CN105168225A - 通过乌头酸酶抑制来抑制微生物生长 - Google Patents

通过乌头酸酶抑制来抑制微生物生长 Download PDF

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CN105168225A
CN105168225A CN201510541075.5A CN201510541075A CN105168225A CN 105168225 A CN105168225 A CN 105168225A CN 201510541075 A CN201510541075 A CN 201510541075A CN 105168225 A CN105168225 A CN 105168225A
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aconitase
activity
cell
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J·R·施瓦茨
C·W·桑德斯
R·S·扬奎斯特
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Procter and Gamble Ltd
Procter and Gamble Co
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Abstract

本发明涉及在个体中抑制真菌细胞的乌头酸酶活性的方法，所述方法包括向所述真菌细胞施用对于抑制所述真菌细胞的乌头酸酶活性有效量的乌头酸酶活性抑制剂。

Description

通过乌头酸酶抑制来抑制微生物生长
本发明专利申请是国际申请号为PCT/US2011/058269，国际申请日为2011年10月28日，进入中国国家阶段的申请号为201180050003.0的发明专利申请的分案申请。
技术领域
本发明涉及在个体中抑制真菌细胞的乌头酸酶活性的方法，所述方法包括向所述真菌细胞施用对于抑制所述真菌细胞的乌头酸酶活性有效量的乌头酸酶活性抑制剂。
背景技术
不受理论的约束，含吡啶硫酮的抗真菌药物的抗真菌作用机制据认为涉及对乌头酸酶和其它线粒体铁-硫蛋白的抑制。抑制的机制据认为涉及吡啶硫酮铜在细胞内的形成，其通过与外源或内源铜的结合以及根据欧文-威廉斯序列(Irving-Williamsseries)进行转移螯合(transchelation)而进行。吡啶硫酮铜可随后穿透线粒体膜并且与铁-硫蛋白(诸如乌头酸酶)相互作用，从而引起铁-硫活性位点的变化和所导致的活性抑制。
在本发明中，ZPT敏感性据发现在CUP2删除菌株中增强，所述菌株在针对高铜水平的保护中是有缺陷的。通过这一和其它观察结果，据认为铜增强了ZPT诱导的生长抑制效应，但是机制未知。
通过本发明(包括酵母(Saccharomyces)删除文库菌株的ZPT敏感性结果)，线粒体铁-硫蛋白的成熟化据发现是ZPT的关键靶点。这由本发明的展示证实，在基本培养基中，ZPT通过抑制谷氨酸和赖氨酸合成来抑制生长，所述合成需要线粒体铁-硫蛋白乌头酸酶的活性。此外，在ZPT的存在下培养细胞已导致乌头酸酶抑制。本发明已将对ZPT作用机制的认识延伸至对关键靶酶的鉴定。
发明内容
在个体中抑制真菌细胞的乌头酸酶活性的方法，所述方法包括向所述真菌细胞施用对于抑制所述真菌细胞的乌头酸酶活性有效量的乌头酸酶抑制剂。
具体实施方式
虽然在说明书之后提供了特别指出和清楚地要求保护本发明的权利要求书，但是据信，通过下面的描述可以更好地理解本发明。
本发明可包括、由或基本上由本文所述发明的基本元素和限制，以及本文所述的任何附加的或任选的成分、组分或限制组成。
除非另外指明，所有的百分比、份数和比率均基于本发明组合物的总重量。所有涉及所列成分的这些重量均基于活性物质的含量，因此不包括可能包含在可商购获得的物质中的载体或副产物。
本发明的各种实施例的组分和/或步骤包括可任选加入的那些，其将在下面详细描述。
所有引用文献的相关部分均引入本文以供参考；任何文献的引用均不可解释为是对其作为本发明的现有技术的认可。
除非另外特别说明，所有比率都是重量比。
除非另外特别说明，所有温度均以摄氏度为单位。
除非另外说明，所有包括数量、百分比、分数和比例的量均被理解为由词“约”所修饰，并且量并不旨在指示有效数字。
除非另外说明，“一个”和“所述”是指“一个或多个”。
本文中，“包括”是指可加入不影响最终结果的其它步骤和其它成分。该术语包括术语“由…组成”和“基本上由…组成”。本发明的组合物和方法/过程可包括、由和基本上由本文所述发明的基本元素和限制，以及本文所述的任何附加或任选成分、组分、步骤或限制组成。
