This project is co-sponsored by the Institute of Chemical Biology, Imperial College London, and BASF SE. 

Student

Niall McIntyre

Title

Characterising novel insecticide transport to maximise efficiency and minimize environmental impact

Supervisors

• Dr Nick Brooks
• Co-supervision with BASF SE. 

Abstract

One of the greatest global priorities is finding strategies that will support the supply of high quality, nutritious food for the worlds fast-growing population. One vital strand that will support this is the development of novel efficient, safe agrochemicals with low environmental impact.

The development of insecticides has been highly successful at targeting specific active protein sites, however, while there has been progress in both modelling and machine learning approaches to predicting the transport and efficacy of insecticides, these approaches are also severely hampered by lack of input characterization data relating to membrane transport.

In this project we aim to develop an integrated measurement platform that will allow rapid characterisation of the transport of insecticides across model membranes and physical barriers. This data will allow direct rapid screening and prediction of efficiency of agrochemical formulations, and we will couple this to machine learning approaches that will allow us to predict membrane transport based on specific molecular features.

By significantly expanding the developmental parameter space beyond target site identification and interactions, we anticipate that, in the future this will lead to development of insecticide formulations with lower applied concentrations, increased specificity and improved environmental performance. 

Student

Amalia Chrysostomou

Title

Biomimetic control of ovarian follicle development: combining multi-scale soft biomaterials with biochemical interactions

Supervisors

• Dr Iain Dunlop
• Professor Kate Hardy
• Professor Stephen Franks

Abstract

Ovarian bioengineering is emerging as a new interdisciplinary field. Recent advances show that eggs, and their encapsulating follicle structures, are directed in their development by their physical and biomechanical microenvironments, in addition to traditional ideas of hormonal control. New work by our labs reveals a complex multiscale biomechanical environment inside the ovary (https://www.biorxiv.org/content/10.1101/2021.01.03.425098v1.)

The student will apply these insights to create new in vitro culture systems, structured over micro- to nano-lengthscales, that mimic the ovary interior. These will combine soft biomaterials chemistry with microfluidic fabrication and biochemical approaches to cell-stimulation. This technology platform will be used to investigate the systems biology of the ovary, aiming for an integrated physical/biochemical understanding. This has implications for fertility, since dysregulation of follicle development is a major driver of female infertility, e.g. polycystic ovary syndrome (PCOS); premature ovarian insufficiency (POI). The project will fit a student with a Chemistry, Materials, Bioengineering, Chemical Engineering or Physics background and a strong interest in interdisciplinary research.

Student

Siân Allerton

Title

Structural and pathological consequences of aSyn/lipid membrane interactions

Supervisors

• Dr Francesco Aprile
• Dr Marina Kuimova
• Professor Joshua Edel
• Dr Aleksander Ivanov

Abstract

Lipid membranes play a key role in biological and pathological processes of our body. The formation of aggregates of several neurodegenerative proteins in the brain is modulated by the interaction of these proteins with lipids [Nat. Chem. 2018, 10, 673]. In particular, alpha-synuclein (aSyn) aggregates are linked to Parkinson’s disease (PD) and dementia and form as a direct consequence of the monomer interaction with neuronal membranes. Currently, we still lack information regarding the mechanism of this process. The goal of our project is to determine the mechanisms by which various lipids affect the formation, structure and toxicity of aSyn aggregates and, in turn, how aggregates affect neuronal membranes. We will do so by combining antibody discovery, fluorescent environmental probes, and single-molecule detection. This project will not only unveil key pathological mechanism in PD and other forms of dementia but will also provide foundational physical knowledge on protein-lipid interactions and lead to new ultrasensitive detection methods for biomolecules.

