The Abell Group

Biologically important small molecules, such as metal ions, reactive oxygen species (ROS) and reactive nitrogen species (RNS) play crucial roles in most physiological processes, and hence are promising biomarkers for disease diagnosis.

In particular, the ability to sense the above-mentioned molecules in vitro and in vivo provides important basis for early diagnosis of developmental diseases, chronic pain and cardiovascular diseases.

The Abell group focuses on the design and development of biocompatible fluorescent chemosensors that allow sensitive and selective detection of ions, ROS and RNS. These sensors enable the biologists to further investigate the connection between the analyte and the biological process of interest.

Furthermore, we incorporate the sensors with solid platforms including optical fibres, nanoparticles and liposomes to create portable sensing devices that facilitate non-toxic, minimally invasive real-time monitoring of disease progression.  

A common limitation of fluorescence measurements is photobleaching of the sensor molecule.

One approach to circumvent this is to attach the fluorophore to a nitrogen-vacancy nanodiamond. The nanodiamonds produce a red fluorescence which does not photobleach under intense illumination, thus providing a versatile platform for tracking and imaging in microscopy. The surface bound fluorophore is freed from any pre-measurement illumination that is typically required, thus significantly reducing any photobleaching that may occur.

We have recently demonstrated this system in M1 macrophages with a surface bound H₂O₂ sensor, with current research efforts to expand this pilot system to other novel sensors for an array of biomolecules.

Key publications

• Biological hydrogen peroxide detection with aryl boronate and benzil BODIPY-based fluorescent probes
• Photoswitchable calcium sensor: ‘On’–‘Off’ sensing in cells or with microstructured optical fibers
• An organic fluorophore-nanodiamond hybrid sensor for photostable imaging and orthogonal, on-demand biosensing

Light is often used as an experimental control of biological systems as it can be fine-tuned with regard to timing, location and intensity, is generally non-invasive, and does not contaminate the sample.

Thus, the ability to control the bioactivity of specific biomolecules using light would be highly desirable.

One of the main ways of introducing light-sensitivity into biological molecules is through the incorporation of a photoswitch, making it possible to control its biological activity by reversibly switching between the two isomeric forms, with ideally, one configuration having high affinity for the biological target and the other with low affinity.

These photoswitching molecules can be used as research tools for biologists to gain insight into cellular events by being able to spatiotemporally control biological processes in vivo using light to turn "on" and "off" a biomolecule.

Additionally, new drugs, termed photopharmaceuticals, can be developed by incorporating photoswitches into bioactive compounds to control the drug’s bioactivity to select locations, such as tumours, resulting in lower toxicity and side-effects.

Current biological targets include proteases, proteasome, GPCRs and GRKs. Our work is focused on the design, synthesis and activity of a library of spiropyran and azobenzene-based photoswitchable inhibitors for these targets.

For example, Gramicidin S is a potent naturally occurring antimicrobial cyclic peptide, though it exhibits toxicity against human erythrocytes. Photopharmacology presents as an ideal approach to regulate the activity of Gramicidin S to allow further exploitation of its desirable antimicrobial properties. 

In this project, cyclic peptidomimetics of Gramicidin S are synthesised incorporating an azobenzene photoswitch to reversibly control secondary structure and hence antimicrobial activity and potentially toxicity. Antimicrobial activity can then be switched ‘on’ or ‘off’ upon irradiation with light of a specific wavelength, with spatiotemporal precision. This important strategy provides an opportunity to turn antimicrobial activity ‘on’ and ‘off’ to allow potential future point-of-care applications.

We are also exploring the use of optical fibres as a tool to help us to deliver light precisely, deep inside the body, hence opening up the potential to photoswitch and hence activate drugs in vivo.

Key publications

• Azobenzene-containing photoswitchable proteasome inhibitors with selective activity and cellular toxicity
• Photoregulation of α‐chymotrypsin activity by spiropyran‐based inhibitors in solution and attached to an optical fiber

⁸⁹Zr is a positron-emitting isotope of zirconium with a half-life of 3.3 days, making it an ideal candidate for monoclonal antibody (mAB)-based PET imaging in the detection of cancers. However, the best current chelator of zirconium - desferrioxamine (DFO) – is prone to in vivo degradation, leading to the accumulation of radioactive Zr cations in bones. The development of more stable chelators is necessary for ⁸⁹Zr to become useful clinically.

This project involves the synthesis of novel hexadentate and octadentate chelators of ⁸⁹Zr, based on chelators previously synthesised by Tieu et al. Experimentation to determine the kinetic stability of the metal-chelator complex and the optimal incubation conditions will be undertaken.

Many therapeutics based on protease inhibitors are currently in late clinical trials or are already available as drugs. However, inhibitors of the cysteine protease family are very much under represented, primarily because of flaws in their design: existing inhibitors are conformationally flexible and biologically unstable structures with a 'reactive warhead' that makes them undruglike.

We have recently computationally designed and prepared (using ring closing metathesis and click chemistry) potent cyclic inhibitors of cysteine proteases that overcome these basic problems.

