PhD Opportunities

Overview

The Chinese Scholarship Council (CSC), in partnership with the University of Leicester, has up to 25 full scholarships per annum available for outstanding Chinese students to undertake full-time PhD study at the University of Leicester.

Further information

Please refer to our CSC studentships website for more details.

Informal enquiries to any of our Academic Staff are welcome.

Project supervisor

Dr Alison Stuart

Project details

An important strategy in the drug discovery process is the incorporation of fluorine into biologically-active molecules because fluorine can increase the potency and improve the pharmacokinetic properties. Consequently, 30% of all agrochemicals and 25% of all pharmaceuticals contain fluorine atoms. In 2013 we introduced the hypervalent iodine(III) reagent 1 as a new, easy-to-handle fluorinating reagent for installing carbon-fluorine bonds. Initially, a transition metal was required to activate the fluoroiodane reagent 1 by coordinat-ing to the fluorine atom, but in 2019 we demonstrated that it can be activated by hydrogen bonding to hexafluoroisopropanol. The aim of this exciting new research project is to combine chiral hydrogen bond donors with the fluoroiodane reagent 1 to develop enantioselective fluorinations.

The successful candidate will gain hands-on-experience in synthetic organic chemistry, asymmetric catalysis, reaction design, molecular modelling and modern analytical techniques using state-of-the-art equipment (multinuclear NMR spectroscopy, stopped-flow NMR spectroscopy, mass spectrometry, chiral GC and chiral HPLC). This PhD project will provide excellent training for a student interested in a career in either academic or industrial research such as in synthetic methodology development, medicinal chemistry, agrochemistry, process chemistry, as well as in fine and speciality chemicals.

References

1. “Alkene vicinal difluorination: From fluorine gas to more favoured conditions” S. Doobary and A. J. J. Lennox, Synlett, 2020, 31, 1333-1342.

2. “Electrophilic fluorination using a hypervalent iodine reagent derived from fluoride” G. C. Geary, E. G. Hope, K. Singh and A. M. Stuart*, Chem. Commun., 2013, 49, 9263-9265.

3. “Intramolecular fluorocyclizations of unsaturated carboxylic acids with a stable hypervalent fluoroiodane reagent” G. C. Geary, E. G. Hope and A. M. Stuart*, Angew. Chem. Int. Ed. Engl., 2015, 54, 14911-14914.

4. “ Activation of the hypervalent fluoroiodane reagent by hydrogen bonding to hexafluoroisopropanol ” H. K. Minhas, W. Riley, A. M. Stuart* and M. Urbonaite, Org. Biomol. Chem., 2018, 16, 7170-7173.

5. “Accessing novel fluorinated heterocycles with the hypervalent fluoroiodane reagent by solution and mechanochemical synthesis” W. Riley, A. C. Jones, K. Singh, D. L. Browne and A. M. Stuart*, Chem. Commun., 2021, 10.10139/d1cc02587b.

Further information

To apply: please refer to our funded opportunities website for more details, such as how to Apply for this PhD position.

Informal enquiries to Dr Stuart are welcome. For further application details, please contact postgraduate admissions (chempgr@le.ac.uk).

Project supervisor

Dr Jake (Minjun) Yang

Project details

Growing industrialisation and anthropogenic emissions are suffocating our planet. Frequent and unnatural harmful algae blooms are directly linked to sewage and agriculture pollution. Deadly viruses are ravaging our nation and posing a threat to the human race. These are global issues asphyxiating our generation and we need to start monitoring our planet now.

Recent electrochemistry-based research showed that different species of marine phytoplankton exhibit a species-specific susceptibility towards electrogenerated oxidative species.[1,2] Marine phytoplankton are the beacon of climate change not least because they are the basis of the food web of our Ocean but certain toxin-producing species are the underlying cause of the so-called ‘red tide’. The breakthrough in electrochemistry offers a promising basis for a sensor technology to be developed to monitor the health status of our ocean which also acts as an early warning system for future harmful algae blooms.

This project provides a platform for the student to develop electrochemical sensing strategies of marine phytoplankton with opportunities to expand into bacteria and viruses sensing by first understanding how electrogenerated species react with single-entity ‘soft-body’ particles. The project is core in electrochemistry with a close connection to environmental monitoring and real-world applications.

