粒体进化的内共生理论。
图2示出了概括根据本策略的实施方案的药物发现策略的示意图。
图3示出了10种候选mitoriboscin化合物对MCF7细胞中ATP消耗的影响。
图4A-4D图示了在表型药物筛选后鉴定的10种mitoriboscin化合物的化学结构。这些结构分为四组-mitoribocycline(图4A上的化合物a-c)、mitoribomycin(图4B上的化合物d-g)、mitoribosporin(图4C上的化合物h和i)和mitoribofloxin(图4D上的化合物j)。
图5示出了7种mitoriboscin化合物对MCF7细胞中微球体形成的影响。
图6A示出了三种mitoriboscin化合物对MCF7细胞的细胞成活力的影响。图6B示出了三种mitoriboscin化合物对hTERT-BJ1细胞的细胞成活力的影响。
图7A示出了化合物23/G4随时间变化对MCF7细胞中氧消耗速率(OCR)的影响。图7B示出了化合物23/G4随时间变化对MCF7细胞中细胞外酸化速率(ECAR)的影响。图7C示出了针对基础呼吸、质子漏、ATP相关的呼吸、最大呼吸和储备呼吸能力,化合物23/G4对OCR的影响。图7D示出了针对糖酵解、糖酵解储备和糖酵解储备能力,化合物23/G4对ECAR的影响。
图8A示出了化合物24/D4随时间变化对MCF7细胞中氧消耗速率(OCR)的影响。图8B示出了化合物24/D4随时间变化对MCF7细胞中细胞外酸化速率(ECAR)的影响。图8C示出了针对基础呼吸、质子漏、ATP相关的呼吸、最大呼吸和储备呼吸能力,化合物24/D4对OCR的影响。图8D示出了针对糖酵解、糖酵解储备和糖酵解储备能力,化合物24/D4对ECAR的影响。
图9A示出了化合物24/F9随时间变化对MCF7细胞中氧消耗速率(OCR)的影响。图9B显示化合物24/F9随时间变化对MCF7细胞中细胞外酸化速率(ECAR)的影响。图9C示出了针对基础呼吸、质子漏、ATP相关的呼吸、最大呼吸和储备呼吸能力,化合物24/F9对OCR的影响。图9D示出了针对糖酵解、糖酵解储备和糖酵解储备能力,化合物24/F9对ECAR的影响。
图10A示出了10种mitoriboscin化合物对MCF7细胞中的最大呼吸的影响。图10B示出了10种mitoriboscin化合物对MCF7细胞中的ATP产生的影响。
图11示出了3种mitoriboscin化合物在2种不同浓度的对MDA-MB-231细胞中的细胞迁移的影响。
图12图示了4个新的种类的线粒体抑制剂-mitoribocycline、mitoribomycin、mitoribosporin和mitoribofloxin。
描述
以下描述以足以实现本策略的实践的细节说明了本策略的实施方案。尽管参考这些具体实施方案描述了本策略,但是应该理解,本策略可以以不同的形式实施,并且该描述不应该被解释为将任何所附权利要求局限于本文阐述的特定实施方案。相反,这些实施方案被提供以使得本公开将是全面和完整的,并且将向本领域技术人员充分传达本策略的范围。
线粒体核糖体是未被开发的用于治疗许多疾病的途径,所述疾病范围从癌症到细菌和真菌感染到衰老。功能性线粒体是癌症干细胞繁殖所必需的。抑制癌细胞中的线粒体生物发生阻碍了这些细胞的繁殖。因此,线粒体抑制剂代表了一类新的抗癌疗法。这些化合物还可以抑制线粒体蛋白质翻译,且因此具有抗微生物活性。因此,线粒体抑制剂可以作为靶向细菌和致病性酵母的广谱抗生素起作用。研究还已表明,线粒体抑制剂具有抗衰老特性。本公开使用术语“mitoriboscin”来广泛地描述这些具有抗癌和抗生素特性的基于线粒体的治疗性化合物。较低剂量的Mitoriboscin可用于治疗性地靶向老化过程并延长寿命。
