Interaction Of New Kinase Inhibitor Drugs With Multi-drug Resistance (MDR) Transporter Proteins.
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, ....Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, multidrug transporters sometimes interfere with drug therapy. They can prevent efficient absorption of drugs, increase the rate of drug elimination from the body, or prevent drug access to some tissues . Moreover, the activity of the transporters is quite variable, both between patients and within the same patient over time. This makes it difficult to provide optimal drug doses, particularly when treating cancer, where the drugs must be given at the maximum tolerated dose. The presence of drug transporter proteins in tumour cells can prevent entry of anticancer drugs, rendering them resistant to treatment. This is the main cause of failure in chemotherapy. This project will investigate a class of very promising new anticancer drugs, kinase inhibitors, to determine whether they are pumped by multidrug transporters, whether they alter the amounts of drug transporters in cells, and whether they alter transporter activity. We will also determine the consequences that follow from this for drug therapy. This information will help clinicians to rationally optimise therapy with the new drugs, to identify in advance both favourable (synergistic) and unfavourable (harmful) drug interactions in combination chemotherapy, to optimise drug doses and to minimise toxic side effects. The information will also add to our general understanding of drug absorption and elimination, and to the basic science of the remarkable multidrug transporter proteins.Read moreRead less
Developing Synergisers Of The Antimalarial Drug, Chloroquine, For The Treatment Of Chloroquine-resistant P. Falciparum.
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselve ....Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselves, can synergise the action of chloroquine. This may involve the inhibition of the activity of proteins that directly or indirectly extrude chloroquine from its site of action in the parasite's digestive apparatus. Unfortunately, thechloroquine synergisers examined to date have been too toxic to be useful in vivo. In preliminary studies we have identified some compounds that would be suitable for use in malaria patients, including a widely used antimalarial drug, primaquine, that can synergise the activity of chloroquine against chloroquine-resistant parasites. We will attempt to understand the molecular basis of this interaction. This will allow us to define optimal combinations of chloroquine and a resistance-reversing quinoline for use treating malaria. This could extend the clinical life of this important antimalarial drug. The information obtained may also help to design novel antimalarial drugs.Read moreRead less
Novel Fluorescent Probes Of Cellular Microenvironments To Study The Mechanism Of Action Of Endoperoxide Antimalarials
Funder
National Health and Medical Research Council
Funding Amount
$983,305.00
Summary
Malaria is responsible for the deaths of about two million children each year. As current drugs become increasingly useless due to the development of parasite resistance, there is an urgent need for new antimalarials. Artemisinin, an ancient Chinese drug that is extracted from wormwood, is now a front-line antimalarial, however its mechanism of action is not clear. Information about how artemisinin works is needed to help design cheap synthetic drugs that work in the same way.
Interactions Between The Malaria Parasite's Chloroquine Resistance Transporter And Antimalarial Drugs
Funder
National Health and Medical Research Council
Funding Amount
$485,641.00
Summary
The malaria parasite is a single-celled organism which invades the red blood cells of its host. The aim of this project is to characterize the parasite protein responsible for conferring resistance to chloroquine, and to study its interaction with other antimalarial drugs. The parasite's susceptibility to chloroquine, and other drugs, is altered by small changes in this protein. This work will advance our understanding of the increasingly widespread phenomenon of antimalarial drug resistance.
Drugs are broken down in the body by the process of metabolism. Metabolism is important as both a detoxification and elimination mechanism, and determines dose rate for chronically administered drugs. Many drugs are metabolised by a reaction called glucuronidation. We will characterise the various components of the glucuronidation reaction in an integrated manner in order to understand and predict factors that influence an individual's capacity to metabolise drugs and other chemicals.
