Biosynthesis and exploitation of marine-derived post-translationally modified ribosomal peptides

来自自然界的化合物仍然是药物发现的支柱，在某些治疗领域，如癌症，临床上使用的70%的药物是天然来源的。这些化合物中有许多是高度复杂的，很难在实验室中重现。最近的一个趋势是试图了解生物体用于生物合成这些分子的机制。这项工作已经在一个非常先进的阶段，为某些类别的这些分子，这是由小亚基，并被称为聚酮和非核糖体肽。每个类别的候选药物已经进入临床，或者正在患者身上进行测试，以评估其作为药物的适用性。在某些情况下，自然界的供应是有限的，生物体的过程已经被移植到易于培养的细菌中，然后产生感兴趣的化合物。这是通过将编码指令（生物合成基因）的DNA引入细菌中来实现的。这种方法已成功地用于生产潜在的候选药物，并通过改变说明书来设计新的化合物。我们最近发现，潜在的抗淋巴瘤化合物，最初从海洋无脊椎动物（海葵）分离，实际上是由其细菌共生体，Prochloron。它对化合物生物合成的指导比上面提到的化合物类别更直接，并且应该可以更容易地修改它们。这类化合物相对来说还未被探索，但科学文献的证据表明，在某些类型的海洋无脊椎动物中可能有更多这类化合物的例子。利用已知的化学结构，我们可以预测它在生产生物体的DNA中编码的方式，从而定位相关的生物合成基因。我们将对一些目标海洋无脊椎动物（海葵、海绵）进行化学筛选，并提取它们的DNA。在此之后，我们将筛选DNA中相关生物合成基因的存在，并确定其DNA序列。对一些产生这种不寻常化合物的物种进行这种研究，将使我们能够了解这些化合物在生物体内合成的规则。然后，综合信息可用于筛选海洋无脊椎动物，这些动物被怀疑但不知道会产生类似的化合物。将这种方法与生态信息相结合，将使我们能够识别可能产生具有有效生物活性的这种类型的其他化合物的生物。这项工作的成果将是从海洋无脊椎动物中发现新的生物活性化合物，以及以可持续的方式生产这些化合物并对其进行修改以调节其活性的方法。该方法只需要收集小样本用于DNA提取，而不是大规模收获。此外，我们将了解这些独特的化合物是如何在这些原始生物中生物合成的。

Compounds from Nature are still a mainstay for drug discovery and in certain therapeutic areas such as cancer, 70% of drugs used in the clinic are of natural origin. Many of these compounds are highly complex and are difficult to re-create in the laboratory. A recent trend has been to try to understand the mechanisms the organisms use to biologically synthesise these molecules. This work is already in a very advanced stage for certain classes of these molecules, which are constructed from small subunits, and are known as polyketides and non-ribosomal peptides. Candidates from each category are already in the clinic, or are being tested on patients to assess their suitability as pharmaceuticals. In some cases the supply from nature is limited, and the organism's processes have been transplanted into easy-to-culture bacteria, which then produces the compound of interest. This is done by taking the DNA which encodes the instructions (the biosynthetic genes) to make the compounds and introducing these into a bacterium. This method has been successfully used to produce prospective drug candidates and to engineer new compounds by changing the instructions. We have recently discovered that potential anti-lymphoma compounds, originally isolated from a marine invertebrate (seasquirt) are in fact produced by its bacterial symbiont, Prochloron. Its instructions for biological synthesis of the compounds are encoded in a much more straightforward way than the classes of compounds mentioned above, and should make it possible to modify them more readily. This class of compounds is relatively unexplored, but evidence from the scientific literature suggests that there may be many more examples of this class of compound in certain types of marine invertebrate. Using the known chemical structure we can predict the way in which it is encoded in the DNA of the producing organism, and thus locate the relevant biosynthetic genes. We will chemically screen a number of target marine invertebrates (seasquirts, sponges) and extract their DNA. After this we will then screen the DNA for the presence of the relevant biosynthetic genes and determine the sequence of their DNA. Doing this on a number of species producing this unusual group of compounds will allow us to understand the rules by which these compounds are synthesised within the organisms. The combined information can then be used to screen marine invertebrates, which are suspected, but not known to, produce similar compounds. Combining this approach with ecological information will enable us to identify organisms, which are likely to produce other compounds of this type with potent biological activity. The outcomes of this work will be the discovery of new biologically active compounds from marine invertebrates together with methods to produce them in a sustainable fashion and modify them to modulate their activity. The method necessitates only a small specimen to be collected for DNA extraction, rather than large scale harvesting. In addition we will gain an understanding of how these unique compounds are biologically synthesised in these primitive organisms.