Leveraging Assets in Human Health Towards Novel Agrochemical Leads

Food security is a pressing, global issue and has been defined by the World Health Organisation as being "when all people at all times have access to sufficient, safe, nutritious food to maintain a healthy and active life". One of the basic tenets of food security is in production: to ensure sufficient quantities of food are available on a sustainable basis. A significant threat to this important goal is the loss of crop yield due to the impact of pests, which can seriously compromise output. It has been posited that climate change will potentially compound this problem, with milder winters contributing to the survival of a variety of pests, such as aphids, resulting in damage to crops both earlier in the farming year and for a longer period. Allied with the pressures of a burgeoning global population, it is clear that new and effective strategies to ensure high and sustainable crop yield are now imperative to safeguard future food production activities.

Insecticidal agents have been at the vanguard of crop protection strategies for over 50 years. In particular, the advent of the neonicotinoid class of insecticides is widely regarded as a major breakthrough in crop protection science. The unique biological profile of neonicitinoids coupled with low mammalian toxicity has led to the establishment of these as high value products, accounting for around 20% of the global insecticide market, with around US$1.6 billion annual worldwide sales in 2008, escalating to US$2.1 billion by 2011. However, in common with many other extensively deployed agrochemical products, resistance is now being encountered, which poses a significant threat to continuing crop protection efforts using this highly successful class of compound.

The development of new, active, and safe insecticidal agents to replace out-dated and ineffective measures is essential for food security. The proposed research describes a novel approach to achieving this goal, ultimately leading to an unprecedented platform for insecticidal research and contributing to the integrity of the global food supply network.

The neonicitinoid class of insecticide have been extraordinarily successful in pest control. However, resistance is now being encountered, which poses a significant threat to continuing crop protection efforts. The phenomenon of resistance has begun to be delineated at the molecular level, for example, through the identification of mutations in individual nAChR subunits in aphids. Such information may signpost alternative chemical approaches for insect control. The neonicotinoids exert their biological effects via agonism of insect nicotinic acetylcholine receptors (nAChR). In human health, there is considerable interest in nAChRs and research in this area has provided a wealth of ligands that could potentially be leveraged to generate new lead compounds with analogous biological profiles to the neonicotinoids. Similarly, the pyrethroids are modulators of insect sodium channels, with a considerable amount known regarding the structure and function of such entities in both an agrochemical and pharmaceutical setting.

Combining the features of both classes of ion channel modulator into a single entity and also hybridising pharmaceutical agents with agrochemicals could offer a means of identifying new lead insecticidal agents worthy of further development. There already exists some precedence for chemical entities having activity at both human and insect nAChRs, suggesting that leads from either source can be tuned to the complimentary target domain. In this novel and adventurous proposal, we aim to capitalise on assets and methodologies used in the pharmaceutical sector towards new insecticidal agents in order to future-proof methods of insect control and address issues such as resistance and potential unwanted activity. This work will provide a pathway towards an alternative means of discovering new agrochemical leads which will serve to address the serious challenges associated with global food security.

1 - Academic Impact

(a) Scientific Advancement
The described research offers considerable opportunities to develop broad ranging academic impact. The proposal utilises elements from a variety of research disciplines and bridges the gap between Agrochemical Research and Medicinal Chemistry in a pharmaceutical setting. Consequently, this research programme will attract the interest of and impact upon a range of disciplines within the community at the chemistry-biology interface. Interdisciplinary collaborations will evolve from the successful development of the described research and key industrial collaborators have already demonstrated their support. Accordingly, this research is expected to lead towards future synergistic cooperation and continued interdisciplinary impact.

Following appropriate intellectual property management, the maximum level of exposure will be pursued through the anticipated series of publications, lectures, posters, and on-line dissemination (webinars, etc.) associated with the overall programme. Moreover, an exchange of co-workers with some of the global leaders in agrochemical research working in associated areas will provide an additional mechanism for achieving international impact and potentially leading to future collaborative research strategies of mutual benefit.

(b) Co-worker Training
The programme of work encompasses a wide range of techniques and will consequently provide the associated PDRA with broad interdisciplinary experience. Collaborative interactions with recognised colleagues in industry will enable the co-worker to absorb new knowledge while taking their own skill set to new environments, providing a mechanism for exchange of knowledge and developing impact in areas beyond the familiar. Overall, the associated co-worker will emerge with an advanced set of skills in a range of research areas and provide the scientific community with a highly adaptable and exceptionally capable colleague.

(c) Knowledge Exchange
As the programme develops, collaboration between Strathclyde and the industrial partner will be extensively utilised to bring the programme to fruition and tailor future expansion. Interdisciplinary collaboration with aligned academic colleagues is also anticipated to lead to new research horizons. Additionally, the exchange of co-workers with colleagues at the industrial site will provide an additional method for interdepartmental and interdisciplinary knowledge exchange, the development of research alliances, and international scientific impact.

2 - Economic and Societal Impact

(a) Industrial Application
This proposal specifically targets outputs that are of increasing value in the biotechnology industry with the specific aim of fostering industrial impact and partnership. It is anticipated that this strategy will be of wide-ranging utility and will provide new and potentially lucrative solutions to the production of vital products.

(b) Business Potential
The expanding market of the agrochemical industry is continually prospecting for new pest control technologies. In this regard, patentable outputs and licensing agreements with industrial partners will be strongly pursued. This has the potential to set the foundations for establishing a spinout company that will utilise the described outputs to market a catalogue of products to the industrial sector.

(c) Societal Relevance
Food security is crucial to our way of life. This new research platform is expected to generate a series of valuable insecticide lead compounds and will therefore positively impact upon food security in the UK and abroad in the medium to long term. Additionally, the business-related outcomes of this research have the potential to generate employment opportunities within the UK and, consequently, impacting favourably upon the overall economy.