Student

Nicole Christou

Title

Understanding Amyloid Post-Translational Modification at the Nanoscale

Supervisors

• Dr Francesco A. Aprile
• Professor Ramon Vilar
• Dr Liming Ying

Abstract

Alzheimer’s disease is a fatal and incurable form of dementia, affecting 40 million people worldwide. Despite the high prevalence of Alzheimer’s disease, currently, there is no cure or biometric diagnostic test for it. Small aggregates of the amyloid-beta peptide, called oligomers, cause toxicity in Alzheimer’s disease, and are associated with the disease’s onset and progression. Increasing evidence suggest that post-translational modifications alter the propensity of amyloid-beta to aggregate. However, there is currently no information on the implications of such modifications for oligomers’ structure and mechanisms, as oligomers are too heterogeneous and sparse to be studied with standard methods. To overcome this challenge, we will deliver a novel analytical platform to study oligomers at the single-molecule level. We will combine ultra-sensitive antibody detection with super-resolution microscopy and rational drug design to determine how pathological post-translational modifications affect the structure, toxicity, and druggability of amyloid-beta oligomers. Our results will provide unprecedented information on key mechanisms of Alzheimer’s disease and open new clinical intervention.

Student

Thomas Mills

Title

Simultaneous imaging of protein-protein and protein-membrane interactions using molecular rotors

Supervisors

• Dr Marina Kuimova
• Dr Anna Barnard
• Professor Bernadette Byrne

Abstract

Protein-protein interactions (PPIs) are integral to all biological processes, including those involved in disease pathways. However, methods to study and quantify the effect of targeting these interactions in real time and at a single cell level are currently lacking. This project will develop an exciting opportunity to use molecular rotors, environmentally sensitive fluorophores, to quantitatively detect the function of a PPI inhibitor as a large change in fluorescence lifetime. We will develop novel peptide-rotor conjugates as tools to study the Bcl-2 family of PPIs, key oncology targets. Additionally, inhibition of these PPIs is inexorably linked to permeabilisation of the mitochondrial outer membrane. By employing rotors with complementary emission properties, we will develop methods to study both PPI inhibition and membrane integrity simultaneously, offering unprecedented insight into these interlinked biological events.

Student

Nicolas Zeitouni

Title

DNA-based, microRNA-sensing artificial cells for diagnostics and therapeutics

Supervisors

• Dr Lorenzo Di Michele
• Professor Charlotte Bevan
• Dr Sylvain Ladame

Abstract

MicroRNAs (miRs) are frequently found to be deregulated in bodily fluids of cancer patients and have great potential for early-stage diagnosis. Surprisingly, there is currently no cancer diagnostic test based on miR detection. Here, we will apply DNA nanotechnology to build “artificial cells” for multiplexed detection and quantitation of cancer-related miRs in patient samples. The technology will be tested in vitro on miRs overexpressed in prostate cancer, and then with cancer-patient serum or plasma, potentially unlocking a new non-invasive diagnostic route for a disease where early detection is particularly critical. The biocompatible artificial cells will then be further engineered to release therapeutic payloads upon miR detection, thus laying the foundations for a future therapeutic platform where ACs could be deployed in vivo as a targeted, low-toxicity cancer treatment activated by local miR upregulation.

Student

Jack Dainton

Title

Plug-and-play discovery of molecular glues: a new drug discovery paradigm

Supervisors

• Professor Ed Tate
• Dr Louise Walport
• Dr Jemima Thomas

(Imperial & Francis Crick Institute)

Abstract

Bifunctional drugs and molecular glues are emerging as powerful drug modalities with the potential to transform treatment of currently intractable diseases by targeting so-called 'undruggable' proteins. However, development of new drugs in this space is held back by the lack of generally applicable strategies for their discovery. This project will establish and develop the first universal screening platform to identify novel molecular glues which recruit a specific protein of interest to any desired endogenous cellular effector system, based on unique chemistry applied to billion-member encoded libraries. Through induction of an effector-target protein complex, compounds will trigger catalytic and versatile modulation of protein function, for example by inducing or removing a specific PTM, or by rewiring protein trafficking or signalling complexes, with profound consequences for chemical probe discovery and future therapeutics. This project would ideally suit a student with a strong chemistry or chemical biology background, with a passion for enabling new paradigms in drug discovery, and enthusiasm for learning and applying a diverse range of modern chemical biology approaches, from organic synthesis to molecular genetics, protein biochemistry, and cell biology.