靶向线粒体核糖体的新型线粒体抑制剂-mitoriboscin-可以通过虚拟高通量筛选的收敛方法然后通过体内验证线粒体抑制来鉴定。图2是通过使用本文公开的计算机药物筛选和表型药物筛选鉴定线粒体抑制剂的方法的概览。可以在步骤S101中使用哺乳动物线粒体核糖体(线粒体核糖体(mitoribosome))的三维结构的全部或一部分通过虚拟高通量筛选(vHTS)(即,计算机药物筛选)鉴定结合线粒体核糖体的新化合物。筛选可以跨分子的文库进行。例如,在初步研究期间,本发明人筛选了45,000个小分子化合物的集合以获得预期结合大线粒体核糖体(39S)的已知大亚基的化合物,所述大线粒体核糖体(39S)是具有超过50个亚基的多亚基复合体。初始vHTS可以使用各种筛选程序,例如eHiTS筛选程序,以鉴定对哺乳动物的线粒体核糖体的大亚基或小亚基具有强结合亲和力的化合物的子集。例如,本发明人基于预测的对哺乳动物的线粒体核糖体的大亚基(39S)的结合亲和力,使用eHiTS鉴定来自初始文库的排名前5,000的化合物。eHiTS是这样的筛选方法,其系统地覆盖构象和位置搜索空间的避免严重的空间位阻的部分,以非常适合虚拟高通量筛选的速度产生高度精确的对接姿势。
应当理解,本领域技术人员可以选择或开发用于鉴定具有期望的结合亲和力的化合物的子集的方法。为了有效地执行对接,可以制备对应于整个蛋白质结构的一系列clip文件,并且每个化合物顺序地对接在这些clip文件的每一个处。可以使用AutoDock 4.2基于从eHiTS筛选预测的每种化合物的相同常规结合位点进行最佳(top)化合物的共识评分。可以使用多种方法进行对预测的结合亲和力和视觉检查的进一步分析,所述方法包括例如从头设计程序例如SPROUT。参见Law等,J Mol Struct.666:651-657(2003),其全部内容通过引用并入,以获得关于SPROUT的信息。取决于初始文库的大小和结果,可以选择许多化合物用于表型药物筛选。例如,本发明人选择了在这些分析步骤中表现良好的880种化合物用于在步骤S103处的表型药物筛选。
表型药物筛选S103可以通过在所选细胞系中测试所选化合物的线粒体抑制来完成。例如,可以使用ATP消耗测定。本发明人测试了所选择的880种化合物在MCF7人乳腺癌细胞中功能性诱导ATP消耗的能力。大约85%的细胞ATP在正常情况下由线粒体中的OXPHOS产生,因此ATP消耗是线粒体抑制的替代标志。应当理解,本领域技术人员可以使用抑制线粒体的其他替代物。然而,对于本发明人所采用的ATP消耗测定,在治疗前将MCF7细胞(6,000个细胞/孔)接种到黑色透明底的96孔板中并孵育过夜。将通过vHTS鉴定的880种化合物以50μM的浓度应用于铺板的MCF7细胞,并针对ATP消耗筛选。随后再筛选在较低浓度(25μM和10μM)显示ATP消耗效应的化合物,以鉴定最有效地诱导ATP消耗的前10种化合物。孵育72小时后测试化合物,并且一式两份地进行实验。治疗后,从孔中吸出培养基,并用补充有Ca2+和Mg2+的温磷酸盐缓冲盐水(PBS)洗涤平板。然后,将细胞与Hoechst 33342(Sigma)染色溶液(10μg/ml)一起孵育30分钟,并用PBS洗涤以估计细胞成活力。用读板器使用355/460nm的激发/发射波长读取荧光。然后,进行CellTiter-Glo发光测定(Promega)以测量用给定化合物处理的相同孔中的代谢活性(ATP含量)。测定根据制造商的方案进行。将荧光强度(Hoechst染色)和发光强度(ATP含量)相对于单独的媒介物处理的对照归一化,并且显示为对照的百分比以便比较。该ATP消耗研究的结果如图3中所示。图3示出了,所有10种测试化合物显著地消耗了活细胞中的ATP水平。应当理解,本领域技术人员可以选择使用相同或相似的ATP消耗测定,修改此类测定,或者可以用另一种方法学(例如,氧消耗测定)替代ATP消耗测定筛选所选化合物的线粒体抑制。
本策略包括确认细胞成活力的方法。本领域技术人员可以选择一种或更多种适合于特定实施方案的用于确认细胞成活力的方法。本发明人最初使用磺基罗丹明(SRB)测定,该测定基于细胞蛋白质含量的测量。在96孔板中处理72小时后,将细胞用10%三氯乙酸(TCA)在冷室中固定1小时,并在室温下干燥过夜。然后,将细胞与SRB一起孵育15分钟,用1%乙酸洗涤两次,并空气干燥至少1小时。最后,将蛋白质结合的染料溶解在10mM Tris,pH8.8的溶液中,并使用读板器在540nm读数。使用SRB测定,本发明人仅选择消耗ATP水平而没有明显的细胞毒性的化合物用于进一步分析。明显的细胞毒性定义为少于30%的细胞仍然在板上。当然,采用其他细胞成活力确认方法学的实施方案可以基于本领域已知的其他考虑因素来选择用于进一步分析的化合物。
