The Abell Group
The Abell Group uses the tools of chemistry and biology to gain a detailed molecular understanding of the function of peptides and proteins.
The function of peptides and proteins is defined by their linear sequence of amino acids and how this folds into a biologically active 3D shape or conformation.
A detailed molecular understanding of these processes allows the rational design and synthesis of small molecules that can bind to a peptide or protein of interest. Such molecules provide important biological probes for studying key metabolic events and also potential therapies for human disease.
These ideas extend to other biomolecules to allow the generation of fluorescent and redox active probes and therapeutic agents.
All projects involve organic synthesis and product characterisation by Nuclear Magnetic Resonance (NMR) and other spectroscopic techniques, with an opportunity to integrate biology, computational chemistry, biophysics and bioengineering.
Sensing and switching
New biocompatible chemosensors for the detection of critical biomarkers for embryo development, chronic pain, and cardiovascular health
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.
- 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
Photoswitchable enzyme inhibitors, agonists and antibacterials for use in photopharmacology and as tools for biologists
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.
Design and investigation of novel zirconium-89 chelator for PET imaging
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.
The inhibition of proteases
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.
Inhibition of biotin protein ligase: new antimicrobial agents
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.
The inhibition of dethiobiotin synthase (DTBS) in mycobacterium tuberculosis: new antituberculosis agents
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.
Targeting essential mediators of replication: proliferating cell nuclear antigen (PCNA)
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.
Developing prodrugs targeting sub-populations of cells with disease state physiology
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.
Electron transfer in peptides and proteins
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.
- 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
The group works closely with many international academic and industrial collaborators and has a strong interest in the commercialisation of basic research.
New members work closely with senior members of our group and gain some exposure to industry and commercialisation of basic research.