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

Student

Amy McIntosh

Title

Photoactivatable molecular probes to study RNA-protein interactions

Supervisors

• Professor Ramon Vilar (Imperial)
• Dr Marco Di Antonio (Imperial)
• Professor Edward Tate (Imperial/Francis Crick Institute)
• Dr David Hewings (Vertex) 

Abstract

Due to their rich structural diversity and broad range of biological functions, targeting RNA with small molecules is becoming an important strategy in drug discovery. Most cellular functions of RNA are controlled by proteins and dysregulation of these interactions can lead to a range of human diseases. Therefore, there is an increasing interest in efficient methods to identify proteins that bind to specific RNA structures. This project aims to develop a new class of molecular probe (based on small organic and/or metal-organic molecules) for the selective photolabeling of RNA-binding proteins. The new probes developed in this project will be applied to study repeat expansions in RNA structures, several of which are responsible for various neurological and neuromuscular diseases.

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

Student

Sofia Philipps

Title

Next generation PHOTACS: A light switchable system for enhanced spatial and temporal precision in targeted protein degradation

Supervisors

• Prof Matt Fuchter (Chemistry, Imperial);
• Dr Avinash Shenoy (Infectious Disease, Imperial;
• Prof Ed Tate (Chemistry, Imperial);
• Dr Argyrides Argyrou (AZ)

Abstract

Light is unsurpassed in its ability to control biological systems with high spatial and temporal resolution. It has the advantages of noninvasive and remote action, reversibility, speed, and facile modulation of the energies involved (through use of different wavelengths/colours). The control of protein degradation by bifunctional PROTAC small molecules has become a highly interesting and rapidly expanding area of activity with a range of applications, from target validation to the identification of new therapeutic modalities. In principle, the ability to turn such PROTACs ‘off’ and ‘on’ with high spatial and temporal precision using light offers yet more opportunities. While a low number of studies have emerged incorporating so-called photoswitches into PROTACs, many questions remain over the most effective designs and the approach is yet to have been applied broadly. By leveraging cutting-edge photoswitch designs from the Fuchter group, we propose to further develop the concept of photoswitchable PROTACs (PHOTACs). The developed PHOTAC system will be employed to unpick fundamental aspects of signalling of a major proinflammatory cytokine (IL1B), which drives inflammatory pathology in several diseases, including gout, rheumatoid arthritis, neurodegeneration, diabetes, and several hereditary fever syndromes.

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

Student

Anna Kukushkina

Title

An interactomics discovery platform for high value intractable cancer drug targets

Supervisors

• Prof Ed Tate (Chemistry, Imperial)
• Marco Di Antonio (Chemistry, Imperial)
• Emanuela Cuomo (AZ)

Abstract

The field of functional genomics, which associates genetic variants with function at a massive scale, has uncovered a new frontier of highly validated and high-value drug targets. For example, there is extensive evidence that amplification or mutation of specific proteins constitutes a direct mechanistic driver of cancer progression, and these variants are correspondingly highly correlated with poor clinical outcome and therapy resistance. Emerging targets include well-known oncogenic transcription factors (e.g. Myc) or signalling hubs (e.g. K-Ras) which have become an intense focus for drug discovery; however, the majority have also proven persistently very difficult or impossible to drug through conventional discovery approaches. These next generation high-value targets are often termed ‘intractable’ or ‘undruggable’ and present a challenge at the cutting-edge of drug discovery science.