This project welcomes students with a strong background in Physical Chemistry, Biology or Biochemistry. The candidate should highlight, although not essential, any prior research experience in electrochemistry and/or soft matter. During this studentship the candidate will develop many desirable scientific skills of wide applicability, embracing electrochemistry, microscopy, instrumentation and sensing strategies, data analysis, surface chemistry as well as other key transferable skills. Patenting and entrepreneurship/start-up opportunities will be explored closely with the Leicester Innovation Hub.

References

1. Yang, Minjun, et al. "Fluoro-electrochemical microscopy reveals group specific differential susceptibility of phytoplankton towards oxidative damage." Chemical Science 10.34 (2019): 7988-7993.
2. Yang, Minjun, et al. "Calcifying Coccolithophore: An Evolutionary Advantage Against Extracellular Oxidative Damage." Small (2023): 2300346.

Further information

To apply: please refer to our funded opportunities website for more details, such as how to Apply for this PhD position.

Informal enquiries to Dr Yang are welcome. For further application details, please contact postgraduate admissions (chempgr@le.ac.uk).

Project supervisor

Dr Philip Ash

Project details

Redox properties of metal-containing active sites are critically important to many biocatalytic processes: one third of all proteins contain a redox-active metal, and ca 22% of submissions to the Protein Data Bank contain a transition metal. Metalloproteins capable of extracting energy from H₂ gas, sequestering CO₂ from the atmosphere, or performing complex monooxygenation reactions, rely upon the ability to access and control a range of often exotic metal oxidation states in an aqueous environment. Much of this crucial chemistry occurs at extremely fast rates, making it challenging to study using conventional structural and spectroscopic methods.

This project aims to investigate the catalytic mechanisms and structural dynamics of metalloenzymes that are vital for chemical energy conversion, with a focus on hydrogenase. State-of-the-art spectroscopic and structural studies will be combined with computational analysis to reveal critical but elusive transient intermediates by studying reactions in real time on sub-microsecond timescales. The outcomes of this project will provide a step change in our understanding of the mechanism of hydrogenase and other metalloenzymes, and will serve as inspirational catalysts for future green energy technologies.

The PhD student will gain a broad range of interdisciplinary skills in spectroscopy, electrochemistry, chemical biology, structural biology, and biophysics whilst addressing critical questions about how nature achieves efficient chemical energy conversion.

Further information

To apply: please refer to our funded opportunities website for more details, such as how to Apply for this PhD position.

Informal enquiries to Dr Ash are welcome.

Project supervisor

Dr Richard Hopkinson

Project details

Aldehydes are highly reactive chemicals that are common pollutants and human metabolites. However, the vast majority of aldehydes’ biological functions are unknown.

We believe that endogenous aldehydes are key regulators of human biology. Given their chemical reactivity, it is likely that aldehydes can affect multiple biochemical pathways by reacting with DNA and proteins. However, it is currently unclear what reactions occur in human cells and how these reactions affect human biology at the molecular and systems levels.

Recent pioneering work has revealed a potential function for aldehydes in human ageing. These studies using mouse models suggest a link between genotoxic aldehyde stress and the p53 response, leading to early cell senescence. This is a hallmark of premature ageing (Wang et al., Mol. Cell, 2023). While these findings are extremely exciting, there is currently little known about the underpinning molecular mechanism. Identifying this mechanism is essential as it would redefine our understanding of human ageing and could lead to the development of anti-ageing therapies.

Defining how aldehydes induce cell senescence requires the development of a simple and robust cell model where (i) cellular aldehyde levels can be easily modulated and quantified, and (ii) where the molecular mechanisms underpinning senescence, e.g. p53-dependent pathways, can be analysed in a sensitive and controlled manner. This project therefore aims to establish such a cell model and to use it to discover how aldehydes affect ageing-related biology. 

Further information

To apply: please refer to our funded opportunities website for more details, such as how to Apply for this PhD position.

Informal enquiries to Dr Hopkinson are welcome.

Project supervisor

Dr Patricia Rodriguez Macia

Project details

Background: In the future we will depend solely on renewable energy (sun, wind, biomass, etc.), CO₂ and H₂O to generate and store energy. To aid this transition, efficient catalysts and new catalytic routes for energy-conversion reactions based on abundant and cheap materials are needed. Solutions to the energy problem require understanding of how energy-conversion processes happen in nature and of what it takes to make catalytic systems as proficient as the natural biocatalytic systems (i.e. energy converting enzymes), while maintaining the relative simplicity of a molecular catalyst or catalytic material.