Student

Thomas Maher

Title

Development of novel photochemical probes to investigate quadruplex DNA interactome in livings cells

Supervisors

• Professor Ramon Vilar Compte
• Professor Ed Tate
• Dr Marco Di Antonio

Abstract

Genomic DNA is mainly folded into a double-stranded structure. However, guanine-rich regions can fold into alternative DNA structures called G-quadruplexes (G4), which have been recently visualized in human cells. G4s have been associated with genomic instability, regulation of gene expression and replication, and they are potential drug targets in a range of diseases. While the past decade has seen significant advances in the characterisation of G4 DNA structures, there remains a significant lack of understanding of the proteins responsible for G4-recongition in cells, which is key to further elucidate G4s’ biological significance. This project aims to bridge this gap by developing photoactivatable probes that can label proteins bound to G4s in living cells. We recently demonstrated that Pt(II) complexes known to bind to G4s can also efficiently generate short-lived reactive oxygen species (ROS) under light irradiation. We propose to use the generated ROS to efficiently label proteins bound to G4s, which will be subsequently analysed by quantitative proteomics methods.

This project is jointly funded by the European Research Counil and Institute of Chemical Biology EPSRC Centre for Doctoral Training

Student

Harry Beaven

Title

Communication within the membrane during complement activation

Supervisors

• Dr Doryen Bubeck
• Dr Nick Brooks

Abstract

The membrane attack complex (MAC) is one of the immune system’s first responders. Complement proteins assemble on target microbial or self-cell membranes to form pores that lyse pathogens and affect tissue homeostasis. While MAC assembly is known to cause changes in some key membrane mechanical properties, there remain significant questions about the protein - membrane interplay and interactions that bring about these changes and the impact that membrane – protein co-structuring has on a wealth of other physiologically critical biophysical membrane parameters. Understanding these biophysical mechanisms is critical to developing new strategies to intervene in complement immune deficiencies that have devastating consequences for human health. Here, we will use newly developed approaches to investigate the effect of MAC assembly on key biophysical parameters of biological and biomimetic membranes, and the feedback of these changes on the subsequent MAC assembly steps and eventual membrane rupture.

Student

Maya Müller

Title

Developing a DNA based synthetic cytoskeleton

Supervisors

Dr Nick Brooks
Dr Lorenzo Di Michele
Professor Jake Baum

Abstract

The cell’s plasma membrane mechanical properties are thought to play a key role in a wide range of diseases, including malaria, atherosclerosis and cancer. The mechanical behaviour of cellular membranes is not only determined by the composition of the lipid bilayer, but also by a myriad of other membrane-anchored cellular elements, including membrane proteins and the cytoskeleton. However, mimicking biology’s exquisite membrane mechanical control via cytoskeleton assembly remains elusive in synthetic assemblies. This shortcoming in bottomup synthetic biology limits our ability to probe the molecular interactions that underpin membrane behaviour and responses under stress, such as osmotic pressure or shear flow, and constricts the application of bottom-up synthetic biology approaches in harsh environments such as environmental remediation and industrial processing. In this project, we will develop methods to build model lipid membranes with synthetic DNA nanostructures, which can be polymerized to form a supporting scaffold. Using these custom designed DNA architectures, whose size, interactions, and stiffness can be finely controlled, we will be able to tune membrane rigidity and viscosity, as well as enabling response to environmental cues (e.g. temperature, pH, enzymatic activity). We will characterize the effect of the DNA scaffolds on the membrane’s mechanical properties by unique in-house synthesized viscosity-sensitive fluorescent probes (molecular rotors) together with other techniques such as the Fourier analysis of membrane’s thermal fluctuations and micropipette aspiration. This highly multidisciplinary project will provide experimental training in soft matter science. membrane biophysics, DNA nanotechnology, fluorescence spectroscopy and microscopy, and rapid prototyping approaches, automation and machine learning will form key pillars of the project.

