A new tool to support drug discovery: Native LESA mass spectrometry (NESA)

The proposed research will develop a new analytical tool to support drug discovery. The tool, known as native liquid extraction surface analysis (NESA) mass spectrometry, combines two emerging mass spectrometry techniques, and has the potential to revolutionise the drug discovery pipeline by addressing a key challenge, namely the ability to make measurements in the full complexity of the biological environment.

Drug discovery is the process whereby new potential medicines are identified. Typically, drug discovery involves initial screening of a library of compounds against a particular 'target' (e.g., a protein that has previously been identified as being involved in a particular illness or disease). This initial screening results in hit compounds ('hits') which are then optimised to improve their performance. At this stage, the potential drug enters the pre-clinical phase of drug development in which its safety, toxicity, and metabolism are assessed prior to clinical trials.

The early stages of drug discovery are very much focused on optimising the interactions (known as non-covalent interactions) between the target and the potential drug. The aims are to improve the binding affinity, i.e., strengthen the interaction between the drug and the target, and to improve target selectivity, i.e., ensure the drug binds to one target only. These measurements, however, are made outside of the physiological context. There are two limitations to this isolationist approach. Firstly, disease states are the result of complex networks of molecular pathways, and the effectiveness of drug discovery is hampered by incomplete understanding of the response of those molecular pathways to the drug(s). The ability to measure interactions between the target and drug in the full biological context would transform this facet of drug discovery. Secondly, the safety and toxicological effects resulting from interaction of the drug with other molecules ("off-target" effects) cannot be assessed at this stage. The latter is particularly important when considering the very high attrition rate of drug development. The success rate for a drug entering clinical trials eventually making it to the market is less than 10%. The number one reason for failure at this stage is non-clinical toxicology. The ability to assess toxicological effects earlier in the drug discovery process would reduce attrition rates, and improve the efficiency of drug discovery and development.

Nevertheless, the ability to make analytical measurements in the physiological context is a major challenge for the physical sciences, and this work seeks to address that challenge. The aim is to develop an analytical chemistry technique - NESA mass spectrometry - for the characterisation of interactions between protein targets and drug compounds directly from complex biological environments, including blood, tissue and cells. Broadly, mass spectrometry is an analytical technique which offers high sensitivity, broad specificity (all molecules have a mass), and the capability for molecular structure elucidation. Two emerging mass spectrometry approaches are native mass spectrometry, which preserves non-covalent interactions such as those between protein targets and drugs thus allowing their interrogation, and liquid extraction surface analysis, which allows sampling of molecules directly from their actual environment. The research described in this proposal will couple these exciting techniques and apply them to the challenge of characterisation of protein - drug interactions in the full biological context.

Who might benefit from this research?
The beneficiaries of this research will be the pharmaceutical industry, the NHS and its patients, and analytical instrumentation manufacturers.

How might they benefit?
The research has the potential to contribute significantly to the nation's health and wealth:

Pharmaceutical industry:
The pharmaceutical industry plays a critical role in both the health of the UK population and the success of the UK's economy, as acknowledged at the highest levels of government: In 2016, Theresa May MP stated "It is hard to think of an industry with greater strategic importance to Britain than its pharmaceutical industry". According to the 2016 report on 'Strength & Opportunity in the UK Life Sciences', commissioned by the Office for Life Sciences, the Life Sciences industry employs >200, 000 people in nearly 6000 companies, with an annual turnover of £61 bn. The biopharmaceutical industry (which comprises pharmaceutical and medical biotechnology companies) employs >100,000 people in 2000 companies generating an annual turnover of £40 bn. The proposed research will improve the efficiency of the drug discovery (and development) process by reducing later stage attrition rates and consequently reducing the time taken between drug candidate identification and availability to patients. Currently, it takes 12 years and costs £300 million for a drug to reach patients [1].

NHS and its patients:
Great improvements in the nation's health have been made in the past 50 years: UK life expectancy has increased by 10 years, the cancer survival rate has increased twofold, deaths due to cardiovascular disease have reduced by 75%, and HIV/AIDS has become a manageable condition. In major part, this progress is due to the development and availability of medicines [2].

Nevertheless, the challenge of the nation's health - to live longer lives of better quality - is ongoing. Despite the improvements described, a quarter of all deaths in the UK are the result of cardiovascular disease, 29% are due to cancer, 7% are due to infectious diseases. Globally, over 7000 drugs are in development, spanning cancer, heart disease, diabetes, and beyond [2]. This research will benefit the NHS/patients by improving the efficiency of the process by which a drug is discovered, developed and ultimately reaches the patient.

One aim of the work is to develop the tool in the context of drug discovery for tuberculosis (TB), which remains a major global health problem, reflected by its inclusion in the WHO's Millennium Development Goals ("reverse the spread of [tuberculosis] by 2015") [3]. The 2011 case of Birmingham teenager Alina Sarag, whose TB infection was not diagnosed in time and ultimately caused her death, is a stark reminder that despite available antibiotics TB remains a serious threat in the UK.

Analytical instrumentation manufacturers:
The work will enable the development of NESA mass spectrometry, a tool which can be employed in a broad range of new applications beyond the focus of this proposal. According to InnovateUK [4], Measurement Science and Technology plays a crucial role in supporting UK industry and research with an estimated £7 billion turnover in the UK and > 200,000 scientists employed. There are >1700 accredited laboratories and 11,000 sites with analytical laboratories in the UK.

The instrumentation exploited in this research is manufactured by Waters Corp., Advion Inc, Bruker and Thermo, all of whom are global companies with a strong base in the UK. Through development of new applications, the proposed work will lead to increased sales thus fostering global economic performance and the economic competitiveness of the UK.

1. https://www.ca-biomed.org/pdf/media-kit/fact-sheets/CBRADrugDevelop.pdf
2. http://www.abpi.org.uk/industry-info/Pages/health-and-wealth.aspx
3. www.who.int/mediacentre/factsheets/fs290/en/
4. https://connect.innovateuk.org/web/3346502