Drug Discovery Projects
Deconstructing the genetic causes of disease to discover new drug targets
Principal Advisor: Assoc Prof. Nathan Palpant (IMB)
Associate Advisor: Andrew Mallett, Sonia Shah, and Mikael Boden (SCMB)
Despite strong vetting for disease activity, only 10% of candidate new drugs in early-stage clinical trials are eventually approved. Previous studies have concluded that pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. This project will take advantage of increasing clinical disease data, rapid growth in GWAS datasets, drug approval databases, and innovative new computational methods developed by our team. The overall goal is to develop unsupervised computational approaches to understand what genetic models and data are most predictive of future drug successes. Underpinning this work, the project will build and implement computational and machine learning methods to dissect the relationships between genome regulation, disease susceptibility, genetic variation, and drug development. The project will not only reveal fundamental insights into genetic control of cell differentiation and function but also facilitate development of powerful unsupervised prediction methods that bridge genetic data with disease susceptibility and drug discovery. Students with background/expertise in computational bioinformatics and machine learning are ideal for this work. Informed by clinical, computational, and cell biological supervisory team, the project will have an opportunity to engage with diverse international companies through internships and collaborations to facilitate co-design of these methods for uptake in industry discovery and prediction pipelines.
Developing mechanism-based treatments for chemotherapy-induced side effects
Principal Advisor: Dr. Hana Starobova (IMB)
Associate Advisor: Prof Irina Vetter (IMB/School of Pharmacy) and Prof Ingrid Winkler (Mater Research/TRI)
More than 60% of patients receiving tubulin targeting chemotherapy develop debilitating side effects, such as peripheral neuropathy, that are often life threatening, decrease the QOL and survival change of cancer patients. Current treatment strategies poorly control those side effects and often cause additional complications, likely due to lack of understanding of the underlying mechanisms. This project investigates the neuroinflammatory mechanisms contributing to development of chemotherapy induced side-effects. Recent research shows that interactions between different cell types lead to release of pro-inflammatory cytokines via inflammasomes in proximity of peripheral nerves driving neuronal sensitisation and damage. The aim of this project is to understand how tubulin targeting agents influence chemotherapy mediated interactions between endothelial cells, immune cells and neurons using immunology techniques, microscopy, in-vitro and in-vivo studies. The findings of this project will contribute to development of effective preventative treatment strategies for chemotherapy-induced side effects.
Developing new drugs targeting acid sensitive channels to treat ischemic heart disease
Principal Advisor: Assoc Prof. Nathan Palpant (IMB)
Associate Advisor: Jennifer Stow and Brett Collins
This project focuses on strategies to prevent organ damage associated with ischemic injuries of the heart. There are no drugs that prevent organ damage caused by these injuries, which ultimately leads to chronic heart failure, making ischemic heart disease the leading cause of death worldwide. Globally, 1 in 5 people develop heart failure, with annual healthcare costs of $108 B. Our team has discovered a new class of molecules, acid sensitive ion channels, that mediate cell death responses in the heart during ischemic injuries like heart attacks. This project will study the function of acid sensing channels using cell and genetic approaches. We will use innovative new drug discovery platforms to find new peptides and small molecules that inhibit acid channel activity. Finally, the project will use disease modelling in stem cells and animals to evaluate the implications of manipulating these channels using genetic or pharmacological approaches to study the implications in models of myocardial infarction. The candidate will benefit from background/expertise in cell biology and biochemistry. Collectively, this project will deliver new insights, tools, and molecules that underpin a key area of unmet clinical need in cardiovascular disease. The project will be supervised by experts in drug discovery, cell biology, and cardiovascular biology and includes opportunities for internships with industry partners such as Infensa Bioscience, a new spinout company from IMB developing cardiovascular therapeutics for heart disease.
Development of PET Imaging Tracers for Bacterial Infections
Principal Advisor: Assoc Prof Mark Blaskovich (IMB)
Associate Advisor: Dr Karine Mardon (NIF Facility Fellow and Molecular Imaging Facility Manager, CAI) and Dr Christoph Barkhausen (NIF Radiochemistry Fellow, CAI)
Bacterial infections, particularly those caused by resistant organisms, are a global threat to human health. While much attention is focused on developing better therapies, there is an urgent need to improve diagnosis in order to more rapidly select and monitor optimal treatment, reducing unnecessary use of ineffective antibiotics and improving therapeutic outcomes. In many cases infections are suspected to be present but their location cannot be determined, reducing the ability to prescribe the best therapy. Chronic infections, such as infective endocarditis and prosthetic joint infections have high mortality and morbidity yet are particularly difficult to accurately diagnose without invasive techniques. There are no clinically-used whole body imaging techniques that can specifically identify bacterial infections.
