RECOMBINANT MALARIAL PYRIMIDINE ENZYMES AS DRUG TARGETS
Funder
National Health and Medical Research Council
Funding Amount
$229,750.00
Summary
Malarial parasites have now developed resistance to most of the available drugs and there is an urgent need for drugs with new mechanisms of action. Institutions collaborating on the Malarial Genome Project have sequenced the majority of DNA in the 14 chromosomes. The nucleotide sequence available on the internet contains thousands of open reading frames (ORFs) which encode proteins essential for survival of the parasite. Many of these proteins are enzymes which are suitable targets for drug dev ....Malarial parasites have now developed resistance to most of the available drugs and there is an urgent need for drugs with new mechanisms of action. Institutions collaborating on the Malarial Genome Project have sequenced the majority of DNA in the 14 chromosomes. The nucleotide sequence available on the internet contains thousands of open reading frames (ORFs) which encode proteins essential for survival of the parasite. Many of these proteins are enzymes which are suitable targets for drug development. A knowledge of the molecular architecture of the active site of such enzymes provides a template for drug design. The malarial parasite, Plasmodium falciparum, can only synthesise pyrimidine nucleotides for DNA via the de novo pyrimidine pathway. We have cloned the genes encoding three of the enzymes of the de novo pathway using sequence information from the Malarial Genome Project. Dihydroorotase, orotate phosphoribosyltransferase, and OMP decarboxylase, catalyse reactions 3, 5 and 6 of the pathway. We have expressed these enzymes in the bacterium Escherichia coli enabling large-scale production of these drug targets. We propose to characterise the catalytic and inhibitory properties of these enzymes, and grow protein crystals for determination of atomic structures by x-ray diffraction. The structures will provide templates for rational design of new antimalarial drugs. In a second approach for develoment of new drugs, the 3 malarial enzymes will be screened against chemical libraries for inhibition of catalytic activity. The initial screen will utilise a high throughput Biacore 3000 instrument which detects strong interactions between a target enzyme and candidate inhibitors. A thorough knowledge of the catalytic mechanisms, the three-dimensional structures and novel first generation inhibitors of these 3 malarial target enzymes, will provide a strong basis for development of new antimalarial drugs.Read moreRead less
Understanding Novel Viral Host Interactions That Modulate Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$764,246.00
Summary
Lethal viruses such as coronaviruses (MERS, SARS-CoV-1, SARS-CoV-2), Dengue, Zika, Hendra, and Nipah have developed effective mechanisms of replication by dampening the host immune system. Here we will examine how viruses carry out these immune evasion functions, and test antiviral drugs that can prevent these effects in a highly specific manner. If this idea can be proved, it will provide great promise for the development of new antivirals whilst minimising the toxic effects to the cell.
Understanding The Role Of Lipid In Membrane Permeabilization By The Bcl-2 Family Executioner Proteins
Funder
National Health and Medical Research Council
Funding Amount
$626,524.00
Summary
Apoptosis is a form of programmed cell death that protects our bodies from dangerous cells, e.g cells infected with viruses or that might become cancerous. A network of protein families control this process and this work will understand how certain members regulate a crucial step in this cell death pathway. Our studies will reveal key insights into apoptosis at the molecular level and inform the development of therapeutics for diseases characterised by dysregulated cell death such as cancer.
Host-virus Protein Complexes In The Immune System Response To Influenza
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
This proposal will investigate the inhibition of the human immune response by viruses. Specifically, an enzyme, TRIM25, which ubiquitinates proteins important for signalling the viral immune response has recently been shown to be inhibited by the non-structural influenza protein NS1. The mechanism of this inhibition is unknown and is thus the subject of this project.
Engineering CYP17A1 Inhibitors For Castrate-resistant Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$519,428.00
Summary
As prostate cancer progresses it becomes resistant to first line treatments and the current second line treatments have untoward side effects. This proposal will provide proof of principal for new selective drugs to be developed. We propose an innovative strategy to develop new selective drugs for the treatment of prostate cancer. This new therapeutic approach will identify new compounds for patients specifically with castrate sensitive and resistant prostate cancer.
Peripheral Membrane Proteins In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$640,210.00
Summary
Peripheral membrane proteins are critical for processes such as cell transport, signaling, neurosecretion and development. As such, their dysfunction can lead to many debilitating diseases including cancer, inflammation and neurodegeneration. This project will establish fundamental new knowledge about how peripheral membrane proteins regulate cell function, how their perturbation or mutation results in human disease, and will inform efforts to target them for future therapeutic outcomes.
Structural Studies On The Conjugative Apparatus Of The Gram-positive Bacteria, Clostridium Perfringens.
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
Antibiotic resistance is a worldwide health problem. It has severely reduced the effectiveness of many antibiotics driving up the health care costs and death rates associated with bacterial infections. This project aims to investigate how antibiotic resistance determinants are transferred in the pathogenic bacteria, Clostridium perfringens. By understanding the mechanism of antibiotic resistance transfer in bacteria we will be better armed to combat antibiotic resistance.