Development Of A Generic Strategy For The Stabilisation Of Peptide-based Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$443,196.00
Summary
There is huge interest in the development of bioactive peptides and proteins for the treatment of a wide range of diseases. However, there are still a number of hurdles that need to be overcome before this source of promising pharmaceuticals can fulfil their vast potential. One of the biggest challenges in the development of peptides and proteins as drugs is overcoming their poor stability in the human body. The broad aim of this research proposal is to develop a novel strategy that provides the ....There is huge interest in the development of bioactive peptides and proteins for the treatment of a wide range of diseases. However, there are still a number of hurdles that need to be overcome before this source of promising pharmaceuticals can fulfil their vast potential. One of the biggest challenges in the development of peptides and proteins as drugs is overcoming their poor stability in the human body. The broad aim of this research proposal is to develop a novel strategy that provides therapeutically promising peptides and proteins the ability to resist the body s natural degradation pathways so they are able to reach their biological target. To develop this strategy we will use the recently discovered peptide hepcidin as a model system. Hepcidin is the major iron-regulatory hormone in the human body and incorrect levels of this hormone result in either iron overload (haemochromatosis), when there is not enough hepcidin produced by the body, or anemia of inflammation when there is too much hepcidin. The development of hepcidin-based therapeutic agents to treat these conditions has the potential to have significant impact as it has been estimated that up to 1 in 300 Australians are affected by haemochromatosis during their lifetimes. Unfortunately, unmodified peptides, like hepcidin, are of limited therapeutic value due to their poor stability within the human body. This research proposal describes the development of stabilised hepcidin analogues with the potential of being useful drug leads for the treatment of haemochromatosis.Read moreRead less
Structure-based Design Of Inhibitors Of Oxidative Protein Folding In Enterobacteriaceae.
Funder
National Health and Medical Research Council
Funding Amount
$523,540.00
Summary
Antibiotic resistance represents a major public health problem. For gram-negative bacteria in particular, the situation is increasingly bleak, with the accumulation of resistance to existing drugs and few if any new drugs in the pipeline. We are using structure-based drug design to develop novel strategies for the treatment of gram-negative bacterial infections.
Exploitation Of Bacterial Transcription Initiation As A Target For New Antimicrobials
Funder
National Health and Medical Research Council
Funding Amount
$540,356.00
Summary
Antibiotic resistant infections from 'superbugs' are a major health problem. We will exploit information we have gathered on the machinery that copies genetic information into a message to discover chemical compounds that can be used for the development of new antibiotics with a novel mechanism of action.
Plasmodium Falciparum Neutral Aminopeptidases: Structure-function Analysis For The Discovery Of Anti-malarial Drugs.
Funder
National Health and Medical Research Council
Funding Amount
$634,027.00
Summary
Malaria is the world's most prevalent parasitic disease. Due to the spread of drug resistant parasites there is an urgent need to identify new anti-malaria targets and develop new drugs. We have shown that two enzymes, termed neutral aminopeptidases, are essential to the parasite's survival in the host. In this proposal we will obtain the structure of these enzymes and bring forth novel lead compounds that will form the basis of a new class of anti-malaria treatment.
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.
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
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