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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.


News Article | May 25, 2017
Site: www.sciencedaily.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 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.


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 25, 2017
Site: www.eurekalert.org

Antibiotic combinations prove effective against two ESKAPE pathogens, a sextet of superbugs that cause the majority of US hospital infections BUFFALO, N.Y. - In the fight against super bacteria, University at Buffalo scientists are relying on strength in numbers to win the battle against drug resistance. A team of researchers found that combinations of three antibiotics - that are each ineffective against superbugs when used alone - are capable of eradicating two of the six ESKAPE pathogens when delivered together. ESKAPE pathogens are a group of antimicrobial-resistant bacteria that pose a grave threat, causing more than 2 million infections and nearly 23,000 deaths a year, according to the Centers for Disease Control and Prevention. The six super bacteria are also responsible for a substantial number of infections in hospitals. The new, triple combination treatments provide a new weapon in the evolutionary arms race between modern medicine and harmful bacteria. "These bacteria are extremely problematic and have become resistant to nearly all available antibiotics. We needed to think differently to attack this problem," says Brian Tsuji, PharmD, an author on two recent studies and associate professor in the Department of Pharmacy Practice in the UB School of Pharmacy and Pharmaceutical Sciences. One study, "Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity," was published in the May issue of the Journal of Antimicrobial Chemotherapy, while another study, "Polymyxin B-Based Triple Combinations Wage War Against KPC-2-producing Klebsiella pneumoniae: New Dosing Strategies for Old Allies," was published in the April issue of Antimicrobial Agents and Chemotherapy. Non-traditional combinations of medication are frequently used to fight against superbug infections, however, questions remain over proper dosage and which combinations are most effective. The UB researchers tested combinations of the antibiotics polymyxin B, meropenem and ampicillin-sulbactam against the pathogen Acinetobacter baumannii. The bacterium Klebsiella pneumoniae was treated with polymyxin B, meropenem, and rifampin. "Each antibiotic was chosen to complement the other drugs' mechanisms of bacterial killing," says Justin Lenhard, PharmD, first author on the investigation of Acinetobacter baumannii and former postdoctoral researcher in Tsuji's lab. Lenhard is now an assistant professor at California Northstate University College of Pharmacy. "By combining antimicrobials that exert their bacterial killing in different ways, it is possible to outmaneuver the ESKAPE pathogens and completely overwhelm the bacteria's defensive countermeasures," he said. The medications were applied to the bacterial samples individually, in pairs and in triple combinations. Both the time needed for the antibiotics to kill the bacteria and the time it took for the pathogens to repopulate were measured. For the tests on Acinetobacter baumannii, none of the antibiotics were able to kill the bacteria when used alone. Of the pairs of antibiotics, only the grouping of polymyxin B and meropenem was able to effectively kill the pathogen, but the bacteria gradually regrew over three days. The triple combination achieved a similar kill rate to the pair of polymyxin B and meropenem, but the addition of ampicillin-sulbactam prevented regrowth of the pathogen. Within 96 hours, no viable bacteria cells were detected after exposure to all three antibiotics. The tests against Klebsiella pneumoniae were led by Zackery Bulman, PharmD, a postdoctoral researcher in Tsuji's lab. Individual antibiotics were unable to sustain the killing of bacteria over a 24-hour period. The most effective double combination was polymyxin B and rifampin, which killed bacteria for up to 30 hours before the population regrew to initial levels. The triple combination of polymyxin B, meropenem, and rifampin produced the highest kill rates and tripled the time it took for bacteria to regrow to 72 hours. Rifampin, the researchers suspect, temporarily suppresses the antibiotic resistance of Klebsiella pneumoniae, allowing the trio to destroy the bacteria. Additional research is required to validate the treatments against other clinically relevant strains of bacteria, but the results of both studies are promising. "These new antibiotic combinations may help to guide therapy in infections where no treatments appear to exist," says Tsuji. The research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Investigators on the study, "Polymyxin B-Based Triple Combinations Wage War Against KPC-2-producing Klebsiella pneumoniae: New Dosing Strategies for Old Allies," include Bulman and Patricia N. Holden, UB School of Pharmacy and Pharmaceutical Sciences; Michael J. Satlin and Thomas J. Walsh, Weill Cornell Medical College in Cornell University; Liang Chen and Barry N. Kreiswirth, New Jersey Medical School in Rutgers University; Beom Soo Shin, Catholic University of Daegu; Alan Forrest, Eshelman School of Pharmacy in the University of North Carolina; and Roger L. Nation and Jian Li, Monash Institute of Pharmaceutical Sciences in Monash University. Additional researchers on the study, "Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity," include Forrest; Shin; Nation; Li; Visanu Thamlikitkul, Department of Medicine in Mahidol University; Fernanda P. Silveira, University of Pittsburgh Medical Center; Samira M. Garonzik, UB School of Pharmacy and Pharmaceutical Sciences; Xun Tao and Jürgen B. Bulitta, College of Pharmacy in the University of Florida; and Keith S. Kaye, University of Michigan Medical School.


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


Galea C.A.,Monash Institute of Pharmaceutical Sciences
Cellular and molecular life sciences : CMLS | Year: 2014

MMP23 is a member of the matrix metalloprotease family of zinc- and calcium-dependent endopeptidases, which are involved in a wide variety of cellular functions. Its catalytic domain displays a high degree of structural homology with those of other metalloproteases, but its atypical domain architecture suggests that it may possess unique functional properties. The N-terminal MMP23 pro-domain contains a type-II transmembrane domain that anchors the protein to the plasma membrane and lacks the cysteine-switch motif that is required to maintain other MMPs in a latent state during passage to the cell surface. Instead of the C-terminal hemopexin domain common to other MMPs, MMP23 contains a small toxin-like domain (TxD) and an immunoglobulin-like cell adhesion molecule (IgCAM) domain. The MMP23 pro-domain can trap Kv1.3 but not closely-related Kv1.2 channels in the endoplasmic reticulum, preventing their passage to the cell surface, while the TxD can bind to the channel pore and block the passage of potassium ions. The MMP23 C-terminal IgCAM domain displays some similarity to Ig-like C2-type domains found in IgCAMs of the immunoglobulin superfamily, which are known to mediate protein-protein and protein-lipid interactions. MMP23 and Kv1.3 are co-expressed in a variety of tissues and together are implicated in diseases including cancer and inflammatory disorders. Further studies are required to elucidate the mechanism of action of this unique member of the MMP family.


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.


Langmead C.J.,Monash Institute of Pharmaceutical Sciences | Christopoulos A.,Monash Institute of Pharmaceutical Sciences
Current Opinion in Cell Biology | Year: 2014

Traditionally, optimizing lead molecule interactions with the orthosteric site has been viewed as the best means for attaining selectivity at G protein-coupled receptors (GPCRs), but GPCRs possess spatially distinct allosteric sites that can also modulate receptor activity. Allosteric sites offer a greater potential for receptor subtype selectivity, the ability to fine-tