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

描述（由申请人提供）：研究衰老生物学的最终目标是确定药物干预措施，以延长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著延长所有模式生物的寿命，包括真菌、苍蝇、蠕虫和老鼠。然而，长期使用雷帕霉素治疗也会引起不良的副作用，包括适度的免疫抑制和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两个独立的信号复合物mTORC1和mTORC2的信号传导起作用。研究表明，对寿命的有益影响是由于雷帕霉素结合后mTORC1信号的下调。另一方面，雷帕霉素的有害副作用是由于雷帕霉素结合后mTORC2信号的下调。因此，理想的抗衰老药物应与雷帕霉素高度相似，但对mTORC1具有高特异性，而对mTORC2的特异性较低。Radiant Genomics相信，通过生物信息学和下一代元基因组和个体生物测序的结合，可以识别出天然产物基因簇的巨大多样性，现在可以挖掘出可能具有所需结合特性的候选天然雷帕霉素类似物，绕过阻碍传统天然产物发现方法的障碍。为此，我们开发了一个合成生物学平台，它有三个主要管道：1)一种生物信息学方法来识别编码天然雷帕霉素类似物的基因簇，2)一种方法来克隆和操纵这些基因簇，将其转化为异源宿主的构建物，3)一种方法来将这些基因簇转化为经过基因改造的工程宿主，以产生选定的雷帕霉素类似物。然后，我们将与Buck衰老研究所合作，测试这些天然雷帕霉素类似物对mTOR1C和mTOR2C的结合特异性。如果我们发现具有所需特性的类似物，未来的实验将通过与Buck研究所和Delos制药公司的合作，使用标准动物寿命分析和其他动物疾病模型进行进一步的药物开发。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，辐射基因组学天然产品发现平台将允许科学家快速询问目标天然产品周围的自然多样性，使用传统的天然产品发现方法是不可能的，并将彻底改变天然产品发现领域。

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.