The aim of the proposed research is to develop a novel type of molecule that will allow validation of a family of enzymes called deubiquitylases (DUB) as therapeutic targets in oncology and provide lead compounds to initiate an anticancer drug discovery programme. DUBs play a major role in the cell by removing the small regulatory protein called ubiquitin from other proteins. The human genome codes for around 80 deubiquitylases (DUB/DUB-like). This enzyme family contains five sub-families, four of which have been studied and targeted previously. The remaining group are called Zn-dependent DUBs and have not been targeted due to a lack of molecules that can be used to probe their function. We have established a team of experts in their respect research fields (Echalier - Structural Biology, Jamieson - peptide chemistry & Kessler - protein mass spectrometry) to develop such molecules based on the natural peptide substrates of the enzymes. Using modern synthetic chemistry techniques we aim to produce a range of molecules that target Zn-dependent DUBs with unprecedented selectivity. The insights gained from these experiments will be used to validate them as a therapeutic target, and inform structure-based drug design of selective DUB inhibitors.

The aim of the proposed research is to develop a novel type of molecule that will allow validation of a family of enzymes called deubiquitylases (DUB) as therapeutic targets in oncology and provide lead compounds to initiate an anticancer drug discovery programme. DUBs play a major role in the cell by removing the small regulatory protein called ubiquitin from other proteins. The human genome codes for around 80 deubiquitylases (DUB/DUB-like). This enzyme family contains five sub-families, four of which have been studied and targeted previously. The remaining group are called Zn-dependent DUBs and have not been targeted due to a lack of molecules that can be used to probe their function. We have established a team of experts in their respect research fields (Echalier - Structural Biology, Jamieson - peptide chemistry & Kessler - protein mass spectrometry) to develop such molecules based on the natural peptide substrates of the enzymes. Using modern synthetic chemistry techniques we aim to produce a range of molecules that target Zn-dependent DUBs with unprecedented selectivity. The insights gained from these experiments will be used to validate them as a therapeutic target, and inform structure-based drug design of selective DUB inhibitors.

The breakup of liquid jets into droplets has been the focus of study for more than two centuries. The fast production of microjets and microdroplets has gained additional importance beyond its pure scientific interest motivated by their application in microfluidics devices and in some modern digital technologies, such as 2D and 3D-Printing. Most current studies of this topic aim to improve the control over the position, number and directionality of droplets and their satellites. The objective of this project is two-fold: (i) we will investigate and exploit self-stimulation (resonance) of liquid jets for a better control of the breakup frequency and length; and (ii) once we are able to extract the most unstable (most efficient) frequency we will study the generation of single drops from a continuous liquid jet by means of intermittent pressure pulses. A liquid jet/column will break up into droplets due to the action of surface tension. In continuous inkjet applications the breakup of a jet (or column) of ink is induced and controlled by applying external perturbations in the pressure (or velocity) of the fluid via piezoelectric elements. If the frequency and amplitude of these perturbations are within the so-called 'most unstable modes' range, droplets of uniform size will be obtained. Although these frequencies are roughly predicted by the Rayleigh/Weber equations, in practice this still requires much adjustment and fine tuning; this fine tuning is an empirical process that has to be repeated when different fluids, or inks, are used, which is both limiting and time consuming. We propose to detect and exploit self-stimulated modes in which the system tunes itself to its most unstable frequency by means of feedback. This, by definition, is the most efficient breakup. In this part of the project, mechanisms for self-stimulation will be investigated. The clear advantage of this approach is that the fine tuning is not needed and the breakup frequency can be readily found for a wide range of fluids (within a reasonable operating regime). The second part of the project, the generation of single drops from an otherwise unperturbed jet will be investigated. These single drops could be used for precise deposition, on demand, of small volumes of fluids for a variety of applications (e.g. Inkjet Printing). Moreover, it is envisaged that within these drops single particles (or cells, or other immiscible liquids in emulsion, etc.) can be trapped in real time and selectively delivered to a specific target. These 'particles' may be functional materials, chemical reactants, cells, etc. which are normally dispersed in a carrier fluid on purpose (e.g. fluids with the correct nutrients to sustain life, or functional materials in 'latent' mode) or unintentional and undesired (e.g. solid pollutants). These two overlapping and complementing studies would increase the predictability and reproducibility of the velocity and volume of droplets, and as a consequence these would increase reliability, efficiency and quality of printing technologies.

