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Mitochondrial- and lysosomal-targeted iron chelators for the monitoring and adjustment of cellular labile iron pools

用于监测和调整细胞不稳定铁库的线粒体和溶酶体靶向铁螯合剂

基本信息

批准号：
BB/J005223/1
负责人：
Charareh Pourzand
金额：
$ 36.5万
依托单位：
University of Bath
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ005223%2F1
关键词：
Mitochondrial lysosomal targeted iron chelators

项目摘要

Iron in the body is necessary for a series of vital functions. The chemical nature of iron makes it highly reactive, and this reactivity can be both useful and potentially harmful. Iron plays its most obvious positive role in the oxygen-carrying protein, haemoglobin, in the blood. However, iron can do damage through stimulating the formation of reactive oxygen species (ROS). These in turn generate 'oxidative stress' and modify cellular components such as proteins, fats and DNA, bringing about abnormal cell function, including possible death. Cells have evolved protective anti-oxidant mechanisms to counter these effects; however excess iron can overcome these mechanisms. In order to induce this damaging effect, iron has to be present in cells in a 'free' form, i.e. not tightly bound by other molecules. Levels of 'free' iron are generally kept very low by the presence of proteins, particularly ferritin, that bind the iron and prevent it from stimulating ROS formation. However recent studies have shown that despite these iron trapping proteins, there is a significant amount of free iron in distinct cell compartments (e.g. mitochondrial and lysosomal organelles) of healthy cells that render them susceptible to oxidative damage and cell death especially in presence of ROS or upon exposure to environmental oxidising agents such as sunlight that generate ROS. Because of the harmful role of free iron, iron trapping drugs (i.e. 'iron chelators') have been proposed as a means to remove excess iron from these subcellular compartments that is detrimental in oxidative stress conditions. Unfortunately the effectiveness of current iron chelators to counteract these effects is much reduced because they have either low permeability and therefore are unable to access their intracellular targets or are highly permeable and therefore upon administration non-specifically diffuse in all cell compartments and cause systemic iron starvation and toxicity. Much effort has gone into the development of novel subcellular organelle-specific iron-chelator drug design strategies to alleviate these problems, but with little success. There is therefore a clear need to develop smart iron chelators that could be specifically delivered to subcellular compartments, where they could register and remove potentially harmful excess iron. We have recently developed a promising iron chelator called HPO-20 that exclusively monitors the free iron content in lysosomal organelles. The high selectivity of HPO-20 for lysosomes represents a considerable step forward toward sensitive evaluation of free iron distribution in subcellular compartments under normal and oxidative stress conditions. However based on current literature, there is no such exclusive equivalent compound for monitoring free iron in mitochondrial compartment. In the present project, we propose to design a series of novel protective mitochondria-specific iron chelators that upon administration directly reach the targeted subcellular compartment. These novel compounds are unique in that they provide the possibility to register and remove potentially harmful residual iron in the organelle. So they have the potential to be used either as biological diagnostics tools or as protective agents. For example our compounds have potential to prevent iron-related oxidative injuries caused by harmful environmental agents notably skin damage caused by sunlight. So in the long term they have potential to be used as photoprotective ingredients in sunscreen formulations and to decrease dramatically the sun-related skin cancer. The possibility of monitoring lysosomal and mitochondrial free iron content with our compounds will also help the identification of pathologies related to subcellular iron-misdistribution. Therefore our compounds will have a major long term impact on public health through availability of combined diagnostic and preventive regimes.

体内的铁是一系列重要功能所必需的。铁的化学性质使其具有高度的反应性，这种反应性既有用又可能有害。铁在血液中的携氧蛋白--血红蛋白中起着最明显的积极作用。然而，铁可以通过刺激活性氧物种(ROS)的形成来造成损害。这些物质进而产生“氧化应激”，改变蛋白质、脂肪和DNA等细胞成分，导致细胞功能异常，包括可能的死亡。细胞已经进化出保护性的抗氧化机制来对抗这些影响；然而，过量的铁可以克服这些机制。为了诱导这种破坏效应，铁必须以“自由”的形式存在于细胞中，即不被其他分子紧密结合。由于蛋白质的存在，尤其是铁蛋白的存在，游离铁的水平通常保持在非常低的水平，这些蛋白质结合铁并阻止它刺激ROS的形成。然而，最近的研究表明，尽管有这些铁捕获蛋白，但在健康细胞的不同细胞室(如线粒体和溶酶体细胞器)中有大量的游离铁，这使得它们容易受到氧化损伤和细胞死亡，特别是在存在ROS或暴露在产生ROS的环境氧化剂(如阳光)中时。由于游离铁的有害作用，铁捕获药物(即铁络合剂)已被提出作为一种手段，从这些亚细胞隔膜中清除在氧化应激条件下有害的多余铁。不幸的是，目前的铁络合剂抵消这些影响的有效性大大降低，因为它们要么通透性低，因此无法进入细胞内靶点，要么通透性强，因此在给药后非特异性地扩散到所有细胞隔间，导致全身铁饥饿和毒性。为了缓解这些问题，人们花了很多精力来开发新的亚细胞细胞器特异性铁络合剂药物设计策略，但收效甚微。因此，显然有必要开发智能铁络合剂，这种螯合剂可以专门输送到亚细胞隔室，在那里它们可以登记和清除潜在有害的多余铁。我们最近开发了一种名为HPO-20的有前途的铁络合剂，它专门监测溶酶体细胞器中的自由铁含量。HPO-20对溶酶体的高选择性代表着在正常和氧化应激条件下对亚细胞内游离铁分布的灵敏评估迈出了相当大的一步。然而，根据目前的文献，还没有这种专属的等效化合物来监测线粒体中的游离铁。在本项目中，我们建议设计一系列新型的保护性线粒体特异性铁络合剂，这些螯合剂在给药后直接到达靶细胞亚细胞间。这些新化合物的独特之处在于，它们提供了登记和清除细胞器中潜在有害残留铁的可能性。因此，它们有可能被用作生物诊断工具或保护剂。例如，我们的化合物有可能防止有害环境因素引起的铁相关氧化损伤，特别是阳光引起的皮肤损伤。因此，从长远来看，它们有可能被用作防晒霜配方中的光保护成分，并显著降低与阳光相关的皮肤癌。用我们的化合物监测溶酶体和线粒体游离铁含量的可能性也将有助于识别与亚细胞铁分布不当相关的病理。因此，我们的化合物将通过提供诊断和预防相结合的制度，对公共卫生产生重大的长期影响。