We have been modifying antibiotics that specifically bind to the surface of bacteria, attaching fluorescent substituents to create fluorescent tracers that selectively illuminate bacteria. This project will create diagnostic tracers to image bacterial infections by replacing the fluorophore with a chelating substituent that complexes radioactive metals. The goal is a probe that can be injected into patients and used to diagnose the presence and location of bacterial infections by imaging with positron emission tomography (PET).
Medicinal chemistry of new Nature-inspired treatments for Inflammatory Bowel Disease (IBD)
Principal Advisor: Prof Rob Capon (IMB)
Associate Advisor: Dr Jake Begun (Mater Medical Research Institute) and Prof Mark Morrison (UQDI)
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, are debilitating life-long relapsing-remitting diseases of the gastrointestinal tract usually diagnosed in otherwise healthy young adults. Despite multiple approved treatments for IBD, up to 25% of patients will fail current therapies and require surgery to remove diseased parts of their intestine.
Gut bacteria produce bioactive metabolites that are absorbed by the intestine and distributed throughout the body, impacting both local and distant sites. The immune system in the gut is generally tolerant of its associated microbiota. In a healthy gut, bioactives produced by gut microbiota have pro and anti-inflammatory actions, and contribute to maintaining balance. This balance is lost in immune mediated gut disorders such as IBD.
This project seeks to acquire knowledge of and develop anti-inflammatory chemicals produced by the gut bacteria of IBD patients. More specifically, the project will define and optimise novel anti-inflammatory pharmacophores, while identifying molecular targets, binding sites and mechanisms of action.
The successful candidate will join a multidisciplinary, multi-institute research team where, supported by in vitro and in vivo biology, they will be instructed and become proficient in analytical, spectroscopic, synthetic and medicinal organic chemistry.
Applicants should have high level undergraduate training, excellent grades and a passion for organic chemistry.
New chemical space as a source of new drug leads
Principal Advisor: Dr Zeinab Khalil (IMB)
Associate Advisor: Prof Phil Hugenholtz (SCMB), Prof Ian Henderson (IMB) and Prof Rob Capon (IMB)
Microbes have been a new promising source of modern medicines, including antibiotics (e.g. penicillin) and immunosuppressants (e.g. sirolimus) and well as agents to treat cancer (e.g. adriamycin) and cardiovascular (e.g. statins) disease, as well as many more. Recent advances in genomics offer the prospect of exciting new approaches to discovering the next generation of medicines hidden within the Australian microbiome.
To this end in 2020 we launched Soils for Science (S4S) as an Australia wide citizen science initiative, designed to engage the public, to collect 10's of thousands of soil samples from backyards across the nation, from which we will isolate 100's thousands of unique Australian microbes.
This project will annotate the S4S microbe library to prioritize those that are genetically and chemically unique. These will be subjected to cultivation profiling, and fermentation, followed by chemical analysis to isolate, identify and evaluate new classes of chemical diversity.
The successful candidate will join a multi-disciplinary team where, supported by microbiological and genomic sciences, they will gain skills and experience in analytical, spectroscopic and medicinal chemistry – to inform and inspire the discovery of future medicines.
Applicants must have a strong background with outstanding grades in organic chemistry, and with an interest in learning multidisciplinary biosciences.
Strategies Toward Phage-Antibiotic Conjugates
Principal Advisor: Dr Karl Hansford (IMB)
Associate Advisor: Dr Karen Weynberg (SCMB), Prof Ian Henderson (IMB) and Assoc Prof Mark Blaskovich (IMB)
We live in an era where antibiotic resistance is a major threat to global health. In this context there has been a resurgence of interest in using bacteriophages, viruses that infect, lyse and selectively kill bacteria. Antibiotics, by way of their indiscriminate killing action, can cause collateral damage to the microbiome. In contrast, phages are much more specific, targeting a narrow range of bacterial hosts. This perceived benefit is offset by the fact that bacteria readily evolve resistance to phage infection, necessitating the use of phage cocktails to cover different bacterial strains or species. Combining the action of phages and sublethal concentrations of antibiotics can lead to synergistic killing as the bacteria are subjected to different selection pressures. This practice could lead to a reduced reliance on antibiotics, supressing the emergence of resistance and the potential for toxic side effects. To this end, the chemical conjugation of antibiotics to phages represents a novel strategy to precisely deliver antibiotic payloads to sites of infection leading to a dual synergistic killing action by both phage and antibiotic. This project will explore this concept by developing chemical methods to conjugate suitably functionalised antibiotics to phage protein motifs leading to stable constructs designed to release the antibiotic cargo under pre-defined conditions. The resulting phage-antibiotic conjugates will be characterised using in vitro and in vivo methods to determine their effectiveness.
