Monash Institute of Pharmaceutical Sciences

Parkville, Australia

Monash Institute of Pharmaceutical Sciences

Parkville, Australia
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News Article | April 26, 2017
Site: phys.org

Treatments for such chronic diseases all target Class B G protein-coupled-receptors, however, there are large gaps in our knowledge of how these receptors function. In part, this stems from their size. They are so small that only in the past few years has technology advanced to a stage where researchers are beginning to be able to "solve the structure" – to attain an understanding of what these receptors look like. This is important because knowing how the receptors are structured helps us understand how they work. This knowledge in turn can enable the design of drugs that target the receptor more accurately and have fewer side effects. The structure solved by Monash Institute of Pharmaceutical Sciences (MIPS) researchers and their collaborators is that of the calcitonin receptor, a receptor targeted by treatments for hypercalcemia and Paget's disease (a bone disorder). The breakthrough is significant not just because of the additional knowledge it reveals, but also because of the method used to uncover it. This is the first time that a cryo-electron microscope has been used to reveal the structure of a G protein-coupled-receptor, and the first time that the full-length structure of a receptor in this class has been solved. "The fact that we have been able to use cryo-electron microscopy to arrive at these important findings is a vindication of investment to date in this area, and makes a strong case for further investment in the future," MIPS Doctor Denise Wootten said. "The information revealed by this study should ultimately enable the design of better drugs to treat not only diseases regulated by the calcitonin receptor but also those involving related receptors including diabetes, obesity, osteoporosis and migraine" Head of Drug Discovery Biology at MIPS, Professor Patrick Sexton said. The research has been published in the journal Nature. Explore further: New discovery in quest for better drugs More information: Yi-Lynn Liang et al. Phase-plate cryo-EM structure of a class B GPCR–G-protein complex, Nature (2017). DOI: 10.1038/nature22327


News Article | May 24, 2017
Site: www.medicalnewstoday.com

Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with the Monash Institute of Pharmaceutical Sciences (MIPS), have shed light on a key aspect of the process. Their findings may help guide the development of new treatments of inflammatory diseases such as atherosclerosis, which can lead to heart attack or stroke, and type 2 diabetes. Published in the journal Science Signaling, the research reveals how certain proteins cause the white blood cells that play a central role in inflammatory responses to behave in different ways. White blood cells are beneficial in helping to eliminate invading microorganisms or repair damaged tissue, but they can prolong the response and damage healthy tissues, leading to disease. The proteins, called chemokines, are secreted into blood vessels and activate chemokine receptors embedded in the outer membranes of the white blood cells. While it was previously thought that this occurred like an on-off switch, the scientists found that the chemokine receptor can behave more like a 'dimmer switch' with one chemokine giving a strong signal and another giving a weaker signal. They found that different responses can be caused by different chemokines activating the same receptor. This explained for the first time the mechanism by which white blood cells produced varying responses: a strong short-lived response (acute inflammation) or a steady, longer-lived response (chronic inflammation). "Until now, we did not understand how this was possible," said co-lead author Associate Professor Martin Stone. "Our work has identified the specific features of chemokines and receptors that are involved in their inflammatory activity," Associate Professor Stone said. "The ultimate goal is to develop anti-inflammatory drugs that target these molecules," he said. The findings, which Associate Professor Stone presented at an international conference on cell signalling last week, will have wide implications as the proteins involved are essential to all inflammatory diseases. Associate Professor Stone, who heads a laboratory in the Infection and Immunity Program at the Monash BDI collaborated closely with co-lead author Dr Meritxell Canals from MIPS. First author was PhD student Mrs Zil E. Huma. This research was supported by the Australian National Health and Medical Research Council, the Australian Research Council, Monash University and ANZ Trustees. Article: Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2, Martin J. Stone et al., Science Signaling, doi: 10.1126/scisignal.aai8529, published 23 May 2017.


