Novel target of amiloride analogues - picornaviral RNA polymerase. Picornaviruses cause a range of diseases such as poliomyelitis, meningitis, myocarditis, hepatitis A, neonatal sepsis and common cold. No antiviral treatment is available for these infections. Nearly 50% of antiviral drugs used in medicine are viral polymerase inhibitors; however picornaviral RNA polymerase has been largely overlooked as a drug target. We have discovered a group of compounds that inhibit picornaviral RNA polymera ....Novel target of amiloride analogues - picornaviral RNA polymerase. Picornaviruses cause a range of diseases such as poliomyelitis, meningitis, myocarditis, hepatitis A, neonatal sepsis and common cold. No antiviral treatment is available for these infections. Nearly 50% of antiviral drugs used in medicine are viral polymerase inhibitors; however picornaviral RNA polymerase has been largely overlooked as a drug target. We have discovered a group of compounds that inhibit picornaviral RNA polymerase. This project aims to define the inhibition mechanism and to evaluate a potential use of these compounds for antiviral drug development.Read moreRead less
Membrane structure and lipid interactions of the pore-forming toxin Equinatoxin II by NMR. The structure of Equinatoxin II, a pore-forming protein, will be determined in model cell membranes using solid-state NMR spectroscopy. The relationship of molecular structure to bioactivity and the nature of the pore-forming mechanism of this toxin will be determined. The results will aid in understanding how toxins lyse cells and could lead to the design of improved antibiotic peptides. Currently the st ....Membrane structure and lipid interactions of the pore-forming toxin Equinatoxin II by NMR. The structure of Equinatoxin II, a pore-forming protein, will be determined in model cell membranes using solid-state NMR spectroscopy. The relationship of molecular structure to bioactivity and the nature of the pore-forming mechanism of this toxin will be determined. The results will aid in understanding how toxins lyse cells and could lead to the design of improved antibiotic peptides. Currently the structure of membrane proteins are difficult to determine and the newly developed techniques used for the structural determination of this membrane-associated protein will be suitable for studying other membrane proteins and receptors of pharmaceutical importance.Read moreRead less
Special Research Initiatives - Grant ID: SR0354892
Funder
Australian Research Council
Funding Amount
$40,000.00
Summary
The Australian Protease Network. Proteases are pivotal enzymes during birth, life, ageing and death of all organisms. Proteases regulate most physiological processes by controlling protein activation, synthesis and turnover and are essential for replication and spread of viruses, bacteria and parasites that cause infectious diseases. Blockbuster drugs and diagnostics already target a few proteases. Australians have made innovative contributions individually to understanding and regulating these ....The Australian Protease Network. Proteases are pivotal enzymes during birth, life, ageing and death of all organisms. Proteases regulate most physiological processes by controlling protein activation, synthesis and turnover and are essential for replication and spread of viruses, bacteria and parasites that cause infectious diseases. Blockbuster drugs and diagnostics already target a few proteases. Australians have made innovative contributions individually to understanding and regulating these enzymes. However this initiative aims to network their efforts by value-adding to the current protease research through promoting national and international collaborations to improve our understanding of biology, and encourage exploitation of proteases/inhibitors/receptors for pharmaceutical and industrial applications.Read moreRead less
Structural investigations into the regulation of programmed cell death. One in three men and one in four women in Australia will develop cancer by the age of 75 at current incidence rates. At its heart, cancer is a disease of uncontrolled cell proliferation. One of the body's main defence mechanisms against excess cell proliferation is Programmed Cell Death, a process which becomes dysfunctional in cancer cells. This work will provide three dimensional images of the machinery that controls Progr ....Structural investigations into the regulation of programmed cell death. One in three men and one in four women in Australia will develop cancer by the age of 75 at current incidence rates. At its heart, cancer is a disease of uncontrolled cell proliferation. One of the body's main defence mechanisms against excess cell proliferation is Programmed Cell Death, a process which becomes dysfunctional in cancer cells. This work will provide three dimensional images of the machinery that controls Programmed Cell Death. This information is critical for the development of drugs designed to re-initiate Programmed Cell Death in cancer cells.Read moreRead less
Malarial parasite surface proteins: structure and interactions of key merozoite antigens. Malaria remains one the most lethal infectious diseases in the world today, being directly responsible for around 2 million deaths annually, many in children under 5 years of age. Related parasitic diseases affect livestock in malaria-endemic regions and more broadly. There is an urgent need for an improved understanding of how these parasites invade target red blood cells. Knowing the structures of key pro ....Malarial parasite surface proteins: structure and interactions of key merozoite antigens. Malaria remains one the most lethal infectious diseases in the world today, being directly responsible for around 2 million deaths annually, many in children under 5 years of age. Related parasitic diseases affect livestock in malaria-endemic regions and more broadly. There is an urgent need for an improved understanding of how these parasites invade target red blood cells. Knowing the structures of key proteins on the parasite cell surface will provide a deeper understanding of host-parasite interactions, as well as a basis for the design of vaccines or drugs that interfere with parasite invasion of host red blood cells. Read moreRead less
