More efficacious and better-tolerated drugs are crucial for the treatment of serious and common medical conditions. Scientists involved in discovering drug compounds require synthetic methods that allow them to design molecules with optimal properties. The development of new methods will also influence the design of such compounds by providing new structural motifs as design options, and by providing new ways to connect and functionalise molecules. Small rings (examples include oxetanes and azetidines) are highly attractive in drug discovery, but are vastly understudied, not least through lack of suitable preparative methods. This prevents their exploitation. The incorporation of these rings can lead to improved properties in a drug molecule. Furthermore, they can be envisaged as replacements for other more common structures that can fine-tune and improve the properties of a compound (the idea of being a 'bioisostere'). This research will harness these ring structures in novel, stable and easily handled reagents that can be prompted to react in a new type of coupling process that generates a reactive intermediate under mild conditions. The new reagents allow the generation of collections of valuable compound collections and the 'late-stage' functionalisation complex drug candidates and biological molecules to improve and tailor their molecular properties. The research consists of 3 parts. The first will prepare new reagents and establish their reactivity and synthetic characteristics. These will be used to prepare new molecules that will be valuable for testing in drug discovery, for example in fragment based drug discovery, a strength of UK industry. Analogues of current drug molecules will also be prepared replacing key features with the new small rings as bioisosteres. Part 2 will compare the properties of some of the new types of molecules prepared with those containing different more common groups to establish the change in properties. This will inform synthetic and medicinal chemists on when to exploit the new designs in drug design. Derivatives that will be prepared in this work present a exciting potential as bioisosteres for amides, perhaps the most common functional group in drug compounds. Finally, the new reagents will be examined in peptide functionalisation using water tolerant derivatives and to establish selectivity. These fundamental studies will lead to new types of probes to investigate biological systems. Each stage will develop new synthetic chemistry and reactivity features, and provide new insights for medicinal chemists.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

The COVID-19 pandemic has exposed two major weaknesses in our preparedness for respiratory viral threats. Firstly, there is a critical lack of available antiviral drugs which can be deployed at the first signs of symptoms or as post-exposure prophylaxis (given as a short course to people who have been in contact with an infected individual). Secondly, a basic principle of treating viral infections is that a combination of drugs with different modes of action is usually required, and for respiratory viruses, antiviral combinations are only effective if started in the first day or two following symptom onset. As with other respiratory viruses such as influenza, SARS-CoV-1 and MERS-CoV, SARS-CoV-2 viral replication rapidly slows following symptom onset with the later severe stage of disease mediated more by the body's response to the infection rather than active viral replication. Most clinical trials to-date have used single antiviral agents rather than combinations, and have studied hospitalised patients (i.e. late stage of the disease) when antivirals are unlikely to work. Most prioritised studies have been Phase III ttrials of agents that have not first been proven to reduce viral load in Phase II. Unsurprisingly, none of the repurposed monotherapies studied in this way have yet shown any benefit, and in the case of (hydroxy)chloroquine, have been proven to cause harm. There is an urgent need to rationally develop combination antivirals which reduce viral load, disease severity and risk of onward transmission. For vaccines, rational development meant small Phase II studies to assess antibody response, with successful vaccines taken forward to Phase III. The analogy for antivirals is small Phase II studies to find antiviral combinations that reduce viral load before progressing successful ones to Phase III. Repurposing trials such as RECOVERY and PRINCIPLE which took antiviral monotherapies with limited in vitro activity straight to Phase III have now comprehensively proven to be an inefficient way to find effective antiviral combinations. A more rational approach based on sound principles of antiviral drug development is now required. This work will focus on mathematical modelling of SARS-CoV-2 viral dynamics in order to optimally design and analyse the results for Phase II antiviral trials. Looking at the difference in viral load in patients receiving antivirals compared to placebo is complicated by the fact that in the normal course of the disease, viral load changes by the hour: after initial infection viral load in the nose and throat rises to a peak around the time of symptom onset, and then falls away again such that by Day 7 up to a third of people no longer have detectable virus. Viral load trajectories also differ in patients of different age, disease severity, and potentially when infected with different variants of the virus. Therefore a mathematical model of the expected time course is needed to tease out drug effects from these other variables. Using data we have collected during a recent individual patient-level meta analysis, we will firstly compare the performance of various recently published viral dynamic models on how they predict viral load with time. Using data from two ongoing Phase II trials, FLARE and FANTAZE, the models will be refined to account for new variants (both are double blind randomised trials with daily viral loads and whole genome viral sequencing) and to develop models of the repurposed drug combinations being tested (favipiravir, lopinavir/ritonavir and nitazoxanide). We will also work with Pfizer to apply these models to novel agents in their antiviral pipeline, and apply the models to real world data from three London hospitals to assess whether certain patient groups with prolonged viral shedding may benefit from antiviral treatment. The final output will be a modelling framework for the design and analysis of combination antiviral Phase II trials.

Microfluidics provides an exceptional environment for the generation of controlled droplet dispersions and their manipulation in prescribed flow fields. The spatio-temporal correspondence between microchannel position and reaction 'time' permits the study of kinetics of (chemical and physical) processes with unprecedented time resolution and dynamic range. Further, the combination of the small volumes of droplet 'reactors' and the precise formulation of their composition opens vast possibilities in chemical synthesis, including screening, discovery and optimisation. Monitoring reactions in real-time with non-invasive probes remains, hitherto, a major shortcoming of microchemical reactors due to the minute sample volumes (pL-nL) and fast travel speeds (1-1000 mm/s). This proposal seeks to develop, implement and validate a novel experimental approach to monitor microchemical reactions in real-time by coupling, for the first time, cavity ring-down spectroscopy and solvent-resistant microfabrication. This approach will permit the online study of model catalytic reactions, with unprecedented reproducibility and flow control. Cavity ring-down spectroscopy will permit the analysis of pL volumes, effectively eliminating the restriction of path length in microchannels, with nanosecond to microsecond time resolution, compatible with microreaction drops. In particular, we will elucidate individual and global reaction population outcomes and the effect of mixing and flow, with spatiotemporal resolution. This approach is applicable to a range of organic chemical reactions and, for this work, we will focus on selected model systems (detailed below) of fundamental and industrial relevance.

When a molecule is oxidised, it either loses electrons (increasing its 'oxidation state') or, more commonly in organic chemistry, it gains an oxygen atom from another molecule (the 'oxidant'). Oxygenated molecules are important intermediates for the preparation of complex molecules, including medicinally interesting compounds, and are thus important for phamaceutical production.However, oxidation reactions are often difficult to achieve on a large scale, due to the following reasons:(i) Many oxidants are either toxic, or are thermally unstable materials that are potentially explosive;(ii) Oxidation reactions are by nature exothermic and may involve induction periods - this makes a reaction inherently unsafe, as thermal runaway is unpredictable and thus difficult to control.(iii) Presence of oxidants in organic solvents may generate organic peroxides, which are explosive at a certain limit, and may also cause thermal runaway reactions;(iv) The reaction can be unselective, producing many products, which may be difficult and costly to separate.This project proposes to overcome these problems by designing a new equipment to perform these reactions safely and cleanly, using largely electricity and water to generate oxidants. As the oxidant is generated and consumed immediately, the effective concentration of the reactive oxidant is kept to a minimum during the process, thus eliminating explosive hazards and environmental exposure. We are interested in 'waste free' reactions that produces side products that are environmentally benign, such as water, or in a form that can be recovered and reused (recycled).