A synthetic biology platform to identify novel anti-aging natural products

描述（由申请人提供）：衰老生物学研究的最终目标是确定药物干预措施，以增加人类的寿命和健康寿命。天然产物雷帕霉素已被证明可以显着延长所有测试的模式生物的寿命，包括真菌，苍蝇，蠕虫和小鼠。然而，雷帕霉素的长期治疗也会引起不必要的副作用，包括中度免疫抑制和葡萄糖耐量和胰岛素功能受损。最近的研究表明，雷帕霉素通过结合和阻断来自两个独立的信号传导复合物mTORC 1和mTORC 2的信号传导来发挥作用。已经表明，对寿命的有益影响是由于雷帕霉素结合后mTORC 1信号转导的下调。另一方面，雷帕霉素的有害副作用是由于雷帕霉素结合后mTORC 2信号转导的下调。因此，理想的抗衰老药剂将与雷帕霉素高度相似，但对mTORC 1具有高特异性而对mTORC 2具有低特异性。Radiant Genomics认为，可以通过生物信息学和宏基因组和个体生物体的下一代测序的组合来识别的天然产物基因簇的巨大多样性现在可以被挖掘，以提供可能具有所需结合特性的候选天然雷帕霉素类似物，绕过阻碍天然产物发现的传统方法的障碍。为此，我们开发了一个合成生物学平台，该平台具有三个主要管道：1）生物信息学鉴定编码天然雷帕霉素类似物的基因簇的方法，2）将这些基因簇克隆并操纵成用于转化到异源宿主中的构建体的方法，3）将这些簇转化到经遗传改变以产生选定的雷帕霉素类似物的工程化宿主中的方法。然后，与巴克衰老研究所合作，我们将测试这些天然雷帕霉素类似物对mTOR1C和mTOR2C的结合特异性。如果我们找到具有所需特性的类似物，未来的实验将通过与巴克研究所和德洛斯制药公司合作，使用标准动物寿命测定和其他动物疾病模型启动，以进一步开发药物。一系列天然雷帕霉素类似物的成功生产和表征将提供强有力的概念证明，即Radiant Genomics天然产物发现平台将允许科学家快速询问目标天然产物周围的天然多样性，这是使用传统天然产物发现方法不可能实现的，并将彻底改变天然产物发现领域。

DESCRIPTION (provided by applicant): The ultimate goal of research into the biology of aging is to identify pharmaceutical interventions to increase both lifespan and healthspan of humans. The natural product rapamycin has been shown to significantly extend the lifespans of all model organisms tested including fungi, flies, worms, and mice. However, chronic treatment with rapamycin also causes unwanted side effects including moderate immunosuppression and impaired glucose tolerance and insulin function. Recent research suggests that rapamycin functions by binding and blocking signaling from two independent signaling complexes, mTORC1 and mTORC2. It has been shown that the beneficial effects on lifespan are due to the downregulation of mTORC1 signaling upon binding by rapamycin. On the other hand, the deleterious side effects of rapamycin result from the downregulation of mTORC2 signaling upon rapamycin binding. Thus, an ideal anti-aging pharmaceutical agent would be highly similar to rapamycin, but have high specificity for mTORC1 and little specificity for mTORC2. Radiant Genomics believes that the enormous diversity of natural product gene clusters that can be identified through a combination of bioinformatics and next generation sequencing of metagenomes and individual organisms can now be mined to provide candidate natural rapamycin analogs that may have desired binding properties, bypassing hurdles blocking traditional methods of natural product discovery. To do this, we have developed a synthetic biology platform that has three main pipelines: 1) a method to bioinformatically identify gene clusters that code for natural rapamycin analogs, 2) a method to clone and manipulate these gene clusters into constructs for transformation into a heterologous host, 3) a method to transform these clusters into an engineered host that has been genetically altered to produce selected rapamycin analogs. Then, in collaboration with the Buck Institute for Research on Aging, we will test the binding specificities of these natural rapamycin analogs for mTOR1C and mTOR2C. If we find analogs with the desired properties, future experiments will be initiated using standard animal lifespan assays and other animal disease models through a collaboration with both the Buck Institute and Delos Pharmaceuticals for further drug development. Successful production and characterization of a range of natural rapamycin analogs will provide strong proof of concept that the Radiant Genomics natural product discovery platform will allow scientists to quickly interrogate the natural diversity surrounding a targeted natural product, an impossibility using traditional natural product discovery methods, and would revolutionize the field of natural product discovery.