本文中，“有效”是指主题活性物质的量足够高以能够向待治疗的病症提供显著积极的改善。主题活性物质的有效量将随待治疗的具体病症、病症的严重程度、治疗的持续时间、同期联合治疗的特性等因素而变化。
本文中，“乌头酸酶抑制”是指可从裂解细胞中取得的乌头酸酶活性的降低。此类乌头酸酶抑制可包括对该酶的直接抑制或防止活性乌头酸酶的合成。活性乌头酸酶的合成可由于乌头酸酶蛋白合成的缺失、乌头酸酶蛋白适当折叠的缺失、功能性铁-硫簇并入乌头酸酶中的缺失、或乌头酸酶中存在受损的铁-硫簇。
本文中，“个人护理组合物”是指用于处理毛发(人、犬和/或猫)的产品和/或与处理毛发相关的方法，所述处理包括漂白、着色、染色、调理、生长、去除、延迟生长、洗发剂洗发、定型；除臭剂和止汗剂；个人清洁；有色化妆品；与处理皮肤(人、犬和/或猫)相关的产品和/或方法，所述处理包括施用乳霜、洗剂、以及消费者使用的其它局部施用的产品；以及与增强毛发、皮肤、和/或指/趾甲(人、犬和/或猫)的外观的口服物质相关的产品和/或方法；以及剃刮。
A.吡啶硫酮或吡啶硫酮的多价金属盐
在一个实施例中，本发明可包含吡啶硫酮或吡啶硫酮的多价金属盐。可使用任何形式的吡啶硫酮多价金属盐，包括板状和针状结构。在另一个实施例中，用于本文的盐包括由多价金属镁、钡、铋、锶、铜、锌、镉、锆、以及它们的混合物的那些，并且在另一个实施例中为锌。在另一个实施例中，用于本文的是1-羟基-2-吡啶硫酮的锌盐(称为“吡啶硫酮锌”或“ZPT”)；在另一个实施例中，ZPT为板状颗粒形式，其中所述颗粒具有至多约20mm的平均尺寸，并且在一个实施例中具有至多约5mm的平均尺寸，并且在另一个实施例中具有至多约2.5mm的平均尺寸。
吡啶硫酮抗微生物和去头屑剂描述于例如美国专利2,809,971；美国专利3,236,733；美国专利3,753,196；美国专利3,761,418；美国专利4,345,080；美国专利4,323,683；美国专利4,379,753；和美国专利4,470,982中。
还设想，当将ZPT用作本文抗微生物组合物中的抗微生物颗粒时，可刺激或调节、或同时刺激和调节毛发生长或再生的附加有益效果，或者可降低或抑制毛发损失，或者毛发可显得更浓密或更丰盈。
如美国专利2,809,971中所举例说明，通过使1-羟基-2-吡啶硫酮(即吡啶硫酮酸)或其可溶性盐与锌盐(如硫酸锌)反应以形成吡啶硫酮锌沉淀，可制得吡啶硫酮锌。
本发明的一个实施例包括约0.01％至约5％的吡啶硫酮或吡啶硫酮的多价金属盐；并且在另一个实施例中为约0.1％至约2％。
方法
在30℃下将啤酒糖酵母(Saccharomycescerevisiae)菌株BY4741的培养物在YPD(每升20克葡萄糖、20克蛋白胨、10克酵母提取物)液体培养基中生长过夜。用YPD将该培养物稀释至100mL的总体积以及0.1的光密度(600nm)。震荡孵育所述培养物直至达到0.2的光密度，此时加入测试物质。将所述培养物孵育过夜并通过离心来沉淀细胞。用100mMNaCl、20mMTrispH7.4洗涤该细胞沉淀物并将其重悬浮于5mL的100mMNaCl、20mMTrispH7.4中。加入玻璃珠粒(0.5mm)。作为另外一种选择，将所述样品涡旋一分钟并且在冰上孵育一分钟，并且总计处理十次。离心之后，收集上清液。在96孔平板中(UV通透型Corning3679平板)，将30μl细胞裂解物与20μl的100mMNaCl、20mMTrispH7.4混合并且根据说明书使用BioxytechAconitase-340试剂盒(OxisResearch)测定。
对于该乌头酸酶测定法，在37℃下将样品孵育六分钟。从启动该反应一分钟后开始，根据以五分钟为间隔的光密度(340nm)的提高来计算反应速率。将经处理样品的裂解物中的乌头酸酶活性除以未经处理样品的裂解物中的乌头酸酶活性。如果对样品进行重复实验，则报告的数据是经处理细胞各裂解物的乌头酸酶活性测量值的平均值除以未经处理细胞各裂解物的乌头酸酶活性测量值的平均值。如果所述乌头酸酶活性在经处理细胞的裂解物中表现为负值，则对乌头酸酶活性报告为数值“0”(表1)。
表1：
(1)来自ArchChemicals,Inc。
理想的物质在指定的条件下抑制乌头酸酶活性的70％或更高(意味着在表1中剩余活性为30％或更低)。根据显示，吡啶硫酮锌和吡啶硫酮铜均具有预期的抑制，如本发明的作用机制所预期。表1中所例示的其它物质对金属离子也具有亲和性，可能以类似于吡啶硫酮的方式影响铁-硫蛋白的活性位点。与之对比，某些传统的螯合剂(诸如EDTA)是无效的，估计是由于较差的细胞膜渗透。