This project is jointly funded by the CRUK Imperial Centre and Institute of Chemical Biology EPSRC Centre for Doctoral Training as a 4 year PhD

Student

Gemma Flint

Title

Targeting G-quadruplex DNA to overcome resistance to PARP inhibitors

Supervisors

• Dr Marco Di Antonio
• Professor Hector Keun
• Professor Ramon Vilar Compte

Abstract

PARP inhibitors such as Olaparib have revolutionised treatment of ovarian and breast cancers, which are typically BRCA2 deficient. However, resistance to PARP inhibitors has been already observed in the clinic, rising the need of alternative BRCA2-selective therapies. G-quadruplex ligands have recently emerged as potential therapeutic tools that displayed increased toxicity in BRCA2 deficient genetic backgrounds, retaining their activity also in Olaparib resistant cancers. However, there is a lack of understanding of the fundamental biology linking PARP activity, NAD+ metabolism and G-quadruplex formation, which hampers to investigate further this therapeutic avenue. In this project, we propose to combine synthesis, metabolomics and genomics to unravel the crosstalk between PARP activity and G-quadruplex formation. This study, will shed light on the fundamental mechanisms linking Gquadruplex formation and NAD+ metabolism, providing a platform for the rational design of the next generation of drugs to treat PARP-resistant cancer patients.

This project is jointly funded by the CRUK Imperial Centre and Institute of Chemical Biology EPSRC Centre for Doctoral Training as a 4 year PhD

Student

Matthew White

Title

Novel senolytic drugs as anticancer therapies

Supervisors

• Professor Jesús Gil
• Professor Ed Tate

Abstract

Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells. In addition to becoming cell cycle arrested, senescent cells undergo a number of changes, the most notorious being the secretion of a complex mixture of mostly pro-inflammatory factors collectively referred as the senescence-associated secretory phenotype (SASP). The chronic accumulation of senescent cells contributes to aging, disease and cancer, whilst eliminating senescent cells genetically or using so called ‘senolytic’ drugs increases health span and lifespan. Targeting senescent cells is rapidly gaining traction as an anticancer therapy and has been highlighted as a Grand Challenge by CRUK. Existing cancer treatments (including chemo-, radio- and targeted therapies) induce senescence of cancer cells which can be eliminated with senolytics in a so-called “one-two punch” approach. 

In this PhD you will be at the centre of a multidisciplinary collaboration to discover and understand the mode of action of senolytic compounds targeting PTM pathways, with broad applications in many cancers and diseases of aging. You will apply chemical proteomic tools and novel drugs currently in preclinical development in the Tate and Gil labs to drive validation of drug targets in these pathways. Your research will be based in the lead supervisors’ labs at the state-of-the-art Molecular Sciences Research Hub and the MRC London Institute of Medical Science, on the adjacent Imperial White City and Hammersmith Hospital campuses. You will also collaborate with scientists in industry and at the Francis Crick Institute. You will receive training in all relevant aspects of chemical biology, proteomics, cancer cell biology and in vivo models, and you will benefit from membership of the Imperial Cancer Research UK Centre and the Institute of Chemical Biology.

This project would ideally suit candidates with a Masters level qualification in chemistry or a closely related subject, with research experience in chemical biology or medicinal chemistry, and a strong interest in drug target validation and novel approaches to target cancer.

This project is co-sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Vertex Pharm. Ltd. Oxford. 

Student

Abdul Zafar

Title

Caught in the act: precision tools to unravel and diagnose glycoprotein misfolding

Supervisors

• Dr Benjamin Schumann (Imperial/Francis Crick);
• Dr Andrew Bayly (Vertex);
• Professor Ed Tate (Imperial/Francis Crick) 

Abstract

Protein glycosylation is among the most abundant posttranslational modifications and fundamentally impacts biological processes. In human cells, glycan biosynthesis is mediated through complex elongation and trimming events in the secretory pathway. Carrying the correct glycoforms at key sites is a prerequisite for correct protein maturation and function, influencing many aspects of physiology. However, the design principles governing glycan elaboration are largely unknown. In this project, we will develop bioorthogonal reporter probes for distinct glycan substructures on glycoproteins in the living cell. We will use a process termed bump-and-hole engineering to equip glycosyltransferases with the capacity to accept novel chemically modified analogues of their native nucleotide-sugar substrates in vitro and in the living cell. Establishment of such reporter tools will enable the diagnosis of dysfunctional glycoprotein maturation