News Article | May 23, 2017
Site: www.eurekalert.org

Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with the Monash Institute of Pharmaceutical Sciences (MIPS), have shed light on a key aspect of the process. Their findings may help guide the development of new treatments of inflammatory diseases such as atherosclerosis, which can lead to heart attack or stroke, and type 2 diabetes. Published today in the journal Science Signaling, the research reveals how certain proteins cause the white blood cells that play a central role in inflammatory responses to behave in different ways. White blood cells are beneficial in helping to eliminate invading microorganisms or repair damaged tissue, but they can prolong the response and damage healthy tissues, leading to disease. The proteins, called chemokines, are secreted into blood vessels and activate chemokine receptors embedded in the outer membranes of the white blood cells. While it was previously thought that this occurred like an on-off switch, the scientists found that the chemokine receptor can behave more like a 'dimmer switch' with one chemokine giving a strong signal and another giving a weaker signal. They found that different responses can be caused by different chemokines activating the same receptor. This explained for the first time the mechanism by which white blood cells produced varying responses: a strong short-lived response (acute inflammation) or a steady, longer-lived response (chronic inflammation). "Until now, we did not understand how this was possible," said co-lead author Associate Professor Martin Stone. "Our work has identified the specific features of chemokines and receptors that are involved in their inflammatory activity," Associate Professor Stone said. "The ultimate goal is to develop anti-inflammatory drugs that target these molecules," he said. The findings, which Associate Professor Stone presented at an international conference on cell signalling last week, will have wide implications as the proteins involved are essential to all inflammatory diseases. Associate Professor Stone, who heads a laboratory in the Infection and Immunity Program at the Monash BDI collaborated closely with co-lead author Dr Meritxell Canals from MIPS. First author was PhD student Mrs Zil E. Huma. This research was supported by the Australian National Health and Medical Research Council, the Australian Research Council, Monash University and ANZ Trustees. Read the full paper titled Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2 Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.


Kenakin T.,University of North Carolina at Chapel Hill | Christopoulos A.,Monash Institute of Pharmaceutical Sciences
Nature Reviews Drug Discovery | Year: 2013

Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure-activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide. Copyright © 2013 Macmillan Publishers Limited.


Zhou Q.T.,Monash Institute of Pharmaceutical Sciences | Morton D.A.V.,Monash Institute of Pharmaceutical Sciences
Advanced Drug Delivery Reviews | Year: 2012

For dry powder inhaler formulations, micronized drug powders are commonly mixed with coarse lactose carriers to facilitate powder handling during the manufacturing and powder aerosol delivery during patient use. The performance of such dry powder inhaler formulations strongly depends on the balance of cohesive and adhesive forces experienced by the drug particles under stresses induced in the flow environment during aerosolization. Surface modification with appropriate additives has been proposed as a practical and efficient way to alter the inter-particulate forces, thus potentially controlling the formulation performance, and this strategy has been employed in a number of different ways with varying degrees of success. This paper reviews the main strategies and methodologies published on surface coating of lactose carriers, and considers their effectiveness and impact on the performance of dry powder inhaler formulations. © 2011 Elsevier B.V.


Wootten D.,Monash Institute of Pharmaceutical Sciences | Christopoulos A.,Monash Institute of Pharmaceutical Sciences | Sexton P.M.,Monash Institute of Pharmaceutical Sciences
Nature Reviews Drug Discovery | Year: 2013

Allosteric ligands bind to G protein-coupled receptors (GPCRs; also known as seven-transmembrane receptors) at sites that are distinct from the sites to which endogenous ligands bind. The existence of allosteric ligands has enriched the ways in which the functions of GPCRs can be manipulated for potential therapeutic benefit, yet the complexity of their actions provides both challenges and opportunities for drug screening and development. Converging avenues of research in areas such as biased signalling by allosteric ligands and the mechanisms by which allosteric ligands modulate the effects of diverse endogenous ligands have provided new insights into how interactions between allosteric ligands and GPCRs could be exploited for drug discovery. These new findings have the potential to alter how screening for allosteric drugs is performed and may increase the chances of success in the development of allosteric modulators as clinical lead compounds. © 2013 Macmillan Publishers Limited. All rights reserved.


Trevaskis N.L.,Monash Institute of Pharmaceutical Sciences | Kaminskas L.M.,Monash Institute of Pharmaceutical Sciences | Porter C.J.H.,Monash Institute of Pharmaceutical Sciences
Nature Reviews Drug Discovery | Year: 2015

The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune control. In cancer, the lymph nodes that drain solid tumours are a primary site of metastasis, and recent studies have suggested intrinsic links between lymphatic function, lipid deposition, obesity and atherosclerosis. Advances in the current understanding of the role of the lymphatics in pathological change and immunity have driven the recognition that lymph-targeted delivery has the potential to transform disease treatment and vaccination. In addition, the design of lymphatic delivery systems has progressed from simple systems that rely on passive lymphatic access to sophisticated structures that use nanotechnology to mimic endogenous macromolecules and lipid conjugates that 'hitchhike' onto lipid transport processes. Here, we briefly summarize the lymphatic system in health and disease and the varying mechanisms of lymphatic entry and transport, as well as discussing examples of lymphatic delivery that have enhanced therapeutic utility. We also outline future challenges to effective lymph-directed therapy. © 2015 Macmillan Publishers Limited.