乌头酸酶抑制此前并未考虑作为真菌控制的靶点。因此，尽管并非旨在进行限制，诸如以下列表的乌头酸酶抑制剂被包括作为抗真菌剂；
氟代柠檬酸–来自氟乙酸
硝化异柠檬酸
4-羟基-反式-乌头酸
草酰苹果酸(OMA，α-羟基-β-草酰琥珀酸)
ROS物质或氧化性物质
过氧亚硝酸盐
一氧化氮
过氧化氢
过氧化物
来自同一文章(onepaper)的有机分子
1,2,3-D,L-三羧基环戊烯-1
均苯三甲酸(1,3,5-三羧基苯)
偏苯三酸(1,2,4-三羧基苯)
均苯四甲酸(1,2,4,5-四羧基苯)
1,2,3,4-四羧基环戊烷
克氏循环(KrebCycle)物质
草酰琥珀酸盐
反式乌头酸
顺式乌头酸
α-酮戊二酸
2-酮戊二酸
草酰乙酸
其它
阿脲
1-甲基-4-苯基吡啶
锰
Lon蛋白酶
去铁酮
吡啶硫酮或吡啶硫酮的金属盐
吡啶硫酮锌
N-羟基-6-辛氧基吡啶-2(1H)酮、乙醇胺盐、(HP-101)(如ArchChemicals,Inc.所供应)是N-羟基吡啶酮的一部分。所述N-羟基吡啶酮在第6位点具有烷基醚取代基以作为游离酸、乙醇胺盐和金属盐，诸如锌、N-羟基-6-辛氧基吡啶-2(1H)酮，锌盐。所述烷基醚类取代基为长度2-22的直链或支化的碳。
在本发明的一个实施例中，另外的铁-硫酶可为与乌头酸酶类似的方式的有用靶点。这些酶的非限制性例子包括生物素合酶、硫辛酸合酶和同型乌头酸酶。
在本发明中，乌头酸酶抑制剂可单独使用或与另外的乌头酸酶抑制剂以及它们的混合物结合使用。例如，吡啶硫酮锌可与一种或多种附加的乌头酸酶抑制剂结合使用。
在本发明的一个实施例中，本发明包括抑制真菌细胞或微生物细胞的乌头酸酶活性的方法，所述方法包括在个体中向所述真菌或微生物细胞施用对于抑制所述真菌细胞的乌头酸酶活性有效量的乌头酸酶活性抑制剂或乌头酸酶抑制剂。
在本发明的一个实施例中，本发明包括在个体中抑制真菌细胞或微生物细胞的乌头酸酶活性的方法，所述方法包括在个体中向所述真菌或微生物细胞施用对于抑制所述真菌细胞的乌头酸酶活性有效量的乌头酸酶活性抑制剂或乌头酸酶抑制剂。
在另一个实施例中，本发明包括抑制真菌细胞的乌头酸酶活性的方法，其中所述个体是头皮屑患者。
在另一个实施例中，本发明包括抑制真菌细胞的乌头酸酶活性的方法，其中所述乌头酸酶的抑制剂选自氟代柠檬酸、4-羟基-反式乌头酸、草酰苹果酸、α-羟基-β-草酰琥珀酸)、ROS物质或氧化性物质、过氧亚硝酸盐、一氧化氮、过氧化氢、过氧化物、1,2,3-D,L-三羧基环戊烯-1、均苯三甲酸(1,3,5-三羧基苯)、偏苯三酸(1,2,4-三羧基苯)、均苯四甲酸(1,2,4,5-四羧基苯)、1,2,3,4-四羧基环戊烷、克氏循环物质、草酰琥珀酸盐、反式乌头酸、顺式乌头酸、α-酮戊二酸、2-酮戊二酸、草酰乙酸、阿脲、1-甲基-4-苯基吡啶、锰、Lon蛋白酶、N-羟基-6-辛氧基吡啶-2(1H)酮、吡啶硫酮乙醇胺盐和吡啶硫酮金属盐、吡啶硫酮锌以及它们的混合物。
在另一个实施例中，本发明包括抑制真菌乌头酸酶活性的方法，其中所述乌头酸酶活性抑制剂是吡啶硫酮锌。
在一个实施例中，本发明包括抑制真菌细胞的乌头酸酶活性的方法，其中所述乌头酸酶抑制剂抑制乌头酸酶活性的至少70％。
在另一个实施例中，本发明包括抑制乌头酸酶活性的用于抗真菌益处的方法，所述方法包括以下步骤：a)将细胞暴露于物质；b)破开细胞并测量乌头酸酶活性，以及c)测量乌头酸酶活性相比于基线或对照/未处理样品的降低。
在另一个实施例中，本发明公开了抑制真菌细胞生长的方法，所述方法包括将所述真菌细胞与一种物质接触，所述物质抑制乌头酸酶活性的至少70％，从而导致对所述真菌细胞生长的抑制和/或导致所述细胞的死亡。
在另一个实施例中，本发明公开了个人护理组合物，所述组合物包含针对乌头酸酶具有抑制活性的一种或多种物质，其中所述物质抑制乌头酸酶活性的至少70％，以提供增强的功效以治疗抗真菌药物介导的病症，诸如抗真菌药物介导的头皮病症。
本文所公开的量纲和值不旨在被理解为严格地限于所述的精确值。相反，除非另外指明，每个这样的量纲旨在表示所述值以及围绕该值功能上等同的范围。例如，所公开的尺寸“40mm”旨在表示“约40mm”。
发明详述中引用的所用文献的相关部分以引用方式并入本文；任何文献的引用均不可解释为是对其作为本发明的现有技术的认可。当本文献中术语的任何含义或定义与以引用方式并入的文献中相同术语的任何含义或定义冲突时，将以赋予本文献中那个术语的含义或定义为准。
尽管已用具体实施例来说明和描述了本发明，但是对那些本领域的技术人员显而易见的是，在不背离本发明的精神和范围的情况下可作出许多其它的更改和修改。因此，随附权利要求书中旨在涵盖本发明范围内的所有这些改变和变型。