 You will develop a new and universal chemical proteomic technology platform which can comprehensively explore and interrogate the interactome for any intractable target in living cancer cells. You will thereby unlock the ability to screen large compound libraries for small molecules which selectively target protein complexes regulating each intractable target, revealing starting points for new classes of medicines. We anticipate that you will discover compounds which exploit novel and cancer-specific modes of action which can only be discovered in the context of an intact cell, including so-called ‘molecular glue’ modalities which degrade or stabilize novel or native complexes with intractable targets. You will develop a deep and wide range of expertise in this essential area for future drug discovery, including chemical probe design, chemical proteomics, proximity labelling, high-throughput screening and CRISPR-Cas technologies.

 This project would suit a candidate with a passion for developing new approaches for drug discovery, through applying chemistry to understand complex biological systems and cell biology. Prior experience in a multidisciplinary research environment, for example in chemical biology, would be an advantage. This project will be supervised by Prof Ed Tate (The Tate Group), Dr Emanuela Cuomo (AstraZeneca, Cambridge UK), and Dr Marco Di Antonio (The Di Antonio Research Group), in state-of-the-art chemical biology labs in the £170M Molecular Sciences Research Hub at Imperial White City campus.

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

Student

Simon Doughty

Title

An on-protein covalent fragment growth platform for PPIs

Supervisors

• Dr James Bull (Imperial)
• Prof Alan Armstrong (Imperial)
• Dr David Mann (Imperial)
• Dr Darren Stead (AZ)
• Dr Simon Lucas (AZ)

Abstract

Covalent inhibitors can provide a powerful means to target challenging ‘undruggable’ targets such as PPIs. A covalent warhead coupled with a specificity element can exploit a suitably located nucleophilic residue. However, progress from a covalent fragment to a selective covalent inhibitor is an enormous task. This project will develop a new platform technology to accelerate the progression of simple covalent fragments to early tool molecules and expedite hit to lead, using the target protein to template the growth of the fragment. This project has broad multidisciplinary elements in developing a new platform strategy for the discovery of covalent inhibitors, involving organic synthesis, kinetic profiling, protein biochemistry, labelling and screening.

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

Student

Angeliki Chatziathanasiou

Title:

Identifying new types of inhibitors in quinone binding sites in photosynthetic enzymes

Supervisors:

• Dr Maxie Roessler (Imperial)
• Prof Peter Nixon (Imperial)
• Dr Neil Carter (Syngenta)
• Dr Darren Baldock (Syngenta)
• Dr Shradha Singh (Syngenta)

Abstract:

With the ever-rising global population, there is an increasing need for efficiency and sustainability in agriculture whilst preserving future food security. Enzymes with quinone binding sites play a key role as targets for agrochemicals, but the modes of inhibition are not well understood, and the discovery of new inhibitors occurs most and foremost through large-scale screening.

In this project, we will investigate the mode of binding of quinone-site inhibitors using novel electron paramagnetic resonance (EPR) based approaches and use this knowledge to identify new inhibitors. Our target enzymes consist of both established targets (photosystem II) and a completely novel target (photosynthetic complex I / NDH). 

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

Student

Sean Nwachukwu

Title

Enhancing plant growth with a novel catalytic “fertiliser” targeted towards the highly inefficient enzyme Rubisco

Supervisors

• Dr Laura Barter (Imperial)
• Prof Nick Long (Imperial)
• Dr Rudiger Woscholski (Imperial)
• Dr Zaida Andres Gonzalez (Syngenta)
• Dr Joerg Leipner (Syngenta)
• Dr Simon Williams (Syngenta)
• Dr Jon Rains (Syngenta)

Abstract:

This 4-year MRes and PhD studentship is jointly funded by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Syngenta. It will explore a new paradigm targeted towards the global challenge of food security, capitalising upon recent breakthroughs at ICL and will involve an exciting mix of synthetic inorganic and organic chemistry, chemical biology and enzymology.     