The Molecular Basis Of Cytochrome P450 And UDP-glucuronosyltransferase Isoform Substrate Selectivity
Funder
National Health and Medical Research Council
Funding Amount
$448,500.00
Summary
Drugs and chemicals (e.g. dietary constituents, environmental pollutants and industrial chemicals) are broken down in the body by specific enzymes, a process referred to as metabolism. Drug and chemical metabolism serves as a detoxification mechanism (since the end products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. Enzymes are highly specialised proteins made up from amino acids as the building blocks. There are two enzymes in ....Drugs and chemicals (e.g. dietary constituents, environmental pollutants and industrial chemicals) are broken down in the body by specific enzymes, a process referred to as metabolism. Drug and chemical metabolism serves as a detoxification mechanism (since the end products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. Enzymes are highly specialised proteins made up from amino acids as the building blocks. There are two enzymes in humans primarily responsible for the metabolism of drugs and other chemicals; cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Indeed, CYP and UGT are together responsible for the elimination of over 90% of metabolised drugs in humans. Both UGT and CYP exist as superfamilies of structurally related enzymes (called 'isoforms'). Approximately fifteen CYP isoforms are known to metabolise drugs, and a similar number of UGT isoforms also appear to have the capacity to metabolise drugs in humans. The separate CYP and UGT isoforms preferentially metabolise different types of drugs and chemicals, due to the fact each isoform comprises a different sequence of amino acids. However, which of the approximately 500 amino acids present in each UGT and CYP isoform that bind and metabolise specific drugs and chemicals is unknown. This project will identify the individual amino acids of several important CYP and UGT isoforms responsible for binding and metabolising drugs and other chemicals. A variety of techniques will be used, including modification of the amino acid sequence of the isoforms and computer modelling of their 'internal' structure. Elucidating the structural basis of how drugs and chemicals interact with CYP and UGT isoforms is fundamental to our understanding of these important enzymes and their function, and can be used to design drugs with better metabolic stability and decreased propensity for troublesome interactions with other drugs.Read moreRead less
Regulation Of Human Arylamine N-acetyltransferase Transcription, Translation And Protein Stability
Funder
National Health and Medical Research Council
Funding Amount
$470,958.00
Summary
Individuals respond very differently to many drugs and other chemicals in the diet and workplace. This variation can be a significant complication in treating patients and in attempting to determine risk with exposure to toxins. Genetic differences between individuals are a common reason for this variation. However, many enzymes and other proteins in humans are controlled by environmental factors that can either increase their activity or inhibit it. In this study, we will investigate how the ac ....Individuals respond very differently to many drugs and other chemicals in the diet and workplace. This variation can be a significant complication in treating patients and in attempting to determine risk with exposure to toxins. Genetic differences between individuals are a common reason for this variation. However, many enzymes and other proteins in humans are controlled by environmental factors that can either increase their activity or inhibit it. In this study, we will investigate how the activity of an important family of enzymes (the acetyltransferases) varies between individuals as a result of environmental factors. We will look at the genes for each of the enzymes and learn about this control mechanism. We will also look careful at the structure of the proteins and determine how this may change when challenged with external stimuli. The expected outcome will be a better understanding of these important enzymes that are involved in the metabolism of many drugs, and also provide a means of determining how different individuals may respond to foreign chemicals and drugs that use these enzymes in the body for metabolism.Read moreRead less
The Mechanism Of Action Of New 5-nitroimidazole Drugs Which Are Effective Against Metronidazole-resistant Giardia
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
We have discovered new 5-nitroimidazole drugs which can overcome giardial resistance to metronidazole, the most prescribed 5-nitroimidazole drug to treat giardiasis. We will focus on defining mechanisms of action of these new 5-nitroimidazole drugs in the anaerobic gut protozoan parasite Giardia. Using biochemical techniques, we will determine whether our potent new drugs are activated more efficiently by the same mechanisms as metronidazole or by novel enzyme pathways in the parasite.
Drug Interactions Involving Complementary Medicines: Effects Of Phytoestrogenic Isoflavones.
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
Isoflavones are naturally occurring chemicals that have become widely recognised as 'phytoestrogens'. These are plant-derived compounds with a biological activity that resembles that of the human hormone, estrogen. Pharmaceutical preparations containing isoflavones, as herbal extracts, are currently available over-the-counter from pharmacies and health-food outlets and are being heavily promoted in the lay press. For example, Promensil, which contains 40mg of isoflavones per tablet, is being pro ....Isoflavones are naturally occurring chemicals that have become widely recognised as 'phytoestrogens'. These are plant-derived compounds with a biological activity that resembles that of the human hormone, estrogen. Pharmaceutical preparations containing isoflavones, as herbal extracts, are currently available over-the-counter from pharmacies and health-food outlets and are being heavily promoted in the lay press. For example, Promensil, which contains 40mg of isoflavones per tablet, is being promoted for use in women over the age of 45 years and Trinovin is being promoted for men over 50. It is well recognised that patients taking more than one drug may experience an adverse event as a consequence of one drug altering the way in which the body handles another. Therefore, a new 'conventional' drug cannot be marketed unless information on its ability to alter the handling of other drugs is provided to the relevant regulatory body. In stark contrast, there is comparatively little information required for the marketing of herbal products such as isoflavones, despite the fact that these products will be made available over-the-counter for self-medication. We hypothesise that isoflavones will be capable of interacting with conventional drugs and we will be conducting a range of experiments to address this hypothesis. At present little or no consideration is given to the safety issues that arise from the use of herbal remedies in general, not only the isoflavones. Therefore a patient taking a range of conventional drugs is able to purchase a herbal remedy, over-the-counter, with no consultation with a health professional. If we discover that isoflavones can alter the handling of conventional drugs by the body, then certain precautions will need to be taken in defining their safety in humans. The result may also have implications for the use of other complementary medicines.Read moreRead less