Centre for Chemistry and Drug Discovery

AEP-mediated biosynthesis of orally active cyclotide-based antagonists for bradykinin B1 receptor

Benchmarking deep learning methods for designing active peptides

Boosting accumulation of cyclisation-stabilised peptide-based pharmaceuticals in plant seeds

C-fos: a measure of pain in chemotherapy induced neuropathy

Characterization of blood-brain barrier nutrient transporters

Supervisor: Dr Rosemary Cater (r.cater@uq.edu.au)

The blood-brain barrier (BBB) is a layer of tightly packed endothelial cells that separate the blood for the brain. The BBB has evolved to protect our brains from blood-borne neurotoxins and pathogens, but unfortunately, it also prevents the majority of potential neurotherapeutics from entering the brain. In fact, it has been estimated that ~98% of all small-molecule drugs are not able to cross the BBB. This creates a major bottleneck in the development of treatments for diseases such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, anxiety, and depression. The more we know about what can enter the brain, the better informed we will be for developing treatments for these diseases. Transporter proteins expressed at the BBB play a very important role in regulating the entrance of molecules in a highly specific manner. For example, the transporters FLVCR2 and MFSD2A allow for the uptake of choline and omega-3 fatty acids into the brain – both of which are essential nutrients that the brain requires in very large amounts. This project will utilise biochemical techniques and structural biology (cryo-EM) to further understand transport proteins at the BBB and how they transport specific molecules into the brain. This will provide critical insights that for the development of neurotherapeutics that can hijack these transporters to allow for entrance into the brain.

Characterisation of Wasp Venom Enzymes

Chemical strategies to deliver peptide drugs into cells

Chemical synthesis and structure-activity-relationship studies of the trefoil factor family

Chemistry of Venomous Plants

Computational design of targeted cancer therapeutics guided by machine learning

Defining cylclotide membrane interactions using nanodisc

Dehydrating microalgal to extend their shelf-life for medical and agricultural use.

Design and characterisation of a new generation of anti-obesity peptides

Design and characterisation of a next-generation antimicrobial peptide

Designing experimental drugs using computers and structure-based drug design

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Huy Hoang (h.hoang@imb.uq.edu.au)

Computational approaches can be powerful aids for drug discovery as they combine and amplify the power of three dimensional structures of both small molecule drug leads and protein targets with molecular insights to disease development. This project will use computer-based methods to design, discover and optimise new candidate drug leads.

Designing protein drugs for the treatment of cancer and inflammatory diseases

Supervisor: Dr Conan Wang (c.wang@imb.uq.edu.au)

Cytokines are signalling proteins that play essential roles in immune responses and have garnered clinical interest in the context of cancer, autoimmunity, and infectious disease. This project aims to overcome their limitations of poor stability, activity, and specificity to develop new therapeutics. Candidates will learn new skills in drug design and characterisation using tools in molecular biology, biochemistry, and structural biology.

Determining three-dimensional structures of protein modulators using NMR spectroscopy

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Huy Hoang (h.hoang@imb.uq.edu.au)

Three-dimensional structures of compounds in solution determine their activities on biological targets (e.g. proteins, DNA, RNA). NMR spectroscopy is the most powerful and versatile method to elucidate solution structures, dynamics and interactions of chemical compounds alone and with their targets. This project will give opportunities to solve three dimensional structures of bioactive fragments of proteins and small molecule modulators of proteins.

Developing microalgae soil additives that improve soil health

Developing new drugs for inflammatory bowel disease

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Eunice Poon (k.poon@uq.edu.au)

Inflammatory bowel disease (IBD) is a collection of complex chronic inflammatory conditions of the gastrointestinal tract. It is currently treated with immunosuppressives that are associated with significant, often severe, side effects. This project will evaluate the effectiveness of new therapeutic compounds with different mechanisms of action using a mouse model of colitis and various molecular biology techniques.

Developing new mass spectrometric methods for the rapid identification and assignment of absolute configuration to chiral amino compounds

Developing next-generation insecticides targeting insect sodium channels

Development of oral gut-specific peptide therapies

Discovering novel analgesic and anti-inflammatory venom peptides

Discovery of novel sodium channel modulators from venoms

Efficient design of drugs using new nanoscale technologies

Supervisor: Dr Conan Wang (c.wang@imb.uq.edu.au)

Powerful technologies have emerged to perform millions of experiments quickly in tiny nanolitre droplets, and have attracted wide interest from major pharmaceutical companies because of the potential to accelerate drug discovery. Honours project opportunities are available to investigate these next-generation tools for drug design and learn new skills in one or more areas of nanotechnology and molecular biology.