Bringing together expertise from the supervisory team at ICL & Syngenta in (i) photosynthesis, (ii) crop enhancement, (iii) agrochemical physical chemical testing / design / synthesis cycles and (iv) synthetic & formulation chemistry, this studentship will design, synthesise, test and optimise (in an iterative manner) novel molecular CO₂ delivery vehicles, and demonstrate their potential as viable, scalable & cost-effective tools able to supercharge photosynthesis in vivo, resulting in increased crop yield.

Key features will be (i) the development & optimization of a suite of bio-mimetics able to convert bicarbonate into CO₂, (ii) the demonstration of the mimics’ ability to improve Rubisco activity in vitro and (iii) in vivo studies using model plants to test their effect on yield.

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

Student

Zak Elliott

Title

Photoadapt: Light-switchable chameleonic molecules for controlled permeability in plants

Supervisors

• Prof Matthew Fuchter
• Dr Laura Barter
• Dr Steve Smith (Syngenta)
• Dr George Giannakopoulos (Syngenta)

Abstract

Light is unsurpassed in its ability to control biological systems with high spatial and temporal resolution. It has the advantages of non-invasive and remote action, reversibility, speed, and facile modulation of the energies involved (through use of different wavelengths/colours). Photopharmacology is a growing area of endeavour that employs photoswitchable ligands of biological targets to allow for light-dependent pharmacological activity. The key component of such light addressable ligands are molecular ‘photoswitches’, such as azobenzene: components that can be interconverted between two different structural states, using light as the stimulus to drive at least one of the switching events. By integrating a photoswitch component into a biologically active ligand, light can be used to ‘switch’ the ligand between two states with different pharmacological activity: for example, switching target-based activity ‘on’ and ‘off’. This project aims to use this emerging technology to address the issue of agrochemical permeability and transport in plants, and potentially lead to the development of multiple light-dependent approaches in plant chemical biology.

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

Student

Abdullah Shahid

Title

Measuring pesticide exposure and microbial-level impacts in soil ecosystems using novel passive sampler devices

Supervisors

• Dr Leon Barron (ICL)
• Dr Bonnie Waring (ICL)
• Dr Will Pearse (ICL)
• Professor Guy Woodward (ICL) 
• Dr Richard Gill (ICL)
• Dr Helen Fain (Syngenta)

Abstract

Microbes represent the lowest trophic level and entry point to the food web and are critical indicators of soil ecosystem health under chemical stress.

This interdisciplinary project will combine our expertise in analytical chemistry, soil science, genomic sequencing, and machine learning to develop and validate a new technology to measure impacts in soil. Specifically, this will focus on the development of a passive sampling probe device (PSD) for soil. This probe will house physical, chemical, and microbial sampling functions to show how specific indicator taxa and the wider soil microbiome are affected upon exposure to (agri)chemicals.

Key to this project is our unique capability to scale this study up and deploy a large number of PSD probes in controlled-condition soils. Using metagenomic sequencing data, machine learning will be used to identify indicator taxa that have been impacted by different chemical classes and evaluate their potential use as biosensors.

Ultimately, this project will provide new, multifunctional and adaptable probes for soil microbiology and chemistry sampling, coupled with scalable supporting analytical methodologies to better understand chemical transport, fate and microbial impacts.

Importantly, this project will provide a much-needed evidence base for the sustainable use of microbes as biosensors of chemical impacts in the terrestrial environment for the first time.

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

Student

Sofia Srdanovic

Title

Unlocking new drug targets through antibody-targeted protein degradation

Supervisors:

• Professor Ed Tate (Imperial)
• Dr Paul Hogg (ADCT, White City)
• Dr Francesca Zammarchi (ADCT, White City)

Abstract:

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although PROTACs can be highly effective against a wide variety of targets, most degraders reported to date display limited intrinsic tissue selectivity, and do not discriminate between cells of different types. We recently reported a novel strategy for selective protein degradation in a specific cell type with one of the first antibody-PROTAC conjugates, demonstrating antigen-dependent degradation of a target protein specifically in HER2-positive breast cancer cells (ACS Chem. Biol. 2020, 1306). These studies demonstrated proof-of-concept for tissue-specific degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.

