º£½ÇÉçÇø

Title

Rational Design Rules for Blood-Brain Barrier-Penetrant Antibody Fragments

This project is generously funded by the Faculty of Natural Sciences

Supervisors

• , Department of Chemistry, º£½ÇÉçÇø
• , Department of Chemistry, º£½ÇÉçÇø
• , Department of Chemistry, º£½ÇÉçÇø
• , Department of Chemistry, º£½ÇÉçÇø

Abstract

The blood-brain barrier (BBB) protects the brain from pathogens and toxic molecules. However, because of its high selectivity, it also prevents over 98% of small-molecule drugs and almost all protein therapeutics from reaching the brain, making it one of the greatest obstacles to treating neurological diseases with antibody-based medicines. Antibody fragments (Fab, scFv, single-domain antibodies) are attractive central nervous system therapeutic candidates because of their small size and ease of engineering, but the sequence and physicochemical rules that determine whether such a fragment, or a cell-penetrating peptide, productively crosses a lipid bilayer rather than simply sticking to it or being trapped in endosomes, remain poorly defined.

This project aims to address this bottleneck by elucidating the engineering rules that control the molecular interactions between antibody fragments and biological membranes. We will develop a novel high-throughput droplet interface bilayer (DIB) platform, in which nanolitre lipid-monolayer-encased droplets are brought into contact to form model membranes whose leaflet composition can be independently controlled, enabling us to mimic selected lipid features of BBB endothelial membranes. We will build both symmetric (matched leaflet composition, as a generic membrane model) and asymmetric DIBs, with distinct leaflet lipid compositions designed to mimic selected features of the luminal and abluminal BBB endothelial membranes, to investigate how membrane asymmetry influences translocation directionality.

Rationally designed and directed-evolution-derived libraries of antibody fragments and peptides will be screened using quantitative electrical and optical readouts, linking sequence directly to translocation efficiency. Experimental data will be integrated with physicochemical descriptors and protein-language-model representations to identify sequence features associated with productive membrane crossing and to guide subsequent rounds of variant design and screening. Hits identified in this reductionist DIB platform will be validated in human brain microvascular endothelial cell monolayers, allowing us to determine which sequence rules identified in model membranes remain predictive in a cellular BBB context. These rules will then be applied to re-engineer a therapeutically relevant antibody fragment for improved BBB penetration.

This work will establish a rational, generalisable, high-throughput framework for designing brain-penetrant biologics, with the potential to reduce reliance on early-stage in vivo screening and complement receptor-mediated transcytosis strategies.

Eligibility

This project is open to candidates with Home or Overseas Fee Status.

Deadline

Monday 18 January 2027, 5pm

Title

PepPERMIT: Decoding Peptide Cell Permeability through High-Throughput Live-Cell LC-MS and Explainable Machine Learning

This project is funded by the EPSRC CDT in Chemical Biology 

Supervisors

• , Department of Chemistry, º£½ÇÉçÇø
• , Department of Chemical Engineering, º£½ÇÉçÇø

Abstract

Peptides are emerging as a promising class of therapeutics which offer a middle ground between small molecules and proteins. However, a key limitation for their progression for intracellular targets is often poor cellular uptake. In this project, we aim to address this by systematically studying peptide uptake in high-throughput in live cells using LC-MS. Combining automated peptide synthesis, high-throughput screening, and machine learning, we will iteratively learn how peptide sequence translates to cellular uptake, using experimental data to guide model development and predict the uptake of new peptides. This will provide a significant advancement in drug discovery, enabling researchers to take cell permeability into account in the design process of peptide drugs, preventing promising compounds from failing later in the discovery pipeline.

Eligibility

This project is open to candidates with Home or Overseas Fee Status.

Deadline

Wednesday 2 December 2026, 5pm

Title

Bio-inspired catalytic fertilisers: Imaging uptake and mode of action in plants

This project is funded by the EPSRC CDT in Chemical Biology

Supervisors

• , Department of Chemistry, º£½ÇÉçÇø
• , Department of Chemistry, º£½ÇÉçÇø
• Dr Ryan Brown, Department of Chemistry, º£½ÇÉçÇø

Abstract

This studentship will develop novel probes to investigate the mode of action of a new class of bio-inspired catalytic fertilisers acts plants. This will enable an already striking biological phenotypic effect to be translated into a rationally engineered agricultural technology poised to reshape global crop security. Increasing world populations, loss of agricultural land due to urbanisation, soil degradation and climate change place enormous demands on our food system, mandating urgent discovery of innovative methods to increase crop yields. Our approach addresses an inefficiency of the photosynthetic carbon-fixation reactions that take place in higher plants and green algae. A key culprit is Rubisco, a remarkably inefficient enzyme with poor substrate specificity for CO2, where O2 binding is competitive. This leads to photorespiration, which lowers carbon-fixation efficiency by approximately 50%. Theoretical studies suggest that minimising photorespiration would significantly increase photosynthetic efficiency and, given the direct correlation with crop yield, would offer a timely and novel route to crop enhancement (Zhu et al., 2008; Long et al., Plant, Cell & Environment, 2006, 29,315–330).