本策略还包括在步骤S105处的功能验证方法,在该步骤期间可确认化合物作为线粒体抑制剂的功能。许多方法可用于功能验证,包括例如代谢通量分析、微球体测定、活力测定和抗生素(抗细菌和/或抗真菌)活性。例如,本发明人使用Seahorse ExtracellularFlux(XF96)分析仪(Seahorse Bioscience,MA,USA)确定了MCF7细胞的细胞外酸化速率(ECAR)和实时氧消耗速率(OCR)。MCF7细胞被维持在补充有10%FBS(胎牛血清)、2mMGlutaMAX和1%Pen-Strep的DMEM中。将每孔5,000个细胞接种到XF96孔细胞培养板中,并在37℃在5%CO2湿润气氛中孵育过夜。24小时后,用选择的化合物处理细胞,所述化合物显示ATP消耗,而在各种浓度(或单独的载体)没有明显的细胞毒性。处理72小时后,在预热的XF测定培养基中洗涤细胞(对于OCR测量,XF测定培养基补充有10mM葡萄糖、1mM丙酮酸盐、2mML-谷氨酰胺并调整至pH7.4)。将细胞在175μL/孔的XF测定培养基中于37℃在无CO2孵箱中维持1小时。在孵育期间,将在XF测定培养基中的25μL 80mM葡萄糖、9μM寡霉素,1M2-脱氧葡萄糖(对于ECAR测量)和25μL 10μM寡霉素、9μM FCCP、10μM鱼藤酮、10μM抗霉素A(对于OCR测量)加载到XFe-96传感器盒的注射口。在实验期间,该仪器在给定时间点将这些抑制剂注入孔中,同时连续测量ECAR/OCR。ECAR和OCR测量通过蛋白质含量标准化(使用磺基罗丹明B测定法)。使用单因素ANOVA和学生t检验计算,通过XFe-96软件分析数据集。所有实验一式三份进行,且结果证实了本文描述的mitoriboscin化合物的线粒体抑制作用。应当理解,用于功能验证的许多方法是已知的,并且本领域技术人员可以根据验证需要选择一种或更多种(例如,测量或粗略估计线粒体功能的其他测定)。
总之,本策略提供了使用计算机药物筛选和表型药物筛选鉴定可能的线粒体抑制剂和mitoriboscin的方法。可以测试使用该方法鉴定的新化合物的抗癌活性(例如,抑制微球体形成和细胞迁移的能力),并且可以在不同的细菌和/或酵母菌株上进一步测试以研究抗微生物活性。图2总结了根据本策略的实施方案的一般方法,但是应当理解,本领域技术人员可以在不脱离本策略的情况下偏离本文公开的具体实例。
本策略已经引导了多个类别的具有抗癌、抗微生物和抗衰老特性的线粒体抑制化合物-特别是mitoriboscin的鉴定。基于发明人的初步筛选和验证,图4中鉴定的化合物具有抗癌、抗微生物和抗衰老特性。因此,这些独特的mitoriboscin是临床试验的候选物。应该理解的是,图4中鉴定的mitoriboscin不是详尽的,而仅仅是使用本文阐述的新方法学迄今为止已经鉴定到的那些mitoriboscin。
已经鉴定了四组mitoriboscin,如图4A-4D和12中所示。图12所示的mitoriboscin的组:mitoribocycline、mitoribomycin、mitoribosporin和mitoribofloxin可被选择用作抗癌、抗生素和/或抗衰老治疗剂。本领域技术人员应理解,每种化合物对于特定疗法的治疗有效量取决于多种因素。在一些实施方案中,来自一个或更多个mitoriboscin组的化合物的组合可用作抗癌、抗生素和/或抗衰老治疗剂。
在一些实施例方案最后,mitoriboscin化合物包含以下通式或其盐:
其中每个R可以是相同或不同的且选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮、基于酮的衍生物、醛、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚、基于醚的衍生物、酯及基于酯的衍生物、胺、基于氨基的衍生物、酰胺、基于酰胺的衍生物、单环或多环芳烃、杂芳烃、基于芳烃的衍生物、基于杂芳烃的衍生物、酚、基于酚的衍生物、苯甲酸、基于苯甲酸的衍生物和一种或更多种线粒体靶向信号。为了澄清,线粒体靶向信号被定义为增加将所附接的分子靶向到线粒体的效率的任何化学物质或肽实体。将预期此修饰增加mitoriboscin的效力和有效性。因此,R可以是任何线粒体靶向信号(肽或化学物质),包括特别是,阳离子化合物,例如三苯基(TPP)、基于胍基的部分和/或胆碱酯。
在一些实施方案中,mitoriboscin化合物包含以下通式或其盐:
其中每个R可以是相同或不同的且选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮、基于酮的衍生物、醛、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚、基于醚的衍生物、酯及基于酯的衍生物、胺、基于氨基的衍生物、酰胺、基于酰胺的衍生物、单环或多环芳烃、杂芳烃、基于芳烃的衍生物、基于杂芳烃的衍生物、酚、基于酚的衍生物、苯甲酸、基于苯甲酸的衍生物和一种或更多种线粒体靶向信号。
在一些实施方案中,mitoriboscin化合物包含以下通式或其盐:
其中每个R选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮、基于酮的衍生物、醛、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚、基于醚的衍生物、酯及基于酯的衍生物、胺、基于氨基的衍生物、酰胺、基于酰胺的衍生物、单环或多环芳烃、杂芳烃、基于芳烃的衍生物、基于杂芳烃的衍生物、酚、基于酚的衍生物、苯甲酸、基于苯甲酸的衍生物和一种或更多种线粒体靶向信号。
在一些实施方案中,mitoriboscin化合物包含以下通式或其盐:
图4中所示的式的特定mitoriboscin被示为图12中鉴定的mitoriboscin的组的具体实例。应当理解,可针对治疗用途单独选择mitoriboscin,或者与多于一种特异性mitoriboscin组合,和/或与其他物质组合以增强其他治疗剂的功效。治疗剂可以以常见的药物组合物的形式使用,该药物组合物可以使用一种或更多种已知的方法制备。例如,药物组合物可以通过使用本领域已知的稀释剂或赋形剂例如,一种或多种填充剂、膨胀剂、粘合剂、润湿剂、崩解剂、表面活性剂、润滑剂等制备。可以根据治疗目的选择各种类型的施用单位形式。药物组合物的形式的实例包括但不限于,片剂、丸剂、粉末、液体、悬浮液、乳液、颗粒、胶囊、栓剂、注射制剂(溶液和悬浮液)、局部乳膏和本领域可能已知的其他形式。为了使片剂形式的药物组合物成形,可以使用任何已知的赋形剂,例如诸如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、环糊精、结晶纤维素、硅酸等的载体;诸如如水、乙醇、丙醇、单糖浆、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、虫胶(shelac)、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等的粘合剂。另外,可以使用崩解剂诸如干淀粉、海藻酸钠、琼脂粉、laminalia粉末、碳酸氢钠、碳酸钙、聚氧乙烯脱水山梨糖醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘油酯、淀粉、乳糖等。可以使用崩解抑制剂诸如白糖、硬脂精、椰子油、氢化油;吸收促进剂诸如季铵碱、十二烷基硫酸钠等。可以使用润湿剂诸如甘油、淀粉和本领域已知的其它润湿剂。可以使用吸附剂,例如诸如淀粉、乳糖、高岭土、膨润土、胶体硅酸等。可以使用润滑剂,诸如纯化的滑石、硬脂酸盐、硼酸粉末、聚乙二醇等。如果片剂是期望的,则它们可以用常用的包衣材料进一步包被以制成作为糖衣片剂、明胶膜包衣片剂的片剂、用肠溶包衣包被的片剂、用膜包被的片剂、双层片剂和多层片剂。适于局部施用的药物组合物可以配制成软膏、乳膏、悬浮液、洗剂、粉末、溶液、糊剂、凝胶、泡沫剂、喷雾剂、气溶胶或油。此类药物组合物可包括常规添加剂,包括但不限于防腐剂、辅助药物渗透的溶剂、共溶剂、润肤剂、推进剂、粘度调节剂(胶凝剂)、表面活性剂和载体。