Efficient extraction of recombinant proteins from algae

Fine-tuning the application of peptide-based antimalarial drugs through understanding their mechanism of action

Supervisor: Dr Nicole Lawrence (n.lawrence@uq.edu.au)

Malaria is a disease caused by Plasmodium parasites. The disease kills half a million people every year and the parasites rapidly evolve resistance to new drugs. Developing new drugs with different ways of killing the parasites is important for staying ahead of the disease progression. We have developed peptide-based drugs that target red blood cells infected with malaria parasites. The peptides are safe and selective and are also less likely to result in the parasites developing drug resistance compared to existing small molecule drugs.
We are seeking a motivated Honours student to join our discovery team and contribute valuable knowledge required for developing lead peptides into new treatments for malaria.
The overall aim of the project is to undertake genetic studies to understand how lead peptides affect malaria parasites at transcription and protein expression levels

GABA-A receptor variants in epilepsy

Genetic exploration of Petunia as a novel platform for producing cyclisation-stabilised peptide-based pharmaceuticals

Improving photosynthetic oxygen for food and therapeutics

Mechanisms of cell uptake by macrocyclic drug

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Liping Liu (liping.liu@uq.edu.au)

Protein-protein interactions are responsible for most biological processes and so proteins and their peptide fragments hold immense promise for treating diseases. However, to be used as medicines they must first penetrate cellular membranes which is a key problem. Endocytosis is the principal mechanism of cellular uptake but peptides often get trapped in endosomes and mechanisms of escape into the cytoplasm are not well understood. This project will study diverse peptide structures for cell uptake and findings may help in designing new drugs with enhanced cellular delivery.

Method development for chemical synthesis of proteins

Modulating Potassium Channels for Immune Cell Activation

Supervisor: Professor Irina Vetter (i.vetter@imb.uq.edu.au); Dr Hana Starobova (h.starobova@imb.uq.edu.au)

Macrophages are innate immune cells that are crucial for initiating immune response. Macrophage activation is implicated in driving many painful pathological stages, including neuropathy and inflammatory pain. Potassium channels, such as Kv1.3, regulate cell potassium homeostasis, and any dysregulation in intracellular potassium can lead to macrophage activation and resultant cytokine and chemokine release, driving pathogenesis of pain. This project will investigate the effects of specific potassium channel-targeting toxins on macrophage activation using electrophysiology techniques, live cell fluorescent microscopy, and in vivo rodent behavioural studies.

Neuro-immune interactions involved in painful neuropathies

Neuropeptides and long-term memory formation

Supervisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)

Memory is probably the single most important brain process that defines our personality and gives us the sense of individuality. Emotional events often cause the generation of strong memories that exist for many years, yet the underlying mechanisms are still poorly understood. Neuropeptides are key players in regulating emotions and have been associated with long-term memory formation. This project is focused on the development of advanced molecular probes to understand how neuropeptides can mediate long-term memory formation.

Novel approaches for high-throughput discovery of bioactive venom peptides

NLRP3 inflammasome activation by chemotherapies and the therapeutic application

NMR structures and computational studies to design bioavailable peptides

Oxytocin and Vasopressin Research

Supervisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)

The oxytocin and vasopressin signalling system regulates fundamental physiological processes such as reproduction, water balance, cardiovascular responses and complex social behaviour. It is also a high-profile target for autism, schizophrenia, stress, depression, anxiety, cancer and pain. Our group is particularly interested in creating a complete molecular toolbox to study this signalling system as well as in discovering novel therapeutic leads for autism, pain, gastrointestinal disorders and breast cancer. This project entails structure-activity-relationship studies and medicinal chemistry approaches to develop novel probes and drug candidates for the oxytocin and vasopressin system.

Pharmacology of Stinging Nettle venom

Protein Engineering using a new class of ligase enzymes

Reassessing the classification of conotoxin genes into superfamilies

Reengineering of wasp venom peptides for antimicrobial applications

Regulating mucin protection against microbes in our gut

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Eunice Poon (k.poon@uq.edu.au)

The intestine is lined with a layer of mucus which acts as a protective barrier against microbial invasion. Mucins are a major component of this layer and are secreted mainly by goblet cells in the epithelium. We have identified a protein that, when activated, depletes mucins from goblet cells. The exact mechanism for this effect is unknown. This project aims to further understand this process by using in vivo and ex vivo techniques and to regulate the process using novel drug leads.

Role of adhesion molecules in chemotherapy induced side effects

Stapled peptides as anticancer drugs

Structure-activity relationships of cyclic dynorphin A analogues targeting kappa opioid receptors

Structure and function of pain-associated ion channel complexes

Synthesis and oxidative folding pathway of disulfide-rich cyclic peptides

Synthesis of bacterial metabolite analogues as anti-inflammatory drugs

Synthesis of DNA-binding peptides for anti-cancer therapy

Synthesis of fluorescent probes for visualising an inflammatory protein in cells

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Jeff Mak (j.mak@imb.uq.edu.au)

Class IIa histone deacetylases (HDACs) are enzymes involved in regulating inflammation in humans. Unlike other HDACs, they do not localise within the nucleus, but shuttle between the nucleus and the cytosol. The project aims to synthesise fluorescent ligands for studying and visualising these processes.