Structural and functional studies of macrocyclic peptides targeting receptors and trafficking molecules essential for SARS-CoV-2 infection
Principal Advisor: Prof. Brett Collins (IMB)
Associate Advisor: Mehdi Mobil (CAI, UQ) and Larisa Labzin (IMB)
This project focuses on the development and characterisation of small stable ‘macrocyclic’ peptides that target key receptors and intracellular complexes important for normal cellular physiology and targets in disease including SARS-CoV-2 infection and cancer. Using the “RaPID” screening approach we are identifying high affinity macrocyclic peptides with activity against proteins that regulate membrane trafficking and cellular uptake. For an example of how this is done see our recent article [1]. There are a number of potential targets that could be studied in this project for which preliminary screens have been performed. These include the neuropilin receptor (NRP1) recently identified as important for cellular infection of SARS-CoV-2 [2], and also a drug target in certain cancers because of its role in creating blood vessels in the tumour environment (angiogenesis). It is also bound by the scorpion toxin ClTx which is being developed as a marker for brain tumours, and new macrocyclic peptides may provide high affinity molecules for improved glioma diagnosis and therapy [3]. Another possible target is the ‘Commander’ complex which regulates the recycling of transmembrane proteins from intracellular organelles to the cell surface. Commander has also been identified as important for SARS-CoV-2 infection, and additionally is mutated in human X-linked intellectual disability.
The project will involve a wide array of techniques from peptide synthesis, biophysical studies of protein-protein interactions, structural biology including NMR, crystallography and cryoEM. Successful discovery of inhibitory peptides might also allow testing in cellular models of infection by SARS-CoV-2. The candidate will benefit from some background in biochemistry, structural biology and/or cell biology. Collectively, this project will deliver new insights, tools, and molecules that underpin key areas of unmet clinical need. The project will be supervised by experts in structural biology, peptide characterisation and membrane interactions, and virology and will includes opportunities for internships with industry partners where appropriate.
Targeting sodium channel accessory proteins for treatment of chronic pain
Principal Advisor: Prof Irina Vetter (IMB)
Associate Advisor: Assoc Prof Mehdi Mobli (CAI)
Chronic pain remains an area of significant unmet medical need. Voltage-gated sodium channels expressed preferentially in primary sensory afferents are recognised as important analgesic targets. Naturally occurring toxins and venom-derived peptides have evolved to target sodium channels channels with high specificity and potency, and thus provide unique opportunities to probe the structure and function of this important class of transmembrane proteins and as potential therapeutics. However, most studies have focused on the pore-forming α subunit of the channel, although it is well known that functional channels occur as multi-protein assemblies.
In this project, students will implement multidisciplinary and innovative approaches using toxins as tool molecules to investigate the role of a recently discovered toxin-binding accessory protein that regulates channel function.
Students will gain experience with peptide synthesis, patch-clamp electrophysiology, sensory neuron culture, nuclear magnetic resonance and in vivo behavioural assays to tackle the global problem of unrelieved chronic pain with innovative molecules targeting peripheral sensory neuron function.
Targeting the Biogenesis of Resistance Enzymes to Combat Antimicrobial Resistance
Principal Advisor: Dr Anthony Verderosa (IMB)
Associate Advisor: Assoc Prof Mark Blaskovich (IMB) and Prof Vito Ferro (SCMB, UQ)
Bacterial enzymes represent a major resistance mechanism driving the emergence of antimicrobial resistance. Inhibitors that directly bind to resistance enzymes and impede their function are an obvious strategy to overcome enzyme-mediated resistance; however, only the highly successful β-lactamase inhibitors have reached clinical use. Drawbacks of this strategy include the specificity of these inhibitors to only one type of resistance enzyme, and the potential for subsequent mutations to quickly restore the enzymatic activity, as the enzyme is still produced. This project explores an innovative new approach for simultaneously deactivating multiple resistance enzymes to restore the efficacy of multiple classes of antibiotics. Instead of directly targeting the resistance enzyme, this project aims to disable the machinery required for resistance enzyme biogenesis, ultimately preventing the active enzyme from being produced. We are looking for a proficient and enthusiastic synthetic chemist interested in medicinal chemistry and microbiology to work on one of the major aspects of this project.