本策略包括测试化合物、且特别是mitoriboscin针对抗癌特性的方法。如以上讨论的,vHTS和计算化学可用于鉴定候选线粒体抑制剂。可以测试那些候选物的特定抗癌特性。例如,本发明人平行比较了七种候选化合物的其抑制MCF7细胞中的微球体形成的能力。图5图示了所测试的七种化合物中的五种如何在5μM浓度显著抑制微球体形成。例如,23/G4(第1组)在该浓度使微球体形成减少50%。同样,24/F9(第2组)和第24/D4组(第3组)均使微球体形成减少了~90%。
基于该分析,本发明人评估了三种候选物对MCF7细胞单层和正常人成纤维细胞(hTERT-BJ1细胞)中总成活力的功能影响(图6)。23/G4(第1组)在5μM的浓度将MCF7细胞的成活力减少了70%。然而,23/G4当在相同浓度下测试时对hTERT-BJ1细胞的成活力没有影响。因此,鉴定优先靶向CSC和“成团”癌细胞、而不是正常成纤维细胞的化合物,例如23/G4是可能的。本领域技术人员可以使用相同的方法或本领域已知的其他方法确定候选mitoriboscin的优先靶向。
本策略包括mitoriboscin化合物的功能验证方法。例如,本发明人使用Seahorse分析仪评估了三种候选物的功能验证,Seahorse分析仪定量测量氧消耗速率(OCR)和细胞外酸化速率(ECAR)。OCR是OXPHOS的替代标志物而ECAR是糖酵解和L-乳酸产生的替代标志物。
本发明人的结果证明,23/G4(组1)、24/F9(组2)和24/D4(组3)均剂量依赖性地抑制MCF7细胞中的线粒体氧消耗,其中23/G4最有效(图7、8和9)。23/G4在仅为500nM的浓度使ATP水平降低>50%。此外,23/G4在2.5μM将ATP水平降低~75%(图7)。值得注意的是,在相同浓度下用23/G4处理对MCF7单层的整体细胞成活力具有极小的影响或几乎没有影响(图6)。因此,23/G4非常有效地消耗了ATP水平,而没有显示出明显的细胞毒性。
该数据证明,23/G4诱导糖酵解速率增加超过1.5倍,而24/F9和24/D4均抑制糖酵解。这可以解释为什么24/F9和24/D4在微球体测定中比23/G4更有效,其中24/F9和24/D4均在5μM浓度将微球体形成减少~90%(图5)。前10个命中物对于其降低i)最大呼吸和ii)ATP产生的能力的效力排序如图10中所示。注意,在这方面最靠前的6种化合物是23/G4、25/B3、24/H9、24/F9、23/E9和24/H6,23/G4是最有效的,在5μM产生大于75%的ATP水平降低。
由于EMT和细胞侵袭是与“干细胞性(stemness)”和远处转移相关的表型特征,因此评估了这些化合物对另一种更具侵袭性的乳腺癌细胞系MDA-MB-231进行细胞迁移的能力的影响。图11示出了23/G4、24/D4和24/F9在2.5μM的浓度对细胞迁移的抑制均超过70%。
本策略允许通过考虑化合物对微球体形成和细胞迁移的影响来测试化合物的抗癌特性。使用本文公开的方法,23/G4(第1组)似乎是有希望的新的先导化合物,因为它在靶向CSC和癌细胞方面更具选择性,同时保留正常细胞(图6)。23/G4是最有效的命中化合物,其有效地降低线粒体ATP水平并诱导糖酵解。应当理解,本领域技术人员可以使用本领域已知的其他方法以评估候选线粒体抑制剂对特定细胞系的作用,而不背离本策略。还应当理解,本领域技术人员可以评估候选线粒体抑制剂对其他癌症类型的影响,因为这些抑制剂靶向癌症干细胞(CSC)。CSC跨大多数癌症类型显示保守性特征。作为脱靶效应与线粒体核糖体结合的抗生素如多西环素和红霉素在代表8种不同的癌症类型的12种不同的细胞系中显示出功效。这些包括:导管原位癌(DCIS)、乳腺癌、卵巢癌、胰腺癌、肺癌以及黑素瘤和胶质母细胞瘤。
图1描绘了需氧细菌经过数百万年的共生和适应向线粒体细胞器的演变。鉴于这种进化历史,靶向癌细胞中线粒体蛋白质翻译的化合物也可能具有抗微生物活性。本策略提供了测试化合物的抗微生物活性的方法,以及具有抗微生物活性的新化合物。为了证明线粒体抑制剂作为广谱抗生素起作用,本发明人测试了前三种化合物(24/F9、24/D4和23/G4)对两种革兰氏阳性细菌菌株(金黄色葡萄球菌(Staph.aureus)和化脓性链球菌(Strep.pyogenes))、三种革兰氏阴性细菌菌株(大肠杆菌(E.coli)、铜绿假单胞菌(P.aeruginosa)、肺炎克雷伯菌(K.pneumoniae))和致病酵母菌株白色念珠菌(C.albicans)的抗微生物活性。
可以使用根据临床和实验室标准研究所(CLSI)的指南进行的Kirby-Bauer纸片扩散法评估候选线粒体抑制剂的抗微生物作用,并使用CLSI断点解释结果。抗革兰氏(+ve)细菌和革兰氏(-ve)细菌(来自OxoidTM)的抗生素纸片可用作阳性对照。本发明人基于以下方法学评估了本文所述的某些mitoriboscin的抗生素作用。本文鉴定的化合物24/D4、24/F9和23/G4通过将它们溶解在二甲基亚砜(DMSO,来自Sigma/Aldrich Company;St.Louis,MO,USA)中制备,并用于浸渍空白抗微生物易感性纸片(OxoidTM)。将测试的细菌的过夜培养物调节至0.5McFarland标准品(106CFU/ml)的浊度,然后用无菌棉签接种到琼脂平板上。将在细胞培养物中浸过的棉签以在整个表面上获得均匀的细菌层的方式划线到琼脂平板表面上。10-15分钟后,将抗生素纸片或新型化合物纸片放置在琼脂平板的接种过的表面上;然后,将所有琼脂平板在37℃孵育过夜。测量抑制直径并将易感性以抗性(R)、中度易感性(I)和易感性(S)的术语表示。用浸渍DMSO的纸片测试的细菌接种的琼脂平板用作对照。通过Sensi测试-革兰氏阳性和Sensi测试-革兰氏阴性试剂盒(Liofilchem S.R.L.)确定关于单个细菌菌株获得的结果。纸片扩散敏感性试验一式三份地进行,并独立地重复三次。
可以使用肉汤稀释法根据CLSI指南测定抗菌化合物的最小抑制浓度(MIC)。用MHB培养基连续稀释测试化合物溶液(或用作阳性对照的抗生素溶液)。然后,将浓度为106CFU/ml的从细菌在MHB培养基中的过夜培养物制备的微生物悬浮液以1:1的比例加入到每个稀释液中。McFarland标准品用作调节微生物悬浮液的浊度的参考。在37℃孵育24小时后通过比浊法(波长600nm)测定微生物的生长(或缺乏)。MIC 50和MIC 99被定义为抑制细菌生长50%和99%所需化合物的最小抑制浓度。阴性对照管不含细菌接种物,而阳性对照管仅含有DMSO。通过测量MIC的易感性试验一式三份地进行并独立地重复三次。使用学生t-检验确定统计学显著性,并且将小于0.05的值认为是显著的。
表1.革兰氏阳性细菌的抗生物敏感性
表1总结了mitoriboscin化合物24/F9、24D4和23/G4跨两种革兰氏阳性细菌菌株(金黄色葡萄球菌和化脓性链球菌)与已知抗生素相比的革兰氏阳性抗菌活性。列标记S标识敏感、I标识中度、R标识抗性。表1和表2说明了所测试的所有五种细菌菌株如何对mitoriboscin化合物(24/F9、24/D4和23/G4)敏感。在对照(DMSO)中未观察到生长抑制。
表2.革兰氏阴性细菌的抗生素敏感性
表2总结了mitoriboscin化合物24/F9、24/D4和23/G4跨三种不同革兰氏阴性细菌菌株(大肠杆菌、铜绿假单胞菌、肺炎克雷伯菌)与已知抗生素相比的抗菌活性。列标记S标识敏感,I标识中度,R标识抗性。
为了确定24/F9、24/D4和23/G4的最小抑制浓度(MIC),可以进行肉汤稀释方法。使用该方法,MIC测定结果证明与纸片扩散易感性测试一致。
表3.最小抑制浓度(MIC):细菌菌株和致病性酵母