This project brings together innovations in targeted protein degradation with the world-leading expertise of ADC Therapeutics in preclinical and clinical antibody-drug conjugate (ADC) development (https://www.adctherapeutics.com/) to discover a new generation of targeted protein degraders as novel ADC payloads. You will push the boundaries of ADC design, exploiting new modalities including high-affinity peptide-based degraders for intractable targets, molecular glues, and autophagy- or lysosome-targeting compounds. You will combine these payloads with clinical grade ADC linker design and monoclonal antibodies to enable precise release of degraders targeted to specific tissue types across a range of disease indications, with an initial focus on cancer.

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

Student

Cecilie Jørgensen

Title

A high-throughput library approach for minimizing peptide off-targets

Supervisors

• Louise Walport
• Ben Schumann
• Martin Münzel (Novo Nordisk)

Abstract

Recent breakthroughs in oral peptide delivery have vastly extended the chemical space which is available to drug protein/protein interactions and other challenging targets. High throughput techniques such as mRNA display that allow screening of enormous libraries of DNA encoded peptides are perfectly suited to provide clinical candidates of this kind. However, in contrast to more standard small molecules, de novo peptides carry an increased risk of engaging off-targets, leading to less effective drugs and higher attrition rates during the drug discovery process. Consequently, innovative technologies to address these challenges are critically needed. In this project we will develop a streamlined mRNA-display-based approach to identify and subsequently minimize peptide off-targets using a photo-affinity labelling strategy. Complementary data from next generation DNA sequencing and mass spectrometry will enable sophisticated in silico optimization of hit peptide sequences. The project will involve learning and applying a diverse range of modern chemical biology approaches, from peptide chemistry to proteomics, and AI and in silico design to cell biology. 

This is a 3 year CDT funded straight-to-PhD studentship.

Student

Charles Brown

Title

Targeting ovarian cancer using fragment-based drug discovery

Supervisors

• Dr David Mann
• Professor Iain McNeish
• Dr James Bull
• Professor Alan Armstrong

Abstract

High-grade serous carcinoma is the commonest type of ovarian cancer and accounts for approximately two-thirds of all cases and nearly 80% of deaths. Treatment relies on the use of platinum agents but resistance arises, which can be driven by amplification of the gene CCNE1.  The protein product of this gene (cyclin E1) is a cell cycle regulator that binds to and activates the kinase cdk2 to promote proliferation.  Thus, the cyclin E1/cdk2 protein/protein interaction (PPI) offers an opportunity for an urgently required targeted therapy. This project will define novel chemical entities to regulate this interaction, exploiting our covalent screening platform (qIT, Angew Chem Int Ed Engl. (2018) 57:5257-5261). The project will be a mix of biochemistry, biophysics, structural biology, synthetic and medicinal chemistry. The student will develop new technology to attach and display chemical fragments for screening, then identify, characterise and develop hit fragments to be regulators of cyclin E1 activity.  These compounds will then be tested in established ovarian cancer cell lines with and without acquired resistance to platinum agents. 