Student

John Britton

Title

The effect of membrane asymmetry on electron transfer in complex membrane proteins

Supervisors

• Dr Maxie Roessler
• Professor Oscar Ces
• Professor Bill Rutherford

Abstract

The asymmetric nature of biological membranes is emerging as an important factor in membrane protein function with the molecular basis and role of asymmetry remaining one of the most poorly understood phenomena in biology. We will investigate the impact of membrane asymmetry on the function and mechanisms of membranebound oxidoreductase enzymes at the heart of bioenergetics building on physical sciences innovation consisting of new microfluidic technology for reconstituting them into artificial membrane vesicles, with tunable lipidcomposition, curvature and asymmetry. The development of novel pulse EPR approaches will allow the detection of low concentrations of spins from key radical intermediates. The technological innovations are expected to be broadly applicable to membrane proteins including redox- and metalloenzymes. The advances in understanding structural and mechanistic aspects of respiration and photosynthesis will pave the way to applications in medicine and energy technology.

This project is co-sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Syngenta. 

Student

Sarah Chapman

Title

Electrons, leaves and light: investigating surface photodegradation of agrochemicals

Supervisors

• Dr Maxie Roessler (Imperial)
• Dr Laura Barter (Imperial)
• Dr Ben Robinson (Syngenta)
• Dr Maddalena Bronzato (Syngenta) 

Abstract

With the ever-rising global population, the needs for efficiency and sustainability in agriculture are increasing. Agrochemicals play a key role in many sustainable farming practices but, when applied to plant surfaces and exposed to sunlight, photodegradation is one key mechanism by which their efficiency can be reduced. The development of better models enabling a more thorough mechanistic understanding of photodegradation processes under realistic conditions will help towards increasing efficiency and sustainability in the development and use of new agrochemicals. In this project, we will investigate the role of the leaf surface and composition in the photodegradation of agrochemicals using electron paramagnetic resonance (EPR) spectroscopy.

This project is co-sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Syngenta.

Student

Yu Cheng

Title

3D bio-printing model tissues for targeted discovery in the agri-tech sector

Supervisors

• Professor Oscar Ces (Imperial)
• Dr Yuval Elani (Imperial)
• Dr James Hindley (Imperial)
• Dr Chris Baker (Syngenta)
• Dr Joe Hawkins (Syngenta)

Abstract

Providing nutritious food for a growing global population is one of the biggest societal, industrial and scientific challenges facing the world today. Sustainably increasing agricultural output will be essential to ensure global food security through the 21st century and well designed, targeted agrochemicals are critical to maximising yields and minimising crop loss to various pests. The design of next generation engineered agrochemicals that function selectively is a major challenge and critical to achieving this goal is development of model systems that mimic the multi-scale three-dimensional structure of key biological tissues such as plant surfaces and insect gut.

In this project we aim to combine model membrane engineering, 3D bioprinting and rapid prototyping to build complex tissue models ranging from synthetic cellular assemblies to targeted scaffolds supporting cellular growth and proliferation. We will use these assemblies to investigate the tissue interactions of agrochemicals and decouple the influence of the tissue architecture across length-scales ranging from molecular to macroscopic. This work will allow us to gain an improved understanding of the key bio-transport properties and mechanisms providing new insights into next generation agrochemical development and formulation design.

This project is co-sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Merck Sharp & Dohme (MSD). 

Student

Abigail Iles

Title

Exploring the druggable interactome using novel ligand-directed proximity labelling chemistry

Supervisors

• Dr James Bull (Imperial)
• Professor Edward Tate (Imperial)
• Dr Avinash Shenoy (Imperial)
• Dr Max Lee (MSD)
• Dr Adam Schwaid (MSD)
• Dr Sam Dalton (MSD)

Abstract

We welcome applications for a 4-year MRes/PhD studentship funded by EPSRC and Merck Sharp & Dohme (MSD), co-supervised by Dr James Bull, Professor Edward Tate and Dr Avinash Shenoy (Imperial College London and the Francis Crick Institute), in collaboration with Dr Max Lee, Dr Adam Schwaid, and Dr Sam Dalton (MSD).

