A method for system-wide identification of target proteins and their ligands from complex extracts of natural products

人口老龄化、与生活方式有关的疾病发病率上升以及药物开发/医疗保健费用的增加是一项全球性的社会挑战。“自我保健”——“个人、家庭和社区在有或没有卫生保健提供者支持的情况下促进健康、预防疾病、保持健康以及应对疾病和残疾的能力”（世卫组织）——将有助于迎接这一挑战。天然产品——由生物体产生的化合物——占保健品行业的近20%，而且消费者对它们的偏好正在上升。广泛的结构多样性和进化压力意味着天然产物具有与蛋白质相互作用并对人类健康产生影响的强大潜力；2010-2014年批准的新化学实体中有25%是天然产物或衍生物（Newman and Cragg 2016）。除了个别“活性”化合物（例如来自姜黄根的姜黄素），许多天然产物是含有100 -1000种化合物的复杂提取物；有时更复杂的几种制剂（阿育吠陀药和传统中药）。这种复杂性可能对通过化合物之间的协同相互作用对健康有益很重要。“随从效应”指大麻（Ben-Shabat）。1998年,_)。然而，天然产品的这种复杂性和固有的可变性（遗传、环境、栽培、加工、提取因素）使得所声称的健康益处难以证实，并使消费者不了解情况，得不到充分的服务。人们认识到需要提供具有标准化生化特性和证明对人类有效的明确规定的天然产品。目前的方法可以基于生物标志物反应特征或蛋白质靶点的识别，深入了解天然产物的健康相关作用机制。类似地，生物测定指导分离或亲和纯化方法（以蛋白质靶标为诱饵）可以支持鉴定复杂天然产物中的活性化合物。然而，目前没有一种方法可以同时识别作用机制和活性化合物，并且通常依赖于一个或另一个因素的先验知识。为了应对这一挑战，合作伙伴的目标是结合现有化学蛋白质组学方法的原理，开发一种新的方法，在全系统水平上平行识别人类细胞中天然产物及其靶蛋白的活性化合物。这种能力将能够解码天然产品及其活动，并支持为营养保健品市场开发更具体的产品，以相对较高的科学理解水平和具有竞争力的成本，更好地满足客户，品牌和监管机构的需求。

Ageing populations, increasing rates of lifestyle-related conditions and costs of drug development/healthcare provision represents a global societal challenge. 'Self-care' - "the ability of individuals, families and communities to promote health, prevent disease, maintain health, and to cope with illness and disability with or without the support of a healthcare provider" (WHO) - will contribute towards meeting this challenge. Natural products - compounds produced by living organisms - account for close to 20% of the Nutraceuticals industry, and there is a rising consumer inclination towards them.Wide structural diversity and evolutionary pressures mean natural products have strong potential to interact with proteins and impart effects on human health; evidenced by 25% of New Chemical Entities approved between 2010-2014 being natural products or derivatives (Newman and Cragg 2016). Alongside individual "active" compounds (e.g. curcumin from Turmeric root), many natural products are complex extracts containing 100s-1000s of compounds; sometimes further complicated in preparations of several species (Ayurvedic and Traditional Chinese Medicines). This complexity may be important for health benefits through synergistic interactions between compounds e.g. "entourage effect" noted for Cannabis (Ben-Shabat _et. al.,_ 1998). However, this complexity and inherent variability of natural products (genetic, environmental, cultivation, processing, extraction factors) makes substantiation of claimed health benefits difficult and leaves consumers ill-informed and under-served.There is a recognised need to provide well-specified natural products with standardised biochemical properties and demonstrated efficacy in humans. Current methods can provide insight into health-relevant Mechanism of Action for natural products, based on biomarker response signatures or the identification of protein targets. Similarly, bioassay guided fractionation or affinity purification methods (using protein targets as bait) can support identification of active compounds within complex natural products. However, no current method can identify Mechanism of Action and active compounds concurrently and typically rely on prior knowledge of one or other factor.To address the challenge, the partners aim to combine the principles from existing chemoproteomic approaches to develop a novel method to identify active compounds for natural products and their target proteins in human cells in parallel on a system-wide level. This capability will enable decoding of natural products and their activities, and support development of better-specified products for the nutraceuticals market, with a comparatively high level of scientific understanding at competitive cost to better serve customer, brands and regulators needs.