Energy converting enzymes have evolved for billions of years resulting in earth-abundant metal active-sites perfectly optimised by the inner and outer coordination spheres in the protein matrix. They are able to catalyse key chemical reactions with very high rates and minimum energy waste. These reactions still represent enormous challenges for industry (e.g. H₂ conversion, reduction of N₂ to ammonia, and reduction of CO₂ to CO or formate).

Objectives: This project is in an exciting emerging area of biotechnology where naturally occurring and de novo protein scaffolds are combined with synthetic catalysts to generate semi-synthetic and artificial metalloenzymes with new catalytic reactivities for sustainable and green chemistry. The project combines the strengths of synthetic chemistry, natural enzymes and de novo protein design to develop a new set of semi-synthetic and artificial metalloenzymes with potential for industrial biotechnology. Artificial metalloenzymes (ArM) consist of a simple synthetic molecular catalyst hosted in a protein scaffold that confers stability, efficiency and specificity. Importantly, the amino acid residues in the 1st and 2nd coordination-spheres can be engineered to tune the catalytic properties of the catalyst. Recent advances allow high yield (~1 g/L) production of small, stable, and easy to purify and characterise scaffold proteins such as the [FeFe] hydrogenase – one of the fastest and most efficient H₂-converting catalyst in nature. These enzymes can be produced in E. coli in a form lacking part of the active site, which can then be reconstituted with synthetic catalysts to produce fully active enzymes. This strategy enables any hydrogenase of interest to be produced and reconstituted with a wide variety of synthetic cofactors.

Further information

To apply: please refer to our funded opportunities website for more details, such as how to Apply for this PhD position.

Informal enquiries to Dr Rodriguez Macia are welcome.

Project supervisor

Dr Patricia Rodriguez Macia

Project details

Global warming caused by greenhouse gases like CO₂ is a major global concern. Understanding the complex natural cycling of greenhouse gases is crucial to address the urgent climate crisis. The cycling of key greenhouse gases, like CO₂, involves microorganisms that fix CO₂ and release methane. Some microorganisms also utilise intermediates like carbon monoxide (CO) and dihydrogen (H₂) in their metabolism. The metabolic pathways of these microorganisms involve specialised gas-processing enzymes, which are key to understand how greenhouse gases can be fixed from the atmosphere, and directly related to biogeochemical cycles, global warming, and climate change.

This project aims to develop new biohybrid catalysts by utilising biological scaffolds to host or bind synthetic catalysts. Biohybrid catalysts hold a lot of potential to fix greenhouse gases from the atmosphere and for carbon capture and storage (CCS). They are sustainable, as they are biodegradable and produced from naturally abundant materials. Biohybrid catalysts combine the advantages of synthetic chemistry with the benefits of natural enzymes (specificity/selectivity). However, biohybrid catalysts based on protein scaffolds from ‘regular’ organisms are generally restricted to ambient conditions, limiting their scope for application in biotechnology.

Extremophiles are organisms that live under extreme environments, such as under high pressures and extremes of temperature and pH. Evolution of organisms under extreme conditions has optimised their enzymes for exquisite performance under harsh conditions. This project aims to make use of the unique properties of extremophiles by mining their genomes in search of ideal scaffolds for synthetic catalysts to build biohybrid catalysts that can work under non-ambient conditions. 

Further information

To apply: please refer to our funded opportunities website for more details, such as how to Apply for this PhD position.

Informal enquiries to Dr Rodriguez Macia are welcome.

Project supervisor

Dr Richard Doveston

Project details

Background: The need for new medicines is greater than ever because of an ageing population and the complex clinical challenges brought about by drug resistance and/or side effects. These problems are particularly acute in the oncology and neurodegeneration therapeutic areas, and this a significant negative impact on society and the economy. As a result, the focus of drug discovery has shifted in recent years away from classical enzyme inhibitors (e.g. kinase inhibitors) to even more challenging targets. Protein-protein interactions (PPI), and in particular inhibitors of these interactions, are at the forefront of this revolution: venetoclax has recently become the first PPI inhibitor approved for the treatment of chronic lymphocytic leukaemia. However, PPI inhibition alone does not fully exploit the potential scope and power of PPIs as drug targets.