Protein complexes are fundamentally important in driving all biological processes, both in normal physiology and in disease, and are coordinated by a network of regulatory processes under exquisite spatiotemporal control, including interactions with other proteins, small molecules and nucleic acids, and post-translational modifications which define the location and duration of complex formation and activity. Traditional approaches to study the ‘interactome’ (ie. the proteins, nucleic acids and small molecules interacting with a protein of interest) have a number of shortcomings, including lack of amplification or spatiotemporal resolution, or requiring considerable genetic manipulation of cells, and offer limited scope to probe function-dependent interactions (e.g. due to ligand binding or changes in protein activity). This studentship seeks to develop novel synthetic chemical probes which can address this challenge in living cells and in native (not genetically modified) systems, to identify potentially druggable interactions of proteins under specific conditions of activation. We will focus on inflammasomes as a target system, protein complexes which form in response to varied inflammation signals to allow the cell to respond to infection or injury through diverse downstream mechanisms. Dysregulated inflammasomes contribute to a wide range of pathologies from cancer to neurodegeneration and sepsis and are a rapidly emerging class of drug targets; identification of novel interactors during inflammasome activation will lead to discovery of new regulatory mechanisms and offer new ways to intervene in inflammasome-driven diseases.

This studentship would suit a talented and motivated chemist or chemical biologist who is passionate about research at the interface with biomedicine, and with a strong interest in studying the chemical probes they design hands-on in living systems. Applicants should have an outstanding academic background in chemistry or a closely related area, with a strong interest in applying medicinal chemistry and chemical biology to living systems in a multidisciplinary project. Training will be provided in all relevant areas (synthesis, molecular cell biology, proteomics, etc.), but previous lab experience in synthetic and/or medicinal chemistry or in cell biology or biochemistry would be an advantage. The successful applicant will undertake research at the new £170M state-of-the-art Molecular Sciences Research Hub at Imperial’s new White City Campus, and at the Tate & MSD labs at the Francis Crick Institute in central London. Informal enquiries may be directed to: j.bull@imperial.ac.uk and e.tate@imperial.ac.uk

Group details:

https://www.imperial.ac.uk/people/j.bull

http://www.imperial.ac.uk/tate-group/

https://www.imperial.ac.uk/people/a.shenoy

Representative references: 

Nature Chemistry 2018, 599–606; ACIE 2019, 14303; Nature Chemistry 2019, 552-61; Nature 2019, 693; EMBO J 2019, e100926; Cell Rep, 2019, 1008-1017; Nature Commun 2020, 1132; JACS 2020, 12020; eLife 2020, 56427; Science 2020, 1091.

This project is co-sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Syngenta.

Student

Shameem Golestaneh

Title

Plug and play microfluidics for frontier Agri-Tech assays

Supervisors

• Dr Yuval Elani (Imperial)
• Dr Leon Barron (Imperial)
• Dr Gerald Larrouy-Maumus (Imperial)
• Dr George Giannakopoulos (Syngenta)
• Dr Ian Southworth (Syngenta)

Abstract

One of the greatest bottlenecks in the agrichemical industry is a poor understanding of how pesticides are metabolised by a given species. This goes to the heart of many unresolved challenges the sector faces. Developing more effective pesticides, minimising harm to non-target species and reducing environmental exposure is critical for building a more sustainable future. Current methods to probe pesticide metabolism are slow, laborious, and low-throughput: compounds are essentially tested one-by-one, considerably reducing possibilities to test new molecules. This project will involve developing novel state of the art lab-on-chip platforms, allowing us to tackle this challenge head-on.