表3示出了所获得的针对所测试的细菌菌株和白色念珠菌与已知抗生素相比的MIC测定结果。与化合物24/F9和24/D4相比,化合物23/G4表现出最广谱的活性和效力。
表4.最小抑制浓度(MIC):MRSA与MSSA
表4示出了,耐甲氧西林金黄色葡萄球菌(MRSA)也对23/G4和24/D4敏感。已确认,该MRSA菌株确实抗阿莫西林。该结果表明,使用这种新的药物发现策略,采用人类癌细胞来分离可以靶向耐药细菌(例如MRSA)的新抗生素是可能的。
该数据表明,通过本策略鉴定的mitoriboscin具有抗癌、抗细菌特性,并且适用于药物组合物。
本发明人已经表明,在癌细胞中诱导急性ATP消耗的化合物可使这些细胞对辐射、紫外线、化学治疗剂、天然物质和/或热量限制敏感。如本文所讨论的Mitoriboscin已经展示了ATP消耗效应。基于这些初步结果,mitoriboscin也可用作放射致敏剂和/或光敏剂。作为放射致敏剂和/或光敏剂的用途可以与其他治疗载体(包括但不限于本领域已知的其他癌症治疗方法)组合以及与如本文公开的通过抑制线粒体生物发生的癌症治疗组合。类似地,mitoriboscin可用于功能性地使大量癌细胞和癌症干细胞对化学治疗剂、药物和/或其他天然物质(例如膳食补充剂和热量限制)敏感。
除了抗癌和抗生素表现之外,可通过本策略鉴定的线粒体抑制剂具有减缓哺乳动物衰老过程的潜力。已显示对线粒体蛋白质翻译的基因抑制具有有益的副作用,且特别是减缓衰老过程和增加模式生物体寿命的副作用。较低稳态水平的Mrps5(mitoribosomal蛋白)与较长的小鼠寿命呈强烈地功能相关,导致~250天的显著增加。此外,在秀丽隐杆线虫(C.elegans)中选择性敲减Mrps5可极大地增加寿命。Mrps5敲低蠕虫显示线粒体呼吸和ATP产生的显著减少。类似地,线粒体复合物I、III、IV和V的蠕虫同源物以及几种TCA循环酶的敲减都强劲地延长了寿命,进一步暗示降低的OXPHOS活性和较低的ATP水平为其机制。最后,线粒体生物发生的药理学抑制(使用多西环素的脱靶效应)也显著增加秀丽隐杆线虫的寿命。因此,较低剂量的mitoriboscin可用于治疗性地靶向老化过程并延长寿命。
Mitoriboscin也可用于逆转癌细胞中的药物抗性。药物抗性被认为至少部分地基于癌细胞中线粒体功能的增加。特别地,预期对内分泌疗法(例如他莫昔芬)具有抗性的癌细胞具有增加的线粒体功能。Mitoriboscin抑制线粒体功能,且因此可用于减少并在某些情况下逆转癌细胞中的抗药性。
Mitoriboscin也可用作男性避孕药和/或作为精子静止剂或精子固定剂。人类精子细胞由头部和鞭毛组成。鞭毛包括颈部、中段和尾部。中段通常具有围绕细胞质中的轴丝的10-14个线粒体螺旋。这些线粒体为精子提供动力,且因此通常被称为“精子的动力室”。Mitoriboscin抑制线粒体功能,且因此可用于固定精子细胞以防止受孕。
用于描述本文的发明的术语仅用于描述特定实施方案的目的,而不意图限制本发明。如在本发明的描述和所附权利要求中所使用的,单数形式“一(a)”,“一(an)”和“该/所述(the)”旨在也包括复数形式,除非上下文另有明确说明。通过考虑以下详细描述,明显的是,本发明包括各种替代、修改和等同物。
应当理解,尽管术语“第一”、“第二”、“第三”、“a)”、“b)”和“c)”等可以在本文中用于描述本发明的各个要素,本发明不应受这些术语的限制。这些术语仅用于将本发明的一个要素与另一个要素区分开。因此,在不脱离本发明的教导的情况下,所讨论的第一要素可以被称为一个要素方面,并且类似地,第三要素也可以被称为一个要素方面。因此,术语“第一”、“第二”、“第三”、“a)”、“b)”和“c)”等不旨在必然将一顺序或其他等级传达给相关的要素,而是仅用于识别目的。操作(或步骤)的顺序不局限于权利要求中展示的顺序。
