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EskITIs INsTITUTE DRUG DIsCOVERY REsEARCH “The Eskitis Institute is at the forefront of discovering new treatments for a wide range of critical diseases.” Professor Ian O’Connor, Vice Chancellor and President, Griffith University griffith.edu.au/eskitis The Eskitis Institute - Multidisciplinary Drug Discovery Our Research Unique resources and capabilities Griffith University provides a setting of international standard for the pursuit of learning, teaching, research and professional practice. Griffith is ranked in the top 5% of universities worldwide. Eskitis is located in two buildings, Eskitis 1 & 2, located on the outskirts of Griffith University’s Nathan Campus. Our research is supported by unique in-house capabilities, including the following: The Eskitis Institute is a flagship research centre of Griffith Universitythat focuses on drug discovery research. Eskitis offers an excellent environment for drug discovery research in areas such as: Nature Bank is a unique drug discovery platform based on natural products from Australia, China, Malaysia and Papua New Guinea. This biodiversity resource comprises >45 000 samples of plants and marine invertebrates, >18 000 extracts, >200 000 semipurified fractions and >3 250 pure compounds. Nature Bank is an ideal resource for drug discovery research and is being actively used by projects in partnership with academic and industry groups. • Cancer (including prostate, pancreatic and breast cancer) Neurodegenerative diseases (including Parkinson’s disease, schizophrenia and Alzheimer’s disease) Infectious diseases (including emerging antibioticresistant infections) Global Health (including malaria, African sleeping sickness, tuberculosis and HIV) Eskitis researchers collaborate widely, with research partners on every continent, and hosts researchers and students from across the world. study with us The Eskitis Institute offers many opportunities for Masters and PhD study in drug discovery projects. Eskitis is a truly multidiscplinary research and training environment with an equal proportion of chemistry and biology researchers. Potential PhD study areas include: Medicinal chemistry Natural product chemistry (including marine invertebrates, plants and microorganisms) Traditional Chinese Medicines synthetic chemistry Bioaffinity Ms screening Neurobiology Cancer tumour biology Adult stem cell biology Parasitology (visit nature-bank.com.au for more) Neuro Bank is a collection of well-characterised human olfactory neurosphere-derived (hONs) cells from over 200 neurology patients. Neuro Bank represents excellent models of neurological diseases to support research on Parkinson’s disease, schizophrenia and other diseases. Queensland Compound Library is an automated library of over 330 000 pure compounds from Australian chemists. The QCL is a national facility conceived to facilitate and drive interactions between chemists and biologists in Australia or overseas. (visit griffith.edu.au/qcl for more) Drug Discovery capabilities include a core of industry-standard drug discovery infrastructure including High Throuhgput screening. High throughput imaging is enabled by high content confocal screening systems, allowing the examination of the effect of compounds on individual cells. Mass Spectrometry facilities include 4.7 and 12 Tesla Fourier transform ion cyclotron resonance mass spectrometers (FTMs) for high resolution protein analysis. These instruments allow real-time observation and isolation of protein complexes. Nuclear Magnetic Resonance facilites include 500 and 600 Mhz units, allowing high resolution spectroscopy to quickly solve the structure of small molecules “The innovative work being conducted at the Eskitis Institute can accelerate and revolutionise our approach to fighting disease.” - Professor Ronald J Quinn AM, Eskitis Institute Director Quinn Group Projects Project 1: Screening of prostate cancer targets against natural product extracts Fourier-Transform Mass spectrometry (FTMs) is an exciting new method to probe interactions between proteins and ligands. This project will use FTMs to screen some or all of the 18,000 optimised natural product extracts in the Nature Bank platform against proteins critical in progression of prostate cancer. This project offers an opportunity to apply modern drug discovery techniques to natural products, while helping to develop the next generation of prostate cancer drugs. Project 2: Fragment-based drug discovery using fourier transform mass spectrometry Malaria is a parasitic disease that kills over 1 million people each year, mostly young children. New drugs are desperately needed to fight increasing parasite resistance. This project will use a novel fragment-based approach to find new lead compounds for development of new malaria drugs. Fragments, low molecular weight compounds (MW<250) with weak binding affinities, are becoming