The Structural Basis For Biased Agonism At The Glucagon-like Peptide-1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$872,536.00
Summary
The glucagon-like peptide-1 receptor plays an essential role in nutrient-regulated insulin release, and is a major target for therapeutic treatment of type 2 diabetes. The binding of different drugs to this receptor can promote distinct signalling profiles inside the cell that can lead to different physiological outcomes. Understanding the mechanistic basis for this will provide a framework to enable rational design of novel, better and safer therapeutics for the treatment of diabetes.
Understanding The Structural Basis For Family B G Protein-coupled Receptor Function
Funder
National Health and Medical Research Council
Funding Amount
$745,082.00
Summary
G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins that enable communication from external signals to the inside of cells of the body. Family B GPCRs are a therapeutically important subclass of these receptors and they play crucial roles in bone and energy homeostasis, cardiovascular control and immune response. This grant will uncover fundamental knowledge on how these receptors work, and will enhance future development of therapeutics.
Understanding Mechanisms Of Allostery And Biased Agonism At The Adenosine A1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$603,033.00
Summary
This project focuses on an important protein found in the heart. Drugs that activate this protein can protect the heart against damage that occurs after a heart attack, but they all have undesirable side effects. We have discovered a new class of molecule that can protect the heart without these side effects. We now seek to understand how these compounds work at the molecular level. This knowledge can facilitate the design of safer medicines for the treatment of cardiovascular disease.
Role Of Extracellular Surface Residues In Agonist Activation Of The Alpha1 Adrenoceptor
Funder
National Health and Medical Research Council
Funding Amount
$414,786.00
Summary
Most modern drugs act on a class of cellular proteins known as GPCRs. Despite their importance, little is known about how agonists acting from the outside of cells produce a change in GPCR structure allowing signalling to the cell's interior. We have identified new residues on the extracellular surface of the alpha1 adrenoceptor that dramatically affect agonist responses, opening the door to understanding the molecular process of GPCR activation and the development of drugs that can target diffe ....Most modern drugs act on a class of cellular proteins known as GPCRs. Despite their importance, little is known about how agonists acting from the outside of cells produce a change in GPCR structure allowing signalling to the cell's interior. We have identified new residues on the extracellular surface of the alpha1 adrenoceptor that dramatically affect agonist responses, opening the door to understanding the molecular process of GPCR activation and the development of drugs that can target different GPCR conformations.Read moreRead less
Formyl Peptide Receptor Biased Agonists As Novel Cardioprotection From Myocardial Infarction
Funder
National Health and Medical Research Council
Funding Amount
$948,291.00
Summary
Heart attack is caused by a blocked heart blood vessel. Current therapy focuses on rapid reopening of the vessel, to allow blood supply to return. However, even if this is successful, affected patients are often left with impaired heart muscle pumping function, ultimately progressing to heart failure. We have discovered an exciting new mechanism to protect heart muscle from injury and preserve its function, and we plan to develop new drugs for heart attack based on this mechanism.
Pharmacological Investigation Of The Glucagon-Like Peptide-1 Receptor (GLP-1R)
Funder
National Health and Medical Research Council
Funding Amount
$367,948.00
Summary
Family B G protein-coupled receptors represent key therapeutic targets for many conditions, including metabolic, bone, growth and neuronal disorders. However, poor mechanistic understanding of this receptor family impacts on their clinical value. Consequently, this research is aimed at gaining a more comprehensive understanding of the structure and function of the family B glucagon-like peptide-1 receptor through use of new and novel pharmacological techniques.
Therapeutic Approaches To Circumvent NO• Resistance In The Type 2 Diabetic Heart And Vasculature
Funder
National Health and Medical Research Council
Funding Amount
$563,337.00
Summary
Type 2 diabetes (T2D) is Australia’s fastest growing chronic disease, affecting almost 2 million Australians (who face poor cardiovascular health outcomes). We have discovered an exciting new avenue that may potentially more effectively counteract heart and blood vessel disorders in T2D patients in an acute cardiovascular emergency, of substantial clinical importance.
Understanding The Function And Regulation Of G Protein-coupled Receptor Signalosomes And Their Role As High Resolution Signalling Platforms
Funder
National Health and Medical Research Council
Funding Amount
$566,588.00
Summary
G protein-coupled receptors are specialised proteins located on the surface of cells. They are the targets of 50% of currently available pharmaceuticals, but these drugs are derived from limited knowledge of only a fraction of proteins. This proposal will examine exciting and novel properties of receptors that only occur following the assembly of the proteins into specialised networks within cells. The new information will expand our current knowledge, and facilitate future targeted drug design.
Many drugs modulate the function of proteins imbedded in cell membranes. Extensive research has been undertaken to better understand drug interactions with these proteins to improve drug therapies, but there has been relatively little progress in understanding the role of the cell membrane. This project will investigate how the cell membrane influences protein function and then use this information to develop novel drugs for the treatment of neurological disorders.
The Putative Drug Metabolising Enzyme SULT4A1 Is A Sulfotransferase Inhibitor
Funder
National Health and Medical Research Council
Funding Amount
$467,851.00
Summary
The sulfotransferase SULT4A1 is a novel protein found predominantly in neurons but its function is unknown. This project will investigate the mechanisms that the body uses to regulate the levels of this protein and how it may interfere with other enzymes essential for metabolising hormones and neurotransmitters.