Some plant species have evolved carbon-concentrating mechanisms to improve carbon fixation by raising intracellular CO2 concentrations. One is based upon the catalytic interconversion of endogenous HCO3– and CO2 by carbonic anhydrase (CA), a zinc metalloenzyme. At the core of our innovation is the use of small-molecule catalytic CA mimics, able to increase local carbon dioxide availability in plants and mitigate the competitive reaction with oxygen. We have developed a suite of complexes across a variety of ligand families that catalyse both carbon dioxide hydration and bicarbonate dehydration, with catalytic activity exceeding that of previously reported mimics (Rains et al., ACS Catalysis, 2019, 9, 1353–1365).

Our recent work has demonstrated: (i) that this family of CA mimetic compounds increases Rubisco enzyme activity, measured via in vitro assays; (ii) the development of water-soluble analogues with improved bioavailability in planta; (iii) that ultra-low dose in vivo studies in spinach show increases of up to 500% in dry biomass, and strikingly, 140% higher biomass in drought stressed spinach plants over drought-stress controls and (iv) that glasshouse trials show approximately 26–28% higher grain yields in wheat and rice. Efficacious doses are approximately 10,000-fold lower than those associated with toxicity in bacterial, fungal or mammalian cells. The challenge now is to determine how these catalytic fertilisers enter and move through plants, whether they remain chemically intact, and how their distribution relates to their biological effects. Tracking agrochemicals in planta is however challenging, in part due to the high background fluorescence that results from the natural pigments found in plants such as chlorophyll and carotenoids. Overcoming this challenge would enable informed active-ingredient optimisation and tailored formulation development resulting in enhanced efficacy and stability.

This studentship aims to address this by developing novel, labelled and chemically modified analogues of our established CA mimetics to track uptake and translocation at biologically relevant, ultra-low doses. Complementary radiotracer/PET, nanoSIMS, orbiSIMS and other mass-spectrometric imaging techniques will resolve catalyst distribution across whole-plant, tissue and cellular scales, with optical imaging used as a secondary, targeted approach. Measurements of the metal and ligand components and their location will be related to Rubisco activity, photosynthetic performance, stomatal behaviour and water-use efficiency, determining whether the biological effects arise from local HCO3– dehydration, direct protein interaction, stomatal signalling, or an alternative mode of action. This mechanistic understanding is essential to guide the rational development of catalytic fertilisers as a sustainable, broadly applicable approach to crop enhancement.

The project involves multidisciplinary research, featuring synthetic organic and inorganic chemistry, metal coordination chemistry, physical and analytical chemistry (kinetics, LC-MS, ICP-MS, radiochemistry and imaging) and plant physiology (growth trials, gas exchange, Rubisco activity assays), thus the student will gain a rare set of skills during their MRes/PhD.

Eligibility

This project is open to candidates with Home or Overseas Fee Status.

Deadline

Wednesday 2 December 2026, 5pm

Title

Targeting DNA G-quadruplex as a key vulnerability of SMARCA4 impaired cancer

This project is co-sponsored by the EPSRC CDT in Chemical Biology and

Supervisors

• , Department of Chemistry, º£½ÇÉçÇø
• , Department of Chemistry, Institute of Cancer Research

Abstract

It is increasingly evident that alteration of the epigenome can be critical to drive tumorigenesis and cancer development as much as genetic mutations. The Downs group has demonstrated that genetic inactivation of the chromatin remodeler SMARCA4 is a common feature in many cancers, further highlighting the strong link between loss of epigenetic homeostasis and cancer development.  SMARCA4 has also been shown to act as a tight binder of DNA secondary structures known as G-quadruplexes (G4s). The Di Antonio group has recently revealed that enrichment of G4s in enhancers is linked with transcriptional activation of key genes that drive chemoresistance in ovarian cancer. Importantly, G4s can be targeted with dedicated small-molecule ligands, which can be used to resensitize resistant ovarian cancer cells to chemotherapy. Given that SMARCA4 displays a nanomolar binding affinity to G4s, we reason that substantial changes in G4-prevalence can be envisaged in cancers genetically impaired in SMARCA4.

In this project we will deploy innovative chemical biology tools to underpin key G4-structures that are populated as a response to SMARCA4 inactivation and identify their interactome. We will achieve this by taking advantage of established genomics methods to map both SMARCA4 and G4s in a genome-wide fashion, which are established in the Downs and the Di Antonio groups. We will identify critical G4s accumulated in response to SMARCA4 inactivation and assess their transcriptional response by means of RNA-Seq and ATAC-seq. In parallel, we will optimize and adapt a chemical biology platform established in the Di Antonio group (ATENA) to decorate CRISPR-Cas9 proteins with G4-ligands and proximity labelling agents to both investigate the therapeutic potential and characterize the interactome of functional G4s formed in SMARCA4 impaired cancer G4-targeting in live cells. The student will synthesize a library of G4-ligands and proximity labelling agents (i.e. mMap and RFT) that are compatible with ATENA and generate stable cell-lines to expand the use of this platform in therapeutically relevant cancer models. By establishing ATENA in cancer models available in the Downs group, we will assess the functional response of specific G4s identified in the genomic studies and assess their interactome, unravelling novel druggable pathways. This knowledge will inspire the rational design of next generation G4-ligands that can be used for cancer intervention by taking advantage of epigenetic vulnerabilities associated with SMARCA4 mutation in the form of specific G4s that are enriched in SMARCA4 impaired cancers. 

Eligibility

This project is being offered as a 4-year PhD with no MRes component. This project is only open to candidates with Home Fee Status. The successful candidate will be part of the .

Deadline

Wednesday 2 December 2026, 5pm