Claims (3)

1.一种在个体中抑制真菌细胞的乌头酸酶活性的非医疗方法，所述方法包括向所述真菌细胞施用包含对于抑制所述真菌细胞的乌头酸酶活性有效量的乌头酸酶活性抑制剂的组合物，其中所述的乌头酸酶活性抑制剂选自1,10-菲咯啉，N-羟基-6-辛氧基吡啶-2(1H)酮，乙醇胺盐，羟甲辛吡酮乙醇胺(羟甲辛吡酮)，8-羟基喹啉和其混合物，其中所述乌头酸酶的抑制剂抑制乌头酸酶活性的至少70％。
2.根据权利要求1所述的抑制真菌细胞的乌头酸酶活性的方法，其中所述个体是头皮屑患者。
3.一种在个体中抑制真菌细胞生长的非医疗方法，所述方法包括使个体与包含对于抑制所述真菌细胞的乌头酸酶活性有效量的乌头酸酶活性抑制剂的组合物接触，其中所述的乌头酸酶活性抑制剂选自1,10-菲咯啉，N-羟基-6-辛氧基吡啶-2(1H)酮，乙醇胺盐，羟甲辛吡酮乙醇胺(羟甲辛吡酮)，8-羟基喹啉和其混合物，其中所述乌头酸酶的抑制剂抑制乌头酸酶活性的至少70％。
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