The project will entail the design, synthesis, and microbiological evaluation of dual-acting antibiotic-biogenesis inhibitor hybrids, where antibiotic activity is supplemented with other mechanisms. Antibiotics will be coupled with inhibitors previously shown to inhibit resistance enzyme biogenesis. These hybrids should simultaneously deactivate resistance mechanisms and eradicate subsequently susceptible bacteria.
Using genomics to inform discovery of new peptide drug for common gastrointestinal disorders
Principal Advisor: Prof. David Craik (IMB)
Associate Advisor: Prof Naomi Wray
There are many advantages of peptide-based drugs including exquisite specificity to in vivo targets, resulting in exceptionally high potencies of action and relatively few off-target side effects (Craik et al, 2013). Limitations of peptide drugs are low systemic stability, poor membrane permeability, low bioavailability and high production costs.
However, these limitations may be overcome for drugs where the target tissue is the gastro-intestinal tract.
The Craik lab (Chemistry and Structural Biology Division) at IMB discovers and re-engineers novel peptides for applications in drug design and agriculture (Wang et al, 2018). Their work has the potential to lead to new drugs for the treatment of a wide range of diseases, including cancer, cardiovascular disease, metabolic disease, infectious disease and pain.
Researchers within the Wray lab (Genetics and Genomics division) at IMB have recently conducted in depth genome-wide association studies for disorders of the gut, specifically peptic ulcer disease and gastro-oesphogeal reflux disease (Wu et al, 2021), diverticulosis (in preparation), integrating with published results for the inflammatory bowel diseases (IBDs) of Crohn’s Disease and Ulcerative Colitis.
In this project the student would use results from genetic studies of gut disease to inform discovery of peptide drugs that specifically target gut tissue and would be jointly affiliated with the Craik and Wray labs.
The ideal candidate will have Honours in chemistry, with an interest in genomics and computational approaches. In the first 6 months the candidate will learn methods to interpret results of genetic association studies and integrate them with the ever-increasing resources of omics data (e.g., Nasser et al, 2021). Armed with this omics toolkit the candidate will undertake a drug design project to develop peptide-based lead molecules to modulate gut targets of interest.
Venom-derived peptides as novel analgesic leads
Principal Advisor: Prof. Irina Vetter (IMB)
Associate Advisor: Dr Richard Clark (SBMS)
Voltage-gated sodium channels are well-validated analgesic targets, with loss-of-function mutations leading to an inability to sense pain, but otherwise normal physiology and sensations. However, efforts to mirror these genetic phenotypes with small molecule inhibitors have highlighted that both selectivity over ion channel subtypes and mechanism of action are key considerations for the development of safe and effective analgesics.
This project will leverage the exquisite potency and selectivity of peptide sodium channel modulators from venoms for the rational development of novel, safe and effective molecules with analgesic activity.
Students will gain experience with peptide synthesis, patch-clamp electrophysiology, sensory neuron culture, microscopy and in vivo behavioural assays to tackle the global problem of unrelieved chronic pain with innovative molecules targeting peripheral sensory neuron function.
The discovery and development of highly stable venom-derived peptide drug leads
Primary advisor: A/Prof. Markus Muttenthaler
Associate advisor: A/Prof. Johan Rosengren
Venoms comprise a highly complex cocktail of bioactive peptides evolved to paralyse prey and defend against predators. The homology of prey and predator receptors to human receptors renders many of these venom peptides also active on human receptors. Venoms have therefore become a rich source for new neurological tools and therapeutic leads with many translational opportunities.
This project covers the discovery, chemical synthesis, and structure-activity relationship studies of venom peptides, with a specific focus on gastrointestinal stability and drug targets in the gut. Venom peptides are known for their disulfide-rich frameworks supporting secondary structural motifs not only important for high potency and selectivity but also for improved metabolic stability. While primarily studied for their therapeutic potential as injectables, this project will break new ground by investigating evolutionarily optimised sequences and structures that can even withstand gastrointestinal digestions, thereby providing new insights for the development of oral peptide therapeutics targeting receptors within the gut. These therapeutic leads will have enormous potential for the prevention or treatment of gastrointestinal disorders or chronic abdominal pain.