Small molecule drugs continue to dominate our collective ability to treat disease. However, the pharmaceutical industry faces challenges on several fronts, and increasing productivity has been framed as the grand challenge for the sector. Against a background of increasingly cost-constrained healthcare systems, the cost of launching new drugs is increasingly high (recently estimated at £1.8 Bn for each new drug!). In order to improve productivity in drug discovery, it is necessary to develop innovative new medicines that address currently unmet medical needs. Protein-protein interactions represent a significant untapped, but challenging, opportunity for treating diseases including cancer, inflammatory disease, cardiovascular disease and infection. Drugs function by binding to a protein target within the body. Most existing small molecule drugs bind to well-defined pockets in proteins - analogous to a key fitting into a lock. In stark contrast, the design of drugs to inhibit protein-protein interactions generally requires a fundamentally different type of interaction of the drug with its protein target - analogous to a hand gripping a ball. Thus, the development of effective drugs that target protein-protein interactions raises new challenges that need to be met in future drug discovery. This programme will develop new tools and understanding that will facilitate future drug discovery against protein-protein interactions. We will develop computational tools to classify protein-protein interactions according to their underlying 3D structure and the probability that they can be inhibited using small molecules. We will then exploit these computational tools to design classes of small molecule that can be prepared readily using state-of-the-art synthetic methods, and that are predisposed to target different types of protein-protein interaction. The resulting small molecule inhibitors will be made available to biological researchers to help understand the role of protein-protein interactions in disease. In addition, the new tools will be made accessible to the research community to facilitate the early-stage discovery of small molecule drugs that target protein-protein interactions. The programme will benefit from the input of major pharmaceutical companies, smaller drug discovery companies, a not-for-profit drug discovery organisation, and international academics. The involvement of a wide range of experts is essential because of the increasing trend for early stage drug discovery to be conducted by a range of organisations (both industry and academic), especially for more challenging target classes. Thus, together with wider research community engagement, we will ensure that the required future capabilities for early-stage drug discovery against protein-protein interactions are met.

We are all familiar with the concept of travel, and visiting York from Glasgow is conceptually a trial matter. When we reflect on this process, however, there are lots of potential questions we might ask about the mode of transport, the route and the potential to get lost. A similar range of questions could be asked about chemical reactions. We select starting materials and seek to transform them into products. The route we choose is equally complex. Now, however, the participants are much smaller and very special methods are needed to view them. Furthermore, with an optimal solution we get the most product from the least starting material using the least amount of energy and other resources as possible. If think of a reaction that is undertaken on the 1,000,000 tonne scale it is also clearly vital to minimise waste. In Chemistry, there is a very special and often expensive method called nuclear magnetic resonance spectroscopy (NMR) that allows us to take pictures of the participants as they travel from starting materials to products. This methods is normally very insensitive and hence very expensive large magnets are required. If we want to use this technology to deliver clean and efficient chemistry on an industrial scale we need to find a way to work with smaller lower cost magnets, ideally using the Earth's magnetic field. In this project we aim to develop a new method using such low-magnetic field NMR devices to follow the route taken by molecules during their conversion into high value products in both laboratory and industrial settings. We will use a special form of hydrogen gas, known as parahydrogen to increase the sensitivity of the NMR measurement to a level that will allow to achieve this goal. Parahydrogen was actually the fuel of the space shuttle and one might view it here as acting like a molecular microscope whilst at the same time removing (filtering) any unwanted signals from spectators to the reaction of interest. We will build-up our understanding of the reactions route by taking our NMR pictures which contains precise information about the identity of the participants (molecules) at different times after the start of the reaction. This means that we will monitor the same process several times in order to produce the necessary molecular level picture that will ultimately allow us to optimise our chosen reaction. The enhanced level of information that will be provided by our new device will enable scientists and industrialists to develop and optimise reactions in a way that was previously impossible and hence contribute more positively to society.