in vivo chemistry

摘要：将探索一套三个高度投机性的项目，所有这些项目都涉及应用化学工具来解决重大的生物学需求和问题。所有这些项目，都有令人兴奋的长期翻译终点和实际应用。(1)。体内介导的抗癌药物合成--这是一种潜在的革命性化疗方法，在癌症附近的体内进行合成化学，以产生所需的细胞毒性活性药物，从而大大减少毒性和副作用。(2)基质金属蛋白酶-9(MMP9)与肿瘤转移以及多种炎症过程(如许多肺部疾病)有关。我们已经在该小组中开发了一种方法，通过这种方法，我们可以确定这种酶的理想底物(一种酶将切割的肽)，但它不会被其他任何东西切割。我们将利用这些信息来制造这种酶的传感器，以便在体内对其进行分析、定位和跟踪(然后被抑制)，并在一个模型系统中允许癌细胞在通过合成传感凝胶时进行成像(同时监测基质金属蛋白酶-9的功能)。《自然》杂志(2010年3月)的一篇论文证明，当患者受伤(例如在车祸中)时，细胞会受损并释放其内容物。其中之一(所谓的线粒体--为细胞制造能量)是对损伤的大部分炎症反应的原因(因此，导致死亡的往往不是损伤，而是我们对此的反应)。移除这些循环中的线粒体可以缓解一个巨大的医学问题。聚合物已经被用来过滤血液以去除白细胞。因此，我们将尝试发现一种新的聚合物，它可以结合循环中的线粒体，然后可以应用于血液过滤介质中，类似于白细胞过滤器，以帮助减少对损伤的不必要的炎症反应。这项提议的主要驱动因素是：(I)。合成化学工具的应用(二)对传统学科界限的内在超越。(三)。临床期前翻译和生活质量的长期改善。(四)。改变化疗方法和炎症治疗革命的潜在缓解期。

Summary: A suite of three highly speculative projects, all involving the application of the tools of chemistry to address significant biological needs and problems, will be explored. All these projects, have exciting longer term translational end-points and practical application. (1). In vivo mediated synthesis of anticancer drugs - a potentially revolutionary approach to chemotherapy in which synthetic chemistry is performed in vivo in the proximity of the cancer to generate the desired cytotoxic active drug, thereby dramatically reducing toxicity and side effects will be explored.(2). MMP-9 (Matrix metalloproteinase-9) has been implicated in tumor metastasis as well as a variety of inflammatory processes (e.g. many lung diseases). We have developed an approach in the group whereby we can identify an ideal substrate for this enzyme (a peptide the enzyme will cleave), but which will not be cleaved by anything else. We will use this information to make a sensor for this enzyme, to allow it be analyzed, localized and followed in vivo (and then inhibited) and in a model system allow cancer cells to be imaged (while monitoring MMP-9 function) as they move through a synthetic sensing gel.(3). A paper in Nature (March 2010) has demonstrated that when patients have been injured (for example in a car accident) cells are damaged and release their contents. One of these (so-called mitochondria - which are make energy for the cell) is the cause of much of the inflammatory responses to injury (thus it is often not the injury that kills but our response to this). Removal of these circulating mitochondria could alleviate a vast medical problem. Polymers are already used to filter blood to remove white blood cells. We will therefore try and discover a new polymer that binds circulating mitochondria and which can then be applied in blood filtration media akin to white blood cell filters to help reduce unwanted inflammatory responses to injury. Key drivers for this proposal are:(i). Application of the tools of synthetic chemistry.(ii). Inherent crossing of traditional disciplinary boundaries. (iii). Pre-clincal translation and longer term improvement in quality of life. (iv). Potential remit changing approach to chemotherapy and revolution in treatment of inflammation.