This studentship is funded by Bruker and the Department of Chemistry

Student

Eleanor Clifford

Title

Using EPR spectroscopy to probe electron transfer in biology: from model molecular wires to complex metalloenzymes

Supervisors

• Dr. Maxie Roessler

Abstract

A fully funded PhD position is available in the Roessler research group as part of the Centre for Pulse EPR spectroscopy (PEPR). PEPR is a major new facility at Imperial College London and was recently launched at the White City Campus. The Roessler group investigates unpaired electrons in redox reactions that underpin essential chemical reactions in respiration and photosynthesis. We apply pulse EPR techniques [1] to understand the mechanisms of challenging enzymes that cannot be obtained in high concentrations and require precise electrochemical potential adjustment [2,3]. We are also developing film-electrochemical EPR spectroscopy (FE-EPR), an exciting technique for studying the evolution of radicals during a reaction [4]. FE EPR allows the accurate determination of the redox potentials of buried redox centres within enzymes and their activity during catalysis. PEPR combines pulse EPR at X- and Q-band frequencies with FE-EPR and instrument development in collaboration with University College London and the London Centre of Nanotechnology [5].

In this project, you will apply the state-of-art instrumentation available at PEPR, together with the unique capabilities of FE-EPR, to build on our recent findings of electron transfer within photosynthetic complex I [2] and energy-coupling in respiratory complex [3]. You will acquire a fundamental understanding of how best to harness the recent advances in pulse EPR to investigate complex paramagnetic centres using model molecular wires. Using this foundation, we will study how complex I type enzymes use electron transfer to pump protons that are essential for ATP synthesis. The project is interdisciplinary and collaborative, and depending on your choice of focus for your project you will have the opportunity to combine physics/physical chemistry (advanced EPR, electrochemistry), material science (for the fabrication and characterisation of electrodes), biochemical methods (making and manipulating membrane proteins) and chemical synthesis (making model molecular wires). You should have a keen interest and background in physical chemistry or biochemistry. Previous exposure to EPR spectroscopy is an asset but not an essential requirement.

We are looking to recruit an outstanding Masters level graduate in Chemistry, Biochemistry, Physics or a related subject. Please see http://www.imperial.ac.uk/roessler-lab/ for further details on current research and a full list of recent publications. The PhD student will be based in the Molecular Sciences Research Hub, the new research home for the Department of Chemistry at Imperial’s White City campus, with access to further top research facilities at the South Kensington Campus.

The PhD studentship is fully funded for 3.5 years and covers home tuitions fees and the standard London living allowance. EEA nationals are eligible if they have permanent residence or pre-settled status in the UK. The prospective PhD student should get in touch via e-mail with a detailed CV and explaining his/her interests and research experience.

1.          M. M. Roessler and E. Salvadori, 'Principles and Applications of EPR Spectroscopy in the chemical sciences', Chemical Society Reviews, 2018, 47 (8), 2534-2553
2.          K.H. Richardson, J.J. Wright, M. Simenas, J. Thiemann, A.M. Esteves, G. McGuire, W.K. Myers, J.J.L. Morton, M. Hippler, M.M. Nowaczyk, G.T. Hanke, M.M. Roessler, ‘Functional basis of electron transport within photosynthetic complex I’, Nature Communications, 2021, 12, 5387, Press Release
3.          N. le Breton, J. J. Wright, A.J.Y.J. Jones, E. Salvadori, H. R. Bridges, J. Hirst, M. M. Roessler, 'Using EPR Hyperfine Spectroscopy to define the Proton-Coupled Electron Transfer Reaction at Fe-S cluster N2 in Respiratory Complex I', J. Am. Chem. Soc., 2017, 139 (45), 16319-16326, Spotlight Article
4.          K. Abdiaziz, E. Salvadori, K.P. Sokol, E. Reisner, M.M. Roessler, ‘Protein film electrochemical EPR spectroscopy as a technique to investigate redox reactions in biomolecules’, Chemical Communications, 2019, 55 (60), 8840-8843
5.          M Šimėnas, J O’Sullivan, CW Zollitsch, O Kennedy, M Seif-Eddine, I Ritsch, M Hülsmann, M Qi, A Godt, MM Roessler, G Jeschke, JJL Morton, ‘A sensitivity leap for X-band EPR using a probehead with a cryogenic preamplifier’, Journal of Magnetic Resonance 2021 322, 106876

This project is sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Prostate Cancer UK

