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

一种从天然产物复杂提取物中全系统鉴定目标蛋白及其配体的方法

• 批准号: 98418
• 金额: $ 26.68万
• 依托单位: SIBELIUS LTD
• 依托单位国家: 英国
• 项目类别: Collaborative R&D
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=98418
• 关键词: method; system; wide; identification; target

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.

人口老龄化、生活方式相关疾病发生率的增加以及药物开发/医疗保健提供成本的增加构成了全球社会挑战。 “自我保健”——“个人、家庭和社区在有或没有医疗保健提供者的支持下促进健康、预防疾病、维持健康以及应对疾病和残疾的能力”（世界卫生组织）——将有助于应对这一挑战。天然产品（由生物体产生的化合物）占营养保健品行业的近 20%，并且消费者对其的兴趣不断上升。广泛的结构多样性和进化压力意味着天然产品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 年至 2014 年期间批准的新化学实体中有 25% 是天然产物或衍生物（Newman 和 Cragg 2016）就证明了这一点。除了单个“活性”化合物（例如姜黄根中的姜黄素）之外，许多天然产物都是含有数百至数千种化合物的复杂提取物；有时，几种药物（阿育吠陀和传统中药）的制剂会更加复杂。这种复杂性可能通过化合物之间的协同相互作用对健康有益，例如：大麻的“随从效应”（Ben-Shabat _et. al.,_ 1998）。然而，天然产品的复杂性和固有的变异性（遗传、环境、栽培、加工、提取因素）使得证实其声称的健康益处变得困难，并使消费者信息不灵和服务不足。人们认识到需要提供具有标准化生化特性并在人类中得到证实的功效的明确天然产品。目前的方法可以根据生物标志物反应特征或蛋白质靶点的识别，深入了解天然产物与健康相关的作用机制。同样，生物测定引导的分级分离或亲和纯化方法（使用蛋白质靶标作为诱饵）可以支持复杂天然产物中活性化合物的鉴定。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其他因素的先验知识。为了应对这一挑战，合作伙伴旨在结合现有化学蛋白质组学方法的原理，开发一种新方法，在全系统水平上并行识别人体细胞中天然产物的活性化合物及其靶蛋白。这种能力将能够解码天然产品及其活性，并支持为营养保健品市场开发更具体的产品，以具有相对较高水平的科学理解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。