 Our technologies will fuse microfluidics, 3D printing, and robotic sampling to build an integrated device that is coupled to a mass spectrometer. The device will produce tens of thousands of droplets with cells inside, with each droplet serving as a distinct data point. This will allow us to probe metabolic degradation of a library of chemicals by model microorganisms.   When coupled to big-data analysis, rapid screening will allow us to build a suite of predictive models to correlate chemical structure with metabolic degradation characteristics. Our technologies will be enabling ones: once established, they can be repurposed to pharmaceutical screens, and extended to transcriptomic, proteomic & lipidomic analysis in future iterations.

 This is a tech development project at its core, with the student working at the forefront of modern science and engineering. It is ideally suited for candidates with physical science training, including in Chemistry, Chemical Engineering, Bioengineering, and related disciplines. The student will receive superb multi-disciplinary training across several labs specialising in Biotechnology (Elani), Analytical Chemistry (Barron), Metabolomics and Microbiology (Larrouy-Maumus). They will also gain experience in applying blue-skies innovations to real-world challenges, as they will also have the opportunity for a short placement at the Bioscience department of Syngenta at Jeallot’s Hill.

This studentship is sponsored by the The Imperial President's PhD Scholarship

Student

Yunfei Dang

Title

In situ EPR investigations of radicals in (electro)catalysis

Supervisor

Dr Maxie Roessler

Abstract

Numerous chemical reactions involve oxidation or reduction and proceed via radical intermediates, and a detailed understanding of their mechanism can result in a better design of catalysts, including biomimetic systems based on redox-active enzymes. Despite the success of film electrochemistry and electron paramagnetic resonance (EPR) spectroscopy to investigate the reaction thermodynamics/kinetics and nature/structure of radical intermediates, respectively, until recently the combination of the two techniques had not been explored. Building on proof of concept studies, this project will harness the full potential of film-electrochemical EPR by investigating novel electrode materials and applying and designing new spectroscopic methods.

This studentship is sponsored by Bruker and the Department of Chemistry

Student

Davide Facchetti

Title

Investigating the mechanism of the bacterial protection system MsrP/Q using EPR spectroscopy

Supervisor

Dr Maxie Roessler

Abstract

The methionine sulfoxide reductases MsrP and MsrQ play an important role in protecting bacteria, including major human pathogens, against reactive oxygen and chlorine species. However, their mechanism of action is not well understood. In this project, we will employ electron paramagnetic resonance (EPR) techniques to identify and understand the role of radical species in these complex reactions. Moreover, the novel methodology developed to study the MsrP/Q system is anticipated to be more generally applicable to redox-active enzymes.

Student

Yifei Liao

Title

Membrane adaptation under pressure

Supervisors

• Professor Rob Law
• Dr Nick Brooks

Abstract

Oceans cover over 71% of Earth's surface at an average depth of 3800 metres and it is remarkable that we still discover hundreds of new species of marine life with every exploration. Life continues to thrive in the ocean trenches which are up to 11 km deep where organisms have to cope with pressures of 1100 bar. The adaptation mechanisms that enable organisms to survive these crushing pressure remain elusive.

Given the extreme pressure in the deep sea, how can organisms cope with such crushing forces? Much like a chameleon changes colour to match it environment, high pressure tolerant organisms are able to modify their molecular make-up to ensure that they remain functional (e.g. their membranes must remain fluid and not crystallise), however, the mechanisms behind this adaptation and the parameters that are regulated remain elusive. This is primarily due to the fact that the laboratory culture of extreme barophiles and the development of analytical high-pressure apparatus is non-trivial. During this project we will develop instrumentation to study barophiles at pressures found in the deepest oceans on Earth and use this to monitor key biomechanical signatures as a function of pressure.