New analgesics based on µ-conotoxins: structure-based design of helical mimetics. Diseases in which voltage-gated sodium channels are implicated are contributors to morbidity and mortality in the Australian population, and this project promises to provide new leads for the future development of drugs to treat such diseases, in particular analgesics for the treatment of chronic pain. The generation of these leads will entail the development of new approaches to mimicking key regions of peptides a ....New analgesics based on µ-conotoxins: structure-based design of helical mimetics. Diseases in which voltage-gated sodium channels are implicated are contributors to morbidity and mortality in the Australian population, and this project promises to provide new leads for the future development of drugs to treat such diseases, in particular analgesics for the treatment of chronic pain. The generation of these leads will entail the development of new approaches to mimicking key regions of peptides and proteins in drug-like molecules. This is a highly interdisciplinary project, spanning structural biology, molecular design, medicinal chemistry, molecular biology and electrophysiology, and the training of PhD graduates with such broad experience represents another national benefit of the project.Read moreRead less
Protein-protein interactions in amyloid deposits. The aggregation of specific proteins to form insoluble amyloid fibrils is characteristic of several age-related diseases such as type-II diabetes, Alzheimer's disease and Parkinson's disease. In vivo amyloid deposits also contain three prominent non-fibrillar protein components, namely serum amyloid P component, apolipoprotein E and alpha1-antichymotrypsin. These non-fibrillar amyloid components bind to a wide variety of amyloid fibrils, irresp ....Protein-protein interactions in amyloid deposits. The aggregation of specific proteins to form insoluble amyloid fibrils is characteristic of several age-related diseases such as type-II diabetes, Alzheimer's disease and Parkinson's disease. In vivo amyloid deposits also contain three prominent non-fibrillar protein components, namely serum amyloid P component, apolipoprotein E and alpha1-antichymotrypsin. These non-fibrillar amyloid components bind to a wide variety of amyloid fibrils, irrespective of the nature of the protein constituent. This proposal is to identify the structural basis for this recognition process, the capacity of non-fibrillar components to cross-link amyloid fibrils to form networks and the influence of these interactions on amyloid fibril cytotoxicity.Read moreRead less
Evolution of a protein fold from toxin to physiological regulator: an endogenous potassium channel blocker in humans. A potassium channel blocking peptide employed by sea anemones as a toxic component of their venom is also found in proteins from a number of higher organisms, including man. In most of these proteins the function of this toxin domain is unknown. This project aims to define the structure and function of this domain in a human protein, matrix metalloprotease 23, which has possible ....Evolution of a protein fold from toxin to physiological regulator: an endogenous potassium channel blocker in humans. A potassium channel blocking peptide employed by sea anemones as a toxic component of their venom is also found in proteins from a number of higher organisms, including man. In most of these proteins the function of this toxin domain is unknown. This project aims to define the structure and function of this domain in a human protein, matrix metalloprotease 23, which has possible roles in prostate and other cancers. Our results will not only be of interest in tracing the structural and functional evolution of this toxin domain but will also provide valuable clues to its role in both the normal physiological function of matrix metalloprotease 23, as well as its potential pathological role in cancer.Read moreRead less
Intrinsically Unstructured Proteins (IUPs): NMR characterization, prediction, and application to malarial proteome. Determination of protein structures with longer DR by NMR will enrich the DR dataset and provide a deeper understanding of protein structure-function relationships and protein folding pathways. The proposal will also provide valuable information in the key applied area of target selection in structural biology. Not all current web services are freely accessible and available servi ....Intrinsically Unstructured Proteins (IUPs): NMR characterization, prediction, and application to malarial proteome. Determination of protein structures with longer DR by NMR will enrich the DR dataset and provide a deeper understanding of protein structure-function relationships and protein folding pathways. The proposal will also provide valuable information in the key applied area of target selection in structural biology. Not all current web services are freely accessible and available services can be improved further by using more reliable training dataset or more effective algorithms, development of a national DR predictor will help Australian structural biologists increase the success rate of structure determination and provide greater insight into a range of proteomes.Read moreRead less