除非另外定义,否则本文使用的所有术语(包括技术和科学术语)具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。将进一步理解的是,术语(诸如在常用词典中定义的那些术语)应当被解释为具有与其在本申请的上下文和相关领域中的含义一致的含义,并且不应该以理想化的含义或过于形式化的含义理解,除非本文明确地如此定义。本文中对本发明的描述中使用的术语仅用于描述特定实施方案的目的,而不意图限制本发明。本文提及的所有出版物、专利申请、专利和其他参考文献都通过引用以其整体并入。在术语冲突的情况下,以本说明书为准。
又如本文所用,“和/或”指并涵盖一个或多个相关所列项目的任何和所有可能组合,以及当在可替代方案(“或”)中解释时缺乏组合。
除非上下文另有说明,否则特别意图的是,本文描述的本发明的各种特征可以以任何组合使用。此外,本发明还在本发明的一些实施方案中设想了,可排除或省略本文列出的任何特征或特征组合。为了说明,如果说明书指出复合物包含组分A、B和C,则特别意图的是可以省略和放弃A、B或C中的任何一个或其组合。
如本文所使用的,过渡措词(transitional phrase)“基本上由......组成”(及其语法变体)被解释为包含所述及的材料或步骤以及那些不会实质上影响所请求保护的发明的基本和新颖特征的那些材料或步骤。因此,如本文所用的术语“基本上由......组成”不应解释为等同于“包含”。
当提及可测量值(例如,量或浓度等)时,本文所用的术语“约”意指包括所指定量的±20%、±10%、±5%、±1%、±0.5%、甚至±0.1%的变化。本文提供的可测量值的范围可包括其中的任何其他范围和/或单个值。
已经如此描述了本发明的某些实施方案,应该理解受由所附权利要求定义的本发明不受以上描述中列出的特定细节的限制,因为在不偏离所请求保护的精神或范围的情况下,其许多明显变化是可能的。
Claims (26)
14.一种使用虚拟高通量筛选和表型药物筛选鉴定mitoriboscin的方法,所述mitoriboscin包括具有以下通式的mitoribocycline:
或其药学上可接受的盐,其中每个R可以是相同或不同的并且选自由以下组成的组:碳、氮、硫、氧、溴、碘、羧基、环烷烃、基于烷烃的衍生物、烯烃、环烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮、基于酮的衍生物、醛、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚、基于醚的衍生物、酯及基于酯的衍生物、胺、基于氨基的衍生物、酰胺、基于酰胺的衍生物、单环或多环芳烃、杂芳烃、基于芳烃的衍生物、基于杂芳烃的衍生物、酚、基于酚的衍生物、苯甲酸、基于苯甲酸的衍生物和一种或更多种线粒体靶向信号,所述方法包括:
使用虚拟高通量筛选鉴定靶向线粒体核糖体的化合物;
合成所鉴定的化合物;
测试所合成的化合物的线粒体抑制活性;和
确认所合成的化合物是mitoriboscin。
15.权利要求14所述的方法,其中所述mitoriboscin结合所述线粒体核糖体的大亚基。
16.权利要求14所述的方法,其中所述mitoriboscin结合线粒体核糖体的小亚基。
17.权利要求14所述的方法,其中所述表型药物筛选是体外药物筛选。
18.权利要求14所述的方法,其中所述表型药物筛选包括ATP消耗测定。
19.权利要求14所述的方法,其中所述表型药物筛选包括细胞外酸化速率测定。
20.权利要求14所述的方法,其中所述表型药物筛选包括氧消耗速率测定。
21.权利要求14所述的方法,还包括测试mitoriboscin的抗癌活性的步骤。
22.权利要求21所述的方法,其中所测试的抗癌活性是微球体形成。
23.权利要求21所述的方法,其中所测试的抗癌活性是细胞迁移。
24.权利要求21所述的方法,还包括测试mitoriboscin的抗微生物活性的步骤。
25.权利要求24所述的方法,其中使用Kirby-Bauer纸片扩散法测试抗微生物活性。
26.权利要求24所述的方法,其中抗微生物活性使用最小抑制浓度测定测试。
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