attractive starting points for drug discovery. This project will apply a mass spectrometry (FTMs) method to screen fragments from the Eskitis natural product library against malaria proteins. This is a novel mechanism-based approach to exploit natural product diversity for anti-malarial drugs. Project 3: Synthesis of part structures of natural products to build a fragment library known naturally occurring fragments cover 56% of natural product diversity space. Aligned with project 2, this project will synthesise fragments derived from part structures of natural products to cover 100% of natural product diversity space. This approach will involve in silico analysis of this diversity space to generate a minimum set of fragments, followed by synthesis. Project 4: The use of natural product scaffolds in the generation of novel chemical libraries Natural products display chemical complexity and diversity often not seen in synthetic collections and they inherently interact with proteins making them an ideal source of unique scaffolds for generation of screening libraries. Core ring structures found in natural products but not present in commercial collections will be used to generate chemically diverse libraries for use in drug discovery programs or molecular probe research. This project will create unique chemical libraries that can be tested against a range of biological targets. Project 5: Protein Fold Topology—a novel molecular modelling approach to drug discovery Natural products are made by nature via interactions with biosynthetic enzymes. They also exert their effect as drugs by interaction with proteins. We have shown that recognition of the natural product by biosynthetic enzymes translate to recognition of therapeutic targets. The concept of Protein Fold Topology (PFT) describes cavity recognition points unrelated to protein fold similarity. We are seeking automated methods to interrogate these interactions. Project 6: Synthetic lethal screening to identify new drugs to fight advanced prostate cancer Current treatments for advanced prostate cancer are largely palliative, however new promising targeted therapeutics such as antisense oligonucleotides on heat shock protein HsP27 and/or YB1are being developed. such treatment is effective but causes tumours to develop resistance. This project will use prostate cancer cells treated with siRNA to discover drugs from Nature Bank that avoid treatment resistance. This project is an opportunity to apply modern drug discovery techniques to natural products, while helping to develop the next generation of prostate cancer drugs. Project 7: Old age and the liver epithelium We are using confocal imaging to identify effects in cell fenestrations to discover natural products that reduce the effects of aging. This will involve establishing a confocal imaging assay to detect cholesterol in lipid rafts. Nature Bank will be screened against endothelial cells to find natural products that modulate lipid rafts associated with fenestrations occurring in aging. This is an opportunity to apply modern drug discovery techniques to natural products, while investigating the aging process. Project 8: Chemical biology using an annotated natural product library on olfactory derived stem cells from Parkinson’s disease patients The project will annotate pure natural products contained within the Nature Bank. Nature Bank includes 3250 pure compounds, many with a known biological target. This annotated library will be used to examine cells from Parkinson’s disease patients. Cells will be investigated in order to identify compounds that correct the phenotype. Project 9: Development of reversible inhibitors of Factor XIa Excessive formation of blood clots within the circulatory system can cause thrombosis, stroke and heart disease. Risk of thrombosis is especially high in patients recovering from surgery. As many as 26,000 Australians suffer from venous thromboembolism (VTE) each year and 10% of deaths in Australian hospitals are thought to be caused by VTE. This project is based on the discovery of potent FXIa inhibitors, dysinosin A and clavatadine A in our laboratory. EskITIs INsTITUTE DRUG DIsCOVERY REsEARCH “At Eskitis we are harnessing the chemical diversity inherent in the natural world to drive our research.” Professor Ronald J Quinn AM, Director, Eskitis Institute ResearcherID URL: www.researcherid.com/rid/A-7931-2008 Contact The Eskitis Institute Griffith University Tel: +61 (07) 3 735 6000 Fax: +61 (07) 373 56001 [email protected], [email protected] griffith.edu.au/eskitis @eskitis (twitter) Location The Eskitis Institute Eskitis 2 Building (N75) Griffith University Brisbane Innovation Park, Don Young Road Nathan Qld 4111 Australia Griffith University CRICOS Provider Number 00233E Front cover images (Clockwise from top left): Professor Ronald J Quinn AM, the Eskitis 2 Building, Professor Ian O’Connor, interior of QCL robot, eucalyptus leaves