Student

XiaoTong (Erin) Lin

Title

Investigating neurodegenerative protein aggregation by ultra-sensitive antibody detection

Supervisors

• Dr Francesco Aprile
• Professor Ramon Vilar

Abstract

Many diseases, including neurodegenerative diseases, depend on protein self-assemblies. These protein species are too heterogenous and transient to be studied with standard biophysical approaches. Erin will deliver an ultrasensitive detection platform that combines nucleic acid and protein probes, e.g., aptamers and antibodies, with quantitative polymerase chain reaction. She will use this technology to study the structure of protein self-assemblies linked to Alzheimer's disease and their druggability by small molecules.

Student

Liquan Long

Title

Nanopore sensing of biomarkers in clinical samples using DNA origami nanostructures

Supervisors

• Professor Joshua Edel
• Dr Alex Ivanov

Abstract

Recent nanopore sensing studies have concentrated on receptor-modified carriers for selective nanopore sensing, and this new technique is emerging as a promising tool for disease diagnosis since it allows selective detection of target analytes in complex biological fluids. This project aims to design and construct a novel configuration changeable DNA origami carrier for single-molecule nanopore sensing of biomolecules. The general idea is that this DNA origami carrier can change its structure when bound with the target biomarkers. We will explore detection strategies for sensing biomarkers in clinical samples.

Student

Suchaya Mahuttanatan

Title

The development of synthetic cells using industry 4.0 technologies

Supervisor

Professor Oscar Ces

Abstract

Chemical biology and the field of synthetic cell science offer the potential to construct biomimetic entities from non-living components, rationally combined to create tailorable structural elements and functional pathways. These constructs, often taking the form of 'artificial cells', are designed to sustain complex life-like responses, including metabolism, communication, decision making, motility, and even evolution, and promise to revolutionise fundamental and applied science.

This studentship will look at the development of a new generation of synthetic cells with the capability for targetted delivery and synthesis at the site of action. Coupled with innovation in the physical sciences their design and construction will be driven through integration with industry 4.0 platforms such as additive manufacturing, artificial intelligence (AI) and machine learning (ML), leading to digitisation of the design-test cycles. This will facilitate the high-throughput sweeping of parameters such as membrane chassis composition which in turn regulate synthetic cell stability, the rate of signal propagation via bio-circuitry and cell-environment communication. Coupling 3D microfluidic printing with robotics and automation with transform the field of synthetic cell construction.

Student

Amina Nigmatulina

Title

Probing formation and regulation of membraneless organelles using chemical biology

Supervisor

• Professor Ed Tate

Abstract

Membraneless organelles are formed by the regulated condensation of biomolecular components including small molecules, lipids, proteins, and nucleic acids, and have recently been shown to play a critical role in regulating a wide range of cellular processes, from signal transduction and inflammation to transcription and protein degradation.

In this project, we will develop and apply chemical probes and chemical proteomic approaches to study the components engaged in membraneless organelles, in particular to understand how different classes of protein post-translational modifications (PTMs) regulate their formation and function. For example, we will combine chemical labelling through proximity labelling technologies (APEX, TurboID, microMap) with metabolic chemical tagging of protein lipidation to probe how changes in this PTM regulate liquid-liquid phase separation (LLPS).

In the longer term, this project will validate new tools and approaches to enable this important emerging field, and suggest means to manipulate condensate formation and regulation for therapeutic purposes.

This studentship is supported by the Government of Botswana

Student

Gaseitsiwe Lame Senatla

Title

Design of chemical probes for hedgehog acyltransferase

Supervisor

• Professor Ed Tate

Abstract

The Hedgehog (Hh) signalling pathway is a conserved paracrine pathway that plays a physiological role primarily in embryonic development. However, in adults upregulated Hh signalling is involved in an estimated 25% of all cancer deaths. Iinhibitors targeting downstream Hh signalling in the 'receiving' cells, are first line therapy in certain Hh-dependent cancers. Although initially highly effective, most patients progress within one year due to resistance indicating the pressing need for new approaches which could be used in combination. Hedgehog acyltransferase (HHAT) is required for generation of the Hh signal through palmitoylation of Hh protein in the 'producing' cell. We have discovered multiple novel, validated and chemically diverse HHAT inhibitor hit series, with outstanding potency (100nM and below) in vitro, up to 50-fold more potent than any previously reported, with varied and developable properties. We have further established synthetic routes and analogues of improved potency, the first cryo-EM structures of HHAT bound to each class of inhibitor, and a full suite of biochemical and cellular assays for HHAT inhibition.

