Understanding G Protein-Coupled Receptors (GPCRs): Accelerating Discovery From Concept To Clinic.
Funder
National Health and Medical Research Council
Funding Amount
$6,871,789.00
Summary
G Protein-Coupled Receptors (GPCRs) form the largest family of receptors (and thus drug targets) in living organisms. Currently, the major reason that new drugs fail to reach the clinic is lack of appropriate drug effect (approx. 30%). Thus, we need a better understanding of how GPCRs work and how this relates to disease. Our Program addresses this knowledge gap, using GPCR models that are relevant to treatment of metabolic, cardiovascular and central nervous system disease.
Relaxin Receptor Structural Determination To Aid Therapeutic Development
Funder
National Health and Medical Research Council
Funding Amount
$1,249,114.00
Summary
The receptor for the peptide hormone relaxin, RXFP1, is being targeted by numerous drug companies for the treatment of cardiovascular disease. However, the lack of molecular detail of how relaxin binds and activates RXFP1 is hindering new drug development. We will determine the structure of the complex of relaxin bound to RXFP1 and the mechanism by which this activates cells. The knowledge gained will aid in the design of new drugs targeting RXFP1 for the treatment of cardiovascular disease.
Cryptococcal Phospholipases: Structure, And Potential Targets For Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$511,650.00
Summary
Mortality and morbidity from invasive fungal infections have increased substantially over the past two decades, especially in immunocompromised patients, such as those with AIDS. Antifungal drugs marketed at present are not very effective or are toxic. There is a need to identify new metabolic and structural targets, some of which are responsible for fungal virulence, as potential areas for development of new drugs. One such virulence factor discovered in our laboratory is an enzyme secreted by ....Mortality and morbidity from invasive fungal infections have increased substantially over the past two decades, especially in immunocompromised patients, such as those with AIDS. Antifungal drugs marketed at present are not very effective or are toxic. There is a need to identify new metabolic and structural targets, some of which are responsible for fungal virulence, as potential areas for development of new drugs. One such virulence factor discovered in our laboratory is an enzyme secreted by the pathogenic fungus, Cryptococcus neoformans, which is acquired by inhalation into the lungs where it can cause lesions, and eventually spreads to other parts of the body, including the brain (median mortality, 17%). This enzyme breaks down cell membranes, aiding invasion into the host lungs and other tissues, and is called phospholipase B (PLB). It is also produced by several other pathogenic fungi, and is different from human phospholipases. In this project we aim to understand how the PLB is constructed, so that we can work out where the cell membrane components bind to it. We will then design drugs which can bind to the PLB enzyme in place of membrane components and in this way block its harmful effects. We will test the effects of such drugs to make sure they do not interfere with human enzyme systems. Inhibitory compounds may also be able to kill the cryptococcal cells, especially if administered together with currently used therapies. Drugs developed to treat Cryptococcus will then be applicable to other systemic fungal infections - a major advance in the treatment of fungal disease, and a saving of some A$60,000 per patient (estimated from a recent U.S. study).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
Ecto-nucleoside Triphosphate Diphosphohydrolases Of Leishmania: Role In Virulence And Potential As Antimicrobial Targets
Funder
National Health and Medical Research Council
Funding Amount
$314,658.00
Summary
Leishmaniasis is a serious disease that affects millions of people worldwide, particularly in developing countries. The disease is caused by a number of species of parasites, and current treatment regimes are not ideal. This research aims to target certain proteins produced by the parasite and define the role of the proteins in causing disease. Furthermore this research will identify new drugs that will block these parasite proteins and may contribute to new therapies for this serious disease.
The Bioactivity And Binding Partners Of Irukandji And Box Jellyfish Venom
Funder
National Health and Medical Research Council
Funding Amount
$596,950.00
Summary
Venom from the Box Jellyfish and Irukandji jellyfish are considered the most leathal known to science yet precious little is known on the nature of these secretions or how they harm humans. This study aims to fully characterise bioactive proteins in jellyfish venom and attempt to block their activity using regulatory-approved and experimental drugs.
Next Generation Imaging To Bridge The Knowledge Gap In Nanomedicine Delivery
Funder
National Health and Medical Research Council
Funding Amount
$483,402.00
Summary
Nanomedicines are generally touted as the next generation in therapeutics. However, despite some landmark successes, their translation into clinical use is limited. This is mainly a result of poor understanding of how they behave under physiological conditions. To address this issue and improve translation, this fellowship aims to develop predictive models of how nanomedicines interact with biological systems, then validate the nanomedicines in dog models of cancer that mimic the human disease.