Synthesis of long-acting antidiabetic agents

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Tim Hill (t.hill@imb.uq.edu.au)

Derivatives of the hormone glucagon-like peptide have been used to treat diabetes and more recently obesity. We have previously developed compounds like this hormone that have profoundly different effects on cells, but with poor drug-like properties such as plasma instability. This project aims to synthesise compounds that can similarly alter cell signalling profiles but have enhanced drug-like properties that make them potential drug candidates for testing in mose models of diabetes and obesity.

Synthesis of modified bacterial metabolites as anti-inflammatory drugs

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Jeff Mak (j.mak@imb.uq.edu.au)

Mucosal associated invariant T cells (MAIT cells) are antibacterial immune cells that are activated by small molecule bacterial metabolites. However, their excessive activation can contribute to inflammatory diseases such as colitis. This project aims to modify bacterial metabolites to produce new MAIT cell inhibitors as potential leads to a new class of anti-inflammatory drugs.

Synthesis of neuropeptide tracers with increased sensitivity for cancer imaging

Supervisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)

Fluorescently labelled peptides have emerged as promising tools for the detection and visualisation of cancer, the specificity of peptide ligands combined with non-invasive optical imaging presents many favourable characteristics over radiopharmaceutical imaging techniques. Several neuropeptide receptors have been identified as significantly upregulated in some cancers and due to the high specificity of their endogenous peptide hormones present an opportunity for the development of fluorescent neuropeptide tracers for the detection and visualisation of these cancers. This project will involve chemical synthesis, purification and characterisation, cell biology, and confocal microscopy.

Synthesis of novel 8-membered heterocycles towards new cancer drugs

Targeted delivery of anticancer drugs

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Tim Hill (t.hill@imb.uq.edu.au)

Most approved cancer therapeutics are designed to be cytotoxic and interfere with cellular proliferation. Consequently, they are usually also toxic to normal cells and cause side effects, presenting a major challenge to achieve both therapeutic efficacy and safety. One way to try and over come this problem is to create targeted drug conjugates which contain a protein or peptide which can selectively interact with cancer cells whilst delivering a known cytotoxic drug to the target. This project aims to create peptide-drug conjugates which can be targeted to cancer cells which overexpress specific receptors.

Targeting gut biofilms in patients with gastrointestinal disorders

Supervisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)

Gastrointestinal disorders affect 10–15% of the Western population, reduce the quality of life and result in substantial socioeconomic costs. Recently, we have observed bacterial biofilms in the gastrointestinal tract of IBD and IBS patients, but their disease relevance, function and composition are unknown. This project aims to (i) use various analytical techniques to profile these gut biofilms and (ii) to develop biofilm-specific modulators to explore novel therapeutic strategies.

Targeting the oxytocin receptor in breast or prostate cancer

Trefoil factor peptides and their role in gastrointestinal disorders

Supervisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)

The gastrointestinal epithelium is a major physical barrier that protects us from diverse and potentially immunogenic or toxic content. A damaged epithelium increases permeability to such content, thus leading to inflammation, uncontrolled immune response, and diseases, such as irritable bowel syndrome and inflammatory bowel diseases that affect 10-15% of the population. Our group is involved in the identification and validation of novel drug targets and therapeutic strategies that can protect or repair this important barrier to prevent or treat such disorders. This project focuses on developing novel trefoil factor family peptide probes to understand their mechanisms of action in gastrointestinal protection and wound healing.

Understanding a new mechanism for treating asthma

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr Eunice Poon (k.poon@uq.edu.au)

Asthma is a chronic condition which leads to narrowing and inflammation of airways in the lung. Common triggers include allergens such as pollen, dust and mould. There is currently no cure. This project will investigate a protein on the cell surface that is associated with allergic asthma, investigate its mechanistic role in promoting lung inflammation, and help in the development of new therapeutics using a mouse model of lung inflammation.

Understanding bacterial metabolites in immunity

Understanding cellular activation through G protein coupled receptors

Supervisors: Professor David Fairlie (d.fairlie@uq.edu.au), Dr James Lim (j.lim@imb.uq.edu.au)

G protein-coupled receptors are the most common therapuetic target on the cell surface. Understanding how they work involves investigating how specific molecules bind to them, triggering a series of fundamental cellular functions. This project aims to unravel the details of this activation process and potentially identify novel drug targets to treat various diseases.