Using drugs that act as molecular glues, to stabilise the interaction between proteins, is a highly novel therapeutic strategy that can greatly expand the number, effectiveness and precision of available treatments. This project will build on exciting discoveries in our labs. We have found that covalent, or irreversible, molecular glues that target specific interactions of an important family of ‘hub’ proteins called 14-3-3 is a highly effective strategy for PPI stabilisation that could address a range of disease states including cancer and neurodegeneration.

Project Aim: The aim of the project will be to optimise and refine this therapeutic approach. This will be achieved by studying the role of cysteine amino acids in 14-3-3 proteins. Cysteine is crucial because its nucleophilic properties make it the ideal site for covalent protein modification. In addition, gain of cysteine mutations to 14-3-3 is significant in neurological diseases. We will take an interdisciplinary chemical biology approach to develop more efficacious and selective molecular glues. Ultimately, we aim to deliver new chemical tools for to help further our understanding of disease, and drugs that can be translated into clinical use.

Further information

To apply: please refer to our funded opportunities website for more details, such as how to Apply for this PhD position.

Informal enquiries to Dr Doveston are welcome.

Project supervisor

Dr Stephen Ball

Project details

Air pollution is responsible for around 350,000 premature deaths per year in Europe [1] and 7 million globally [2]. In the UK and in Europe, the three most toxic air pollutants are NO₂ (nitrogen dioxide), tropospheric O₃ (ozone) and PM (particulate matter). NO₂ and PM are emitted directly from various human-made sources and a few natural sources, but the majority of NO₂ comes from road vehicles. Substantial decreases in NO₂ concentrations were observed during COVID lockdown restrictions when people’s activity was severely reduced [1,3]. Contrastingly, tropospheric ozone is not emitted directly but rather it is produced within the atmosphere itself from the photochemical oxidation of volatile organic compounds in the presence of nitrogen oxides (NO_x = NO+NO₂). Some types of PM are also generated and/or chemically transformed in the atmosphere. Controlling these secondary air pollutants is challenging because it requires control of their precursors, and such efforts must be informed by a thorough understanding of the chemical pathways.

Observations of air pollutants are vital. The UK’s main monitoring is done by the Automated Urban and Rural Network (AURN) which runs 150 air monitoring sites [4]. Additionally, three “air quality supersites” have been established that contain more extensive instrumentation for conducting detailed studies of atmospheric composition and variability. One supersite is on Birmingham University’s campus [5], where this project will deploy additional research instruments from our group to quantify oxidised nitrogen compounds.

To further complicate the picture, air pollutant concentrations are highly dynamic, especially close to pollution sources. As an example, Figure 1 shows measurements of NO₂ and aerosol optical depth (related to PM concentrations) made close to a roadside over a brief 10 minute interval. Concentrations can change by a factor of 3 in just a few seconds with the passing traffic. Notice also how some vehicles were strong emitters of both NO₂ and aerosol (peaks at 15:21:40 and 15:22:27); others emitted aerosol but only small amounts of NO₂ (15:15:55 and 15:17:12); and others strongly emitted NO2 but very little aerosol (15:19:47).

Figure 1: A time series of emissions from road vehicles. NO₂ mixing ratios are in red, overlaid by wavelength-resolved aerosol extinctions (coloured as stated in the legend). The BBCEAS instrument sampled from a second-storey window of a university building overlooking a public road.

The CENTA student will use a broadband cavity enhanced absorption spectrometer (BBCEAS) built at Leicester University. This instrument acquired the data shown in Figure 1. A light beam is reflected many times through ambient air samples, thereby producing a highly sensitive measurement. The instrument is configurable for different nitrogen-containing trace gases: (i) simultaneous measurements of HONO and NO₂ (HONO is a source of OH radicals) [6], (ii) fast time-resolution NO2 observations [Figure 1], (iii) quantifying the night-time NO₃ radical and its reservoir compound N2O5 [7]. It is anticipated that the student will measure different oxidised nitrogen species at different stages of the project to complement the ongoing “core” observations at the Birmingham supersite, plus a more intensive measurement period to study the formation of aerosol nitrate from the deposition of N₂O₅ and HNO₃.

Further information

To apply: please refer to our funded opportunities website for more details, such as how to Apply for this PhD position.

Informal enquiries to Dr Ball are welcome.