Gibbs M.E.,Monash Institute of Pharmaceutical Sciences
Frontiers in Integrative Neuroscience | Year: 2016

This paper reviews the role played by glycogen breakdown (glycogenolysis) and glycogen re-synthesis in memory processing in two different chick brain regions, (1) the hippocampus and (2) the avian equivalent of the mammalian cortex, the intermediate medial mesopallium (IMM). Memory processing is regulated by the neuromodulators noradrenaline and serotonin soon after training glycogen breakdown and re-synthesis. In day-old domestic chicks, memory formation is dependent on the breakdown of glycogen (glycogenolysis) at three specific times during the first 60 min after learning (around 2.5, 30, and 55 min). The chicks learn to discriminate in a single trial between beads of two colors and tastes. Inhibition of glycogen breakdown by the inhibitor of glycogen phosphorylase 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) given at specific times prior to the formation of long-term memory prevents memory forming. Noradrenergic stimulation of cultured chicken astrocytes by a selective β2-adrenergic (AR) agonist reduces glycogen levels and we believe that in vivo this triggers memory consolidation at the second stage of glycogenolysis. Serotonin acting at 5-HT2Breceptors acts on the first stage, but not on the second. We have shown that noradrenaline, acting via post-synaptic α2-ARs, is also responsible for the synthesis of glycogen and our experiments suggest that there is a readily accessible labile pool of glycogen in astrocytes which is depleted within 10 min if glycogen synthesis is inhibited. Endogenous ATP promotion of memory consolidation at 2.5 and 30 min is also dependent on glycogen breakdown. ATP acts at P2Y1receptors and the action of thrombin suggests that it causes the release of internal calcium ([Ca2+]i) in astrocytes. Glutamate and GABA, the primary neurotransmitters in the brain, cannot be synthesized in neurons de novo and neurons rely on astrocytic glutamate synthesis, requiring glycogenolysis. © 2016 Gibbs.


Christopoulos A.,Monash Institute of Pharmaceutical Sciences
Molecular Pharmacology | Year: 2014

It is now widely accepted that G protein-coupled receptors (GPCRs) are highly dynamic proteins that adopt multiple active states linked to distinct functional outcomes. Furthermore, these states can be differentially stabilized not only by orthosteric ligands but also by allosteric ligands acting at spatially distinct binding sites. The key pharmacologic characteristics of GPCR allostery include improved selectivity due to either greater sequence divergence between receptor subtypes and/or subtype-selective cooperativity, a ceiling level to the effect, probe dependence (whereby the magnitude and direction of the allosteric effect change with the nature of the interacting ligands), and the potential for biased signaling. Recent chemical biology developments are beginning to demonstrate how the incorporation of analytical pharmacology and operational modeling into the experimental workflow can enrich structure-activity studies of allostery and bias, and have also led to the discovery of a new class of hybrid orthosteric/ allosteric (bitopic) molecules. The potential for endogenous allosteric modulators to play a role in physiology and disease remains to be fully appreciated but will likely represent an important area for future studies. Finally, breakthroughs in structural and computational biology are beginning to unravel the mechanistic basis of GPCR allosteric modulation at the molecular level. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.


Bunnett N.W.,Monash Institute of Pharmaceutical Sciences
Journal of Physiology | Year: 2014

In addition to their role in the digestion and absorption of dietary fats, bile acids (BAs) are tightly regulated signalling molecules. Their levels in the intestinal lumen, circulation and tissues fluctuate after feeding and fasting, and as a result of certain diseases and therapies. BAs regulate many cell types in the gut wall and beyond by activating nuclear and plasma membrane receptors. Of these, the G protein-coupled receptor TGR5 has emerged as a key mediator of the non-genomic actions of BAs. TGR5 is a cell-surface receptor that couples to Gαs, formation of cAMP, activation of protein kinase A and extracellular signal-regulated kinases, and inhibition of inflammatory signalling pathways. TGR5 has been implicated in mediating the actions of BAs on secretion of glucagon-like peptide 1 and glucose homeostasis, gastrointestinal motility and transit, electrolyte and fluid transport in the colon, bile formation and secretion, sensory transduction and inflammation. TGR5 agonists have been developed as treatments for metabolic, inflammatory and digestive disorders, and emerging evidence suggests that TGR5 mutations are associated with inflammatory diseases. Thus, TGR5 plays an important role in the normal processes of digestion and is a new therapeutic target for important digestive diseases. © 2014 The Physiological Society.

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