Supported by a team of scientists in drug discovery, structural biology and pharmacokinetic analysis, this project will contribute to discovery of the first highly potent and selective HHAT inhibitors as chemical biology tools to validate HHAT as a novel target in preclinical translational cancer models.

Student

Shradda Vadodaria

Title

Targeted inhibition of Ras superfamily proteins through covalent ligand discovery

Supervisor

• Professor Ed Tate

Abstract

Despite enormous potential for drug discovery, targeting small GTPases of the Ras superfamily with small molecule inhibitors remains extremely challenging due to their conformational mobility. However, targeted covalent inhibitors have recently delivered major breakthroughs in the clinic against cancers driven by the Ras superfamily mutant KRasG12C, disproving the supposed "undruggability" of this notorious target in cancers bearing this mutation, and providing a paradigm for clinical development of a new class of covalent drugs targeting small GTPases. Displacing effector proteins from the GTPase/effector interface is a highly attractive approach but presents a significant barrier for conventional small molecule drug discovery due to an extended protein-protein interaction (PPI) surface. We have recently identified the first covalent small molecule inhibitors of this PPI for a novel Ras superfamily drug target, offering a new approach to reduce metastasis in breast cancer, and potentially other cancers with related immune landscapes.

This project will further develop these inhibitors into powerful tools to probe small GTPase biology, and as potential starting points for new drug discovery, using a combination of chemical synthesis, structure-guided design and chemical biology.

This studentship is sponsored by the Chinese Scholarship Council and the Department of Chemistry 

Student

Xinyue Zhang

Title

A discovery platform for novel bifunctional probes and molecular glues

Supervisor

• Professor Ed Tate

Abstract

Traditional small molecule drugs and chemical probes achieve their effect through stoichiometric binding of their protein targets, with the majority modulating just four protein classes. Much of the proteome is currently considered 'undruggable', leaving a clear need for new modalities that manipulate protein function through mechanisms which do not depend on tight binding to a conventional druggable pocket. Effector-driven pharmacology has emerged as a revolutionary approach to impact protein function, exemplified by bifunctional proteolysis-targeting chimeras (PROTACS) and molecular glues (>£10 billion sales in 2020). The drug induces ternary complex formation between a target protein of interest (POI) and an effector protein, often an enzyme, which acts catalytically on the POI to trigger a specific cellular effect. The potential of effector-recruiting drugs to modulate protein function is currently limited by the lack of general approaches to discover new bifunctionals/glues.

This project will develop a platform for de novo discovery of these entities leveraging massive encoded molecular libraries, novel covalent ligand screening technologies, synthetic chemistry and chemical biology.

Student

Ziyan (Sherry) Wu

Title

Non-specific binding of drugs to membrane

Supervisors

• Dr Nick Brooks
• Professor Oscar Ces

Abstract

Student

Runxin Xu

Title

Design, development and testing of novel inflammation resolving stimuli-responsive nanogels

Supervisor

• Dr Nazila Kamaly

Abstract

Nanogels are hydrogels within the nanometer range consisting of cross-linked porous polymer networks with the ability to retain high volumes of water or biological fluids while maintaining their structure. They have a wide range of flexibility in their design, allowing their characteristics such as size, charge, degree of porosity, and degradability to be easily tuned by the choice of monomeric building blocks. Because nanogels can retain a high volume of water, they are extremely biocompatible. This excellent and unique property makes them an ideal nanoplatform for the delivery of biological drugs, such as enzymes and proteins.

To this end, this project will focus on the development of stimuli-responsive nanogels that can deliver highly potent innate biological payloads such inflammation resolving proteins, peptides and also nucleic acids.