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首页> 外文期刊>Life sciences >Novel approaches to plant drug discovery based on high throughput pharmacological screening and genetic manipulation.
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Novel approaches to plant drug discovery based on high throughput pharmacological screening and genetic manipulation.

机译：基于高通量药理筛选和基因操作的植物药物发现的新方法。

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Plants are potentially important for novel therapeutic drug leads, but the slowness of conventional methods for investigation of plants limits enthusiasm in the pharmaceutical industry. To overcome some of the drawbacks, we have applied high throughput pharmacological screening (HTPS) to crude plant extracts. Using a "differential smart screen", (DSS) the spectrum of activity contained in a crude extract is measured at several closely related receptor subtypes. This spectrum is then compared to that of known compounds. A unique spectrum suggests that the extract merits further investigation. Evaluation of species and environmental libraries of whole plants has demonstrated the value of this approach for rapid prioritization of plants for investigation. In addition, genomic and genetic manipulation of plants and plant cell cultures can increase the value of DSS. For example, the whole genomic potential of a plant species for biodiversity can be accessed by using gain of function mutations to generate a "functional genomics library" of mutant clonal cultures, and the bioactivity of these cultures tested by DSS. Clones that overproduce activity differing from the wild-type plant can be identified in this way. This "Natural Products Genomics" (NPG) strategy is limited by the massive numbers of clonal cultures that are required to cover all possible gain-of-function mutations. The rapidity and efficiency of this process can be improved by using transgenic plants expressing appropriate mammalian proteins. These may be designed to make the plant cell resemble a human cell for a specific form of toxicity. Now, "unnatural selection" of resistant mutant clones can be used to provide a sub-population potentially enriched in useful compounds. Alternatively, transgenic plant cells can be used for "in situ screening" in which a mammalian receptor protein, linked to a reporter construct, such as green fluorescent protein, is expressed. Clonal cultures that produce ligands for this receptor can now be rapidly identified visually in an ultra-HTPS. Overall, our aim is to use pharmacological screening, together with functional genomic approaches, to make plant drug discovery competitive with combinatorial chemistry.
机译：植物对于新型治疗药物的潜在潜在重要意义，但是传统的植物研究方法的缓慢性限制了制药行业的热情。为了克服某些缺点，我们对粗植物提取物应用了高通量药理筛选（HTPS）。使用“差异智能屏幕”（DSS），可以在几种紧密相关的受体亚型下测量粗提物中所含的活性谱。然后将该光谱与已知化合物的光谱进行比较。独特的光谱表明该提取物值得进一步研究。对整个植物的物种和环境文库的评估证明了这种方法对于快速确定植物的研究优先级的价值。此外，对植物和植物细胞培养物进行基因组和遗传操作可以增加DSS的价值。例如，可以通过利用功能突变获得突变克隆培养物的“功能基因组学文库”来获得植物物种对于生物多样性的全部基因组潜力，并通过DSS测试这些培养物的生物活性。以此方式可以鉴定出过量生产与野生型植物不同活性的克隆。这种“天然产物基因组学”（NPG）策略受到覆盖所有可能的功能获得性突变所需的大量克隆培养物的限制。通过使用表达适当哺乳动物蛋白的转基因植物，可以提高该过程的速度和效率。这些可以被设计成使植物细胞类似于人细胞，从而具有特定的毒性形式。现在，抗性突变体克隆的“非自然选择”可用于提供可能富含有用化合物的亚种群。或者，可将转基因植物细胞用于“原位筛选”，其中表达与报道构建体连接的哺乳动物受体蛋白，例如绿色荧光蛋白。现在可以在超HTPS中通过视觉快速识别产生该受体配体的克隆培养物。总体而言，我们的目标是使用药理学筛选以及功能基因组学方法，使植物药物发现与组合化学竞争。

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