Student

Dominika Daremiak

Title

Fragment-based drug discovery for the sweet tooth of prostate cancer

Supervisors:

• Dr Benjamin Schumann (Imperial)
• Professor Matthew J. Fuchter (Imperial)
• Dr Jennifer Munkley (Newcastle University)

Abstract:

One in eight men get prostate cancer in their lifetime, making improved therapy options an absolute necessity. Altered sugar structures, also called glycans, are a consistent feature of prostate cancer but are vastly underexplored in drug discovery. Very recently, we have identified a glycosylation enzyme as a novel therapeutic target and an exciting opportunity to develop better treatments for prostate cancer. This project, co-funded by Prostate Cancer UK and the Institute of Chemical Biology, will focus on fragment-based drug discovery target this enzyme. We will combine newly-available chemical space and modelling approaches to generate lead compounds with suitable interaction profiles. Biological evaluation will be performed to envisage a drug that hits glycosylation, the sweet tooth of prostate cancer.

This studentship is sponsored by the Francis Crick Institute and the Department of Chemistry

Student

Aria Baghai

Title

Rapidly connecting infection targets and phenotypes

Supervisor

• Dr Louise Walport

Abstract

This project involved the development of new methodology to screen cyclic peptide libraries against pathogenic bacteria in a target agnostic manner. An ultra-high throughput, miniaturised assay will be developed to gather quantitative phenotypes with which to characterise macrophage infection with M. tuberculosis. In parallel, they will generate very large libraries of genetically barcoded, cell-permeating cyclic peptides from the RaPID platform. The miniaturised assays and peptide libraries will then be applied to identifying new bioactive peptides and their quantitative phenotypes, whilst simultaneously isolating the targets of these bioactive peptides, directly linking infection phenotypes to cellular targets and mechanisms.

This studentship is funded via the Faculty of Natural Sciences' Schrödinger Scholarship Scheme

Student

Jonathan Bostock

Title

Protected dimeric protein pores for selective interface between living and artificial systems

Supervisors

• Professor Oscar Ces
• Dr James Hindley

Abstract

Synapses enable exchange of material between cells. Artificial cells (ACs) - microrobots displaying cell-like behaviours - hold great promise in fundamental biology and healthcare, and the ability to form synapses between artificial and biological cells would unlock new and powerful diagnostic and therapeutic solutions. However, the complexity of natural synapses makes their reconstitution in ACs challenging, pointing at the need for de novo routes to establish synapse-like functionalities. To overcome this hurdle, the proposed project will combine protein engineering and DNA nanotechnology to create a molecular toolkit that will afford ACs with the ability to form synthetic synapses with cells.

This studentship is sponsored by the European Research Council and the Department of Chemistry

Student

Isabel Holmes

Title

Covalent Warhead-Functionalised Cyclic Peptide Discovery

Supervisor

• Dr Louise Walport

Abstract

This project involves developing a modified mRNA-display-based platform (RaPID) to allow identification covalent cyclic peptides. Initially covalent cysteine reactive warheads will be incorporated into RaPID peptide libraries using genetic code reprogramming and selection methodology optimised to allow identification of covalent inhibitors of PADI4, an arginine deiminases frequently misregulated in inflammatory diseases. Subsequently, the optimised selection methodology will be combined with efforts in the lab to encode DNA-templated chemistry into RaPID libraries allowing the screening of libraries encoding multiple covalent warheads into a single library, facilitating the discovery of covalent chemical probes against a wide range of targets, even where readily ligandable residues are unknown.