The candidate should have a degree in synthetic chemistry, biochemistry or pharmacology, good hands-on laboratory skills, and strong ambition and work ethics. The candidate will be involved in solid phase peptide synthesis, medicinal chemistry, mass spectrometry, NMR structure determination, CD studies, structure-activity relationship studies, gut stability assays, and receptor pharmacology.
Venom-derived sodium channel inhibitors as drug leads for motor neuron disease
Principal Advisor: Dr Fernanda C Cardoso
Associate Advisor: A/Prof Mark Bellingham (SMBS) and Professor Glenn King
Motor neuron disease (MND) is a neurodegenerative condition caused by progressive loss of motor neurons leading to paralysis and death. Investigation of ion channels in motor neurons unravelled a cluster of voltage-gated sodium (NaV) channel subtypes playing key role in the pre-symptomatic stages of this disease. Spider-venoms are an exceptional source of peptides modulating NaV channel with higher potency and selectivity than small molecules such as the drug riluzole used in the treatment of MND.
This project involves systematically interrogating spider venoms via high throughput cellular screens and assay-guided fractionation to discover spider-venom peptides that selectively target central ion channels in motor neurons and therefore have the potential to reverse MND.
This project involves multidisciplinary approaches in discovery, characterization, and structure-function studies of bio-active compounds in spider venoms and other natural repertoires. PhD scholars will develop skills in manual and automated whole-cell patch clamp electrophysiology, ex vivo electrophysiology in motor neurons, high performance liquid chromatography, mass spectrometry, recombinant expression, peptide synthesis, amongst other state-of-the-art methods and techniques. Students will author papers and be involved in writing and figures preparation for research publications from their work.
Structural and cellular analysis of Rab GTPases for drug discovery in cancer.
Principal Advisors: Prof Jennifer Stow (IMB)
Associate Advisor: Dr Quan Nguyen (IMB) and Prof Brett Collins (IMB)
Small GTPases of the Rab protein family control membrane trafficking and signalling inall eukaryotic cells. Rabs function with the help of accessory proteins that switch them on and off, and then act to recruit and activate effector protein complexes in many different cellular pathways. Recently, several Rabs have emerged as oncogenes in cancer. Rab13 for instance is overexpressed in cancers, including aggressive forms of breast cancer, where it drives metastasis and tumour growth. Rab14 has been implicated in various cancers including lung cancer, and its effector Nischarin is noted tumour suppressor in breast cancer.
Combined with experimental approaches, new machine learning computational methods are revolutionising structural biology and our understanding of how proteins interact with each other. In this project you will undertake in silico interrogation of Rabprotein-protein interactions with known or potential effectors and accessory proteins. These interactions will then be verified through imaging for colocalization and functional assays in cancer cell lines and spheroids. Spatial transcriptomics and spatial proteomics on sections of tumour samples will provide direct evidence for protein interactions in cancer.
Together these approaches will allow the identification, characterization and optimization of protein binding sites as new targets for drug development, preclinical analysis and potential therapeutic intervention.
This project will involve a close collaboration between three groups across two divisions at IMB, offering students the opportunity for cross-disciplinary training in cancer research using in silico structural modelling, cell and cancer biology and tumouranalysis.
Noninvasive peptide tracers for improving immunotherapy outcomes
Principal Advisor: Dr Conan Wang (IMB)
Associate Advisors: Prof David Craik (IMB) and Prof Kristofer Thurecht’s (AIBN)
Non–small cell lung cancer (NSCLC) is the leading cause of cancer mortality, with nearly 1.6 million cancer-related deaths each year worldwide. In Australia, NSCLC is the most prevalent form of lung cancer (64% male and 61% female). At diagnosis, one in three NSCLC patients are inoperable.
Immune checkpoint inhibitors are cancer drugs that help the immune system fight cancer and have revolutionised treatment of NSCLC, but predicting patient benefit using approved core needle biopsies are erroneous and painful. Core needle biopsies are hampered by intra- and inter-tumoral heterogeneities. They are impractical for metastatic and risky for advanced cases.
This project aims to develop next-generation molecular imaging agents for patient-friendly, safe and accurate whole-body visualisation of tumours, allowing clinicians same-day feedback to select the proper treatment and monitor progress. The molecules will be suitable for noninvasive imaging by positron emission tomography (PET), which provides quantitative, real-time assessment for patient stratification. Methods to be explored in this project span across chemistry, biology, and physics.