Towards The Rational Design Of Calcium Sensing Receptor Allosteric Modulators For The Treatment Of Osteoporosis And Calcium Handling Disorders
Funder
National Health and Medical Research Council
Funding Amount
$741,390.00
Summary
Drugs that target the human calcium sensing receptor can be too strong or too weak, resulting in side effects or lack of efficacy. This proposal thus seeks to establish whether the strength of drug activity can be rationally altered and exploited to treat different disease states by fine-tuning CaSR activity in a disease-specific manner.
Biased Allosteric Modulators Of Metabotropic Glutamate Receptors: Novel Therapeutic Targets For CNS Disorders
Funder
National Health and Medical Research Council
Funding Amount
$611,534.00
Summary
Metabotropic glutamate receptor 5 (mGlu5) is a major therapeutic target for depression and schizophrenia. The proposed studies will improve our understanding of how drug-like chemicals interact with mGlu5 and therefore change the activity of these receptors and in turn the activity of brain cells leading to therapeutic effectiveness. The research undertaken in this program will allow us to be smarter in developing new mGlu5 drugs that are both effective and have minimal side effects.
Understanding Allosteric Modulation And Biased Signalling At Family B GPCRs
Funder
National Health and Medical Research Council
Funding Amount
$428,065.00
Summary
Family B GPCRs are therapeutic targets for drugs treating osteoporosis, hypercalcaemia, Paget’s disease, type II diabetes and are being actively pursued for other diseases that represent major global health burdens. Despite huge financial input, there are no orally available drugs that act on these receptors. This speaks to a lack of mechanistic understanding of how they work. My research focuses on addressing this question and how to exploit these receptors to design and identify better drugs.
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
?4-containing GABA-A Receptors As Targets For ?-hydroxybutyric Acid (GHB)
Funder
National Health and Medical Research Council
Funding Amount
$610,572.00
Summary
?-Hydroxybutyric acid (GHB) is an elusive substance. On one hand, it is a prescribed drug to treat narcolepsy, and ameliorate alcohol withdrawal. On the other hand, GHB is the club drug “Fantasy” or “Liquid Ecstasy”, taken by many Australians for its social, sexual and euphoric effects. This proposal will identify GHB targets and provide insight to its mechanism of action.
Extrasynaptic GABA-A Receptors As Novel Targets For -Hydroxybutyric Acid (GHB)
Funder
National Health and Medical Research Council
Funding Amount
$525,946.00
Summary
GHB (known as Fantasy) is a curious substance. It is a drug of abuse, a therapy and occurs naturally in the brain. GHB targets brain proteins including the enigmatic _GHB receptor� which participates in the therapeutic benefits of GHB. Our research will determine whether the delta-containing GABA-A receptors are the elusive "GHB receptor". Uncovering the identity of the the elusive _GHB receptor� would be a major breakthrough in terms of our understanding of the therapeutic and recreational use ....GHB (known as Fantasy) is a curious substance. It is a drug of abuse, a therapy and occurs naturally in the brain. GHB targets brain proteins including the enigmatic _GHB receptor� which participates in the therapeutic benefits of GHB. Our research will determine whether the delta-containing GABA-A receptors are the elusive "GHB receptor". Uncovering the identity of the the elusive _GHB receptor� would be a major breakthrough in terms of our understanding of the therapeutic and recreational use of GHB and its action as a brain chemical.Read moreRead less
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.