This studentship is sponsored by Cancer Research UK

Student

Fatemah Kassamali

Title

Discovery and validation of novel protein lipidation drug targets in cancer

Supervisor

• Professor Ed Tate

Abstract

Lipidation is a rich and widespread class of protein post-translational modification (PTM), with key roles in signalling, cell death, immunity, protein stability and trafficking. More than 150 oncoproteins and potential cancer drug targets are lipidated, including many not amenable to traditional drug discovery. Intervening in the extensive network of enzymes regulating protein lipidation presents a unique opportunity to target these 'undruggable' proteins, an approach recently validated with the first FDA approval of a lipid transferase inhibitor in 2020. We have developed chemical proteomic technologies to study all the major classes of protein lipidation and delivered target validation and novel lipidation inhibitors into preclinical development for oncology, founding Myricx Pharma in 2019 to translate our findings into first in class therapeutics to benefit cancer patients. In this project, in collaboration with scientists at the Francis Crick Institute, Cancer Research UK (CRUK) and in industry working on development of lipidation inhibitors in cancer, we will apply chemical probe design, chemical genetics, proteomics, and mechanistic drug target validation using modern gene editing and screening approaches to identify and validate novel targets for cancer therapy.

This studentship is supported by the Hong Kong Croucher Foundation Scholarship

Student

Tin Hang Titan Lai

Title

Biomedical Dual-Action Imaging Probes for Cancer Therapy

Supervisor

Professor Nick Long

Abstract

This project aims to synthesize a series of dual-action therapeutic probes as novel anticancer agents. The compounds will incorporate an imidazole-based heme oxygenase-1 (HO-1) inhibitor along with an anti-cancer drug (e.g. PS, intercalating agent) to target tumors more susceptible to drug resistance. HO-1 regulates the concentration of cytotoxic free heme, but it is also known has a defensive role in cancers where it is overexpressed. Therefore, inhibiting HO-1 provides a possible alternative strategy in treating cancer. Examples in the literature have demonstrated the use of combinational therapy to overcome cancer resistance leading to an increased effectiveness in treatment. For example, Canti and co-workers discovered that the combinatorial administration of AlS2Pc, a photosensitizer (PS) used in photodynamic therapy, and chemotherapy drugs (i.e. Adriamycin and cisplatin) produced a synergistic therapeutic effect on murine tumors. In light of that, there is potential that a combinatorial probe that incorporates a PS for use in photodynamic therapy or an intercalating agent for use in chemotherapy while simultaneously inhibiting HO-1 activity can improve the success rate of the anticancer treatment.

Student

Zihan Zhang

Title

Microfluidic platforms for high-throughput generation of stimuli-responsive liposome libraries

Supervisor

• Professor Oscar Ces
• Dr James Hindley

Abstract

Stimuli-responsive liposome systems have emerged as a promising way to deliver and release drugs in a site-selective manner. This project aims to develop a novel high-throughput microfluidic platform for fabricating stimuli responsive liposomes. This system will be coupled with machine learning approaches and robotics with a view to constructing liposome libraries that can be screened and optimised against user defined performance characteristics that are aligned with in-vivo delivery performance.

Student

Kai Zheng

Title

New screening approaches in photopharmacology

Supervisor

• Professor Matt Fuchter

Abstract

The potential of photopharmacology is limited, in part, by the methodologies suitable for bespoke discovery of new photopharmaceuticals. This project will pioneer a new approach to the discovery of next generation agents through screening.

Student

Xixian Yi

Title

Next-Generation Point-of-Care Tests for Longitudinal Monitoring of Patients Treated for Human Papilloma Virus (HPV)-Driven Cancer

Supervisors

• Professor Joshua Edel
• Dr Alex Ivanov
• Dr Sylvain Ladame

Abstract

Circulating human papilloma virus DNA (cHPV-DNA) has shown great promise as a biomarker of residual disease and for disease surveillance following radical treatment for HPV related cancers. For example in feasibility studies at The Royal Marsden Hospital, next generation sequencing assays have been performed for measuring cHPV-DNA that included patients with head and neck, cervical and anal squamous cell carcinoma. However, this assay is resource intense, in terms of personnel, cost and time required. In the proposed project we will develop a rapid, cost-effective assay to measure cHPV-DNA in plasma, and will ultimately enable the development of next-generation HPV-selective point-of-care tests.