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

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.