Targeting Protein Synthesis In The Apicoplast And Cytoplasm Of Plasmodium
Funder
National Health and Medical Research Council
Funding Amount
$453,768.00
Summary
New antimalarial drugs are desperately needed. Protein synthesis in Plasmodium falciparum is a validated target for existing drugs and is a promising target for new drugs. This project brings together malaria biologists with chemists and computer scientists to explore this promising field. We will apply modern methods of drug target characterisation to find the most promising enzyme targets involved in protein synthesis and to identify inhibitors as leads for developing antimalarial therapies. A ....New antimalarial drugs are desperately needed. Protein synthesis in Plasmodium falciparum is a validated target for existing drugs and is a promising target for new drugs. This project brings together malaria biologists with chemists and computer scientists to explore this promising field. We will apply modern methods of drug target characterisation to find the most promising enzyme targets involved in protein synthesis and to identify inhibitors as leads for developing antimalarial therapies. Australian researchers involved in this project will provide expertise in bioinformatic prioritisation of Plasmodium drug targets from the aminoacyl tRNA synthetase family of enzymes. We will use structural modelling and docking experiments to identify promising antimalarial inhibitors, and will optimise assays to assess the effects of these inhibitors. We will also apply modern molecular biology tools to validate these enzymes as anti-malarial drug targets.Read moreRead less
The PH Of The Malaria Parasite's Digestive Vacuole And Its Role In Antimalarial Drug Resistance
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
Malaria is an infectious disease that infects an estimated 300-500 million people and kills an estimated 1.5-2.7 million people annually. The microscopic parasite responsible for the disease is becoming increasingly resistant to most of the antimalarial drugs presently available. However the mechanisms by which it does so are very poorly understood. The malaria parasite invades the red blood cells of its victim. Once itside, it sets about consuming the contents of the cell, ingesting them and de ....Malaria is an infectious disease that infects an estimated 300-500 million people and kills an estimated 1.5-2.7 million people annually. The microscopic parasite responsible for the disease is becoming increasingly resistant to most of the antimalarial drugs presently available. However the mechanisms by which it does so are very poorly understood. The malaria parasite invades the red blood cells of its victim. Once itside, it sets about consuming the contents of the cell, ingesting them and depositing them in a small acidic compartment called the digestive vacuole. Many of the antimalarial drugs presently in use target this compartment and interfere with the processes going on inside it. There is evidence that resistance to antimalarial drugs arises as a result of changes in this compartment, though what these changes are, and how they occur remains a mystery. This work focuses on the mechanisms involved in controlling the acidity of the parasite's digestive vacuole. We have preliminary evidence that parasites showing different levels of antimalarial drug resistance have different levels of acidity in their vacuoles, and that this may be due to differences in the rate at which acid leaks from this compartment. The aim of this work is to obtain a detailed understanding on the mechanisms by which the acidity of the parasite's digestive vacuole is regulated and to gain some insight into whether and how these mechanisms might differ between drug-resistant and drug-sensitive parasites. By so doing, this work might be expected, in the long term, to provide a basis for the devolpment of new drugs with which to combat this deadly and increasingly threatening disease.Read moreRead less
Analysis Of The Plasmodium Falciparum M18 Aspartyl Aminopeptidase
Funder
National Health and Medical Research Council
Funding Amount
$613,683.00
Summary
Malaria remains a major cause of death and disease in many parts of the world. There is widespread resistance to all currently used drugs and an urgent need for new treatmants. We have identified the malaria enzyme, aspartyl aminopeptidase as a new drug target. This proposal will investigate the biological role of this enzyme and has the potential to identify new compounds which may be effective antimalarial drugs.
The Quinoline Antimalarials: Mechanisms Of Action And Resistance In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
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 these antimalarials so that replacement drugs can be designed. We propose to test the hypothesis that chloroquine acts by interfering with the detoxification of the by-products that are produced when the parasite f ....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 these antimalarials so that replacement drugs can be designed. We propose to test the hypothesis that chloroquine acts by interfering with the detoxification of the by-products that are produced when the parasite feeds on haemoglobin. We propose that the parasite develops resistance to chloroquine by excluding either the drug or the toxic by-products from the site of action. We further propose that proteins of the digestive vacuole of the parasite are involved in the development of resistance to chloroquine. We plan to identify and characterise these proteins and to use this information to design novel antimalarial drugs.Read moreRead less
Characterization Of The Chloroquine Resistance Transporter Of The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$400,527.00
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 characterise the mechanism by which parasites have become resistant to the antimalarial drug chloroquine. Resistance is conferred by small changes in a single protein, but the underlying mechanism is not known. The results of this project will constitute a major advance in our understanding of the increasingly widespread phenomenon of antimalarial drug resistance.