The constituent cycle constrains the inhibitor into a beta-strand geometry that is known to favour binding to the enzyme, resulting in improved biostability, an entropic advantage to inhibitor binding, and increased potency without the need for a 'reactive warhead'.

We have shown that these inhibitors stop the progression of cataract in lens culture (see image) and also in animal trials by inhibiting a cysteine protease and the study is entering a commercial phase.

This project involves the stereoselective synthesis of examples of these macrocyclic inhibitors and their assay against a range of proteases (including the proteasome) and an investigation into their potential to stop the growth of various cancer cell lines.

Key publications

• Macrocyclic Protease Inhibitors with Reduced Peptide Character
• A Macrocyclic Calpain Inhibitor Slows the Development of Inherited Cortical Cataracts in a Sheep Model
• Molecular Modelling, Synthesis, and Biological Evaluation of Macrocyclic Calpain Inhibitors

Antibiotic resistance is a significant threat to human health world-wide and new antibiotics are desperately required to control bacterial infections that are currently untreatable.

Two million patients contract infections each year at a cost of $5 billion annually in extended stays and expensive drug regimens. Around 90,000 of these will die from hospital-acquired infections untreatable with current antibiotics.

Biotin protein ligase (BPL) is an attractive target for the development of a new class of antibiotics. We have designed inhibitors of BPL from the pathogenic bacterium Staphylococcus aureus based on our solved x-ray structures of this enzyme.

These structures have been prepared and shown to be specific inhibitors of the Staphylococcus aureus BPL. We have recently reported the synthesis and evaluation of 5-halogenated-1,2,3-triazoles as BPL inhibitors.

The halogenated compounds exhibit significantly improved antibacterial activity over their nonhalogenated counterparts. The project involves all aspects of this study.

Key publications

• Halogenation of Biotin Protein Ligase Inhibitors Improves Whole Cell Activity against Staphylococcus aureus
• Optimising in situ click chemistry: the screening and identification of biotin protein ligase inhibitors

Tuberculosis (TB) is one of the most common causes of human mortality worldwide. More than a third of the world’s population is currently infected with the latent form of TB, with the risk of progression to active TB highest in immune-compromised individuals.

The recent emergence of Mycobacterium tuberculosis strains resistant to first and second line drugs is severely reducing the number of antibiotics available for clinical use, resulting in a desperate need to replenish the antibiotic pipeline.

The inhibition of biotin biosynthesis represents a promising approach to the discovery of new anti-TB chemotherapeutics. In this application we focus on dethiobiotin synthase (DTBS), one of the key enzymes in the biotin synthetic pathway, as a target for the development of new anti-TB therapeutics.

Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair, acting as a central docking platform for essential factors to interact with the DNA.

PCNA is over-expressed in cancerous cells and an inhibitor of PCNA may act as an effective cancer therapeutic. Peptides with defined secondary structure provide an effective means to inhibit protein-protein interactions with a high degree of specificity.

This project focuses on design and synthesis of small conformationally controlled peptides to characterise the binding interface of PCNA en route to develop an effective and selective cancer therapeutic.

Key publications

• Rational design of a 3₁₀‐helical PIP‐box mimetic targeting PCNA ‐ the human sliding clamp

The development of prodrugs to deliver drug molecules selectively to populations of cells or regions within the body that exhibit disease state physiology is extremely important to reduce off target side effects.

We are developing prodrug moieties that are designed to be cleaved and release the active drug molecule in certain environments such hypoxia and oxidative stress. These environments are implicated in a range of disease states from cancer to inflammatory diseases.

The ability to transfer an electron from one biomolecule to another forms the basis of a number of key biological processes, including photosynthesis and respiration.

This ‘flow of electrons’ is catalysed by oxidoreductases over surprisingly large molecular distances (10 Å or more) through the interaction of associated redox partners. These oxidoreductases are rich in α-helices, the structures of which are defined by a characteristic network of hydrogen bonds.

This, together with the fact that the rate of electron transfer decay across a hydrogen bond is approximately twice that of a covalent bond, suggests that these structures provide the molecular ‘shortcut’ necessary for electron transfer.

This project involves the solid phase synthesis and characterisation of peptides for electron transfer studies, and/or a computational study on the associated mechanisms of electron transfer.

Key publications

• Exploiting the interplay of quantum interference and backbone rigidity on electronic transport in peptides: a step towards bio-inspired quantum interferometers
• Unravelling the interplay of backbone rigidity and electron rich side-chains on electron transfer in peptides: the realisation of tunable molecular wires

• Professor Andrew Abell, Group leader

• Dr Sabrina Heng
• Dr Victoria Peddie
• Dr Malcolm Purdey
• Dr Denis Scanlon
• Dr Xiaozhou (Michelle) Zhang

• Dr Thomas Avery
• Dr John Horsley
• Dr Erin Smith
• Dr Georgina Sylvia
• Dr Jingxian Yu

• Sarah Bagster
• Rouven Becker
• Patrick Capon
• Theresa Chav
• Aimee Horsfall
• Aniket Kulkarni
• Kwang Jun Lee
• Molly Lloyd
• Kathryn Palasis
• Nic Schumann
• Damian Stachura
• Yuanqi Yeoh
• Dion Turner