Understanding how blood vessels in the brain are formed

Supervisor: Dr Rosemary Cater (r.cater@uq.edu.au)

The human brain comprises ~650 kilometres of blood vessels lined by brain endothelial cells, which supply the brain with oxygen and essential nutrients. The growth of cerebral blood vessels begins early in development via a process called sprouting angiogenesis. Despite its importance, the molecular mechanisms underlying brain angiogenesis and formation of the blood-brain barrier are poorly understood. It has recently been demonstrated that the gene Flvcr2 is critical for blood vessels to grow in the brain, and last year we discovered that the protein encoded by this gene (FLVCR2) transports choline – an essential nutrient – across the blood brain barrier and into the brain. This project will utilise biochemical techniques and structural biology (cryo-EM) to investigate what other molecules may regulate this transport process, and how choline regulates angiogenesis in the brain.

Understanding the complex spatial distribution of cone snail venom peptides across the venom gland

Understanding the molecular structures of proteins involved in rare disease.

Supervisor: Dr Rosemary Cater (r.cater@uq.edu.au)

Rare diseases are often caused by genetic mutations that disrupt protein function. In some cases, we already understand the three-dimensional structure and functional role of these proteins in healthy individuals. However, unfortunately, for some rare diseases, we lack this knowledge. This lack of information prevents us from understanding how mutations within the protein can lead to malfunction and disease onset, which in turn prevents us from understanding the disease and how to treat it. This project will employ biochemical techniques, structural biology (cryo-EM), and computational approaches to understand the normal 3D structure and role of proteins implicated in rare diseases. By elucidating these aspects, we will provide critical insights for the development of drugs to treat these rare diseases.

Upgrading the potency of a cancer drug using structure-based design

Using venom peptides to understand the function of sensory neurons

Venom-Derived Blood-Brain Barrier Shuttles

Supervisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)

The blood-brain-barrier (BBB) is a biological barrier that tightly controls the transfer of substances between the blood and the brain. There is evidence that some peptides found in animal venom can pass the BBB via receptor-mediated transcytosis, for example the bee venom peptide apamin. This project aims to identify new venom peptides that can pass the BBB, and develop peptide-based shuttles to transfer cargo across it.

Venom peptide drug discovery

Supervisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)

Venoms comprise a highly complex cocktail of bioactive peptides evolved to paralyse prey and defend against predators. Homology of prey/predator receptors to human receptors render these venom peptides also active on human receptors and they have become a rich source for neurological tools and therapeutics. This project comprises discovery, synthesis and structure-activity relationship studies of these venom peptides with the goal to develop novel probes for neuroscientists as well as therapeutic drug leads.

Venom peptides as next-generation bioinsecticides

Deorphaning membrane transporters of unknown function

Supervisor: Dr Rosemary Cater (r.cater@uq.edu.au)

Solute carrier (SLC) transporters are a large family of membrane proteins that move nutrients, ions, drugs, and metabolites across cell membranes. They are essential for normal physiology and are implicated in a huge range of diseases, from cancer to neurodegeneration to metabolic disorders, making them one of the most important classes of drug targets in the genome. Remarkably, despite their importance, around 25% of SLC transporters remain "orphans" – we don't yet know what molecules they transport or what role they play in the cell. This project will use a combination of biochemistry, biophysics, and structural biology (including cryo-EM) to deorphan one or more of these uncharacterised transporters: expressing and purifying the protein, testing candidate substrates using transport assays, and determining its structure to understand how it works at a molecular level. By assigning function to a previously unknown transporter, this project has the potential to open up an entirely new area of biology and reveal a novel therapeutic target for disease.

Developing inhibitors of choline transport to treat brain cancer

Supervisor: Dr Rosemary Cater (r.cater@uq.edu.au)

Cells need a nutrient called choline to build their membranes and to grow. Cancer cells are especially hungry for it – almost all cancers ramp up how much choline they take up and use, which is why choline levels can even be used in scans to help diagnose tumours. This project focuses on glioblastoma, the most aggressive and hardest-to-treat form of brain cancer. Choline transporters, the proteins that carry choline into cells, are switched on at higher levels in glioma tumours, and patients with higher levels tend to have worse outcomes – making them promising targets, although exactly how much they drive tumour growth is still being tested. Our lab recently worked out the 3D structure of one of these choline transporters using a technique called cryo-EM (which lets us "see" proteins at near-atomic resolution), showing exactly how it grabs and moves choline across the blood-brain barrier. We now want to use this structure as a blueprint to design molecules that block choline transporters, and test whether cutting off the tumour's choline supply can slow its growth. This project will involve hands-on training in core molecular biology and biochemical and structural biology techniques (including protein purification, transport assays, and cryo-EM) to test candidate inhibitors and figure out how they work, contributing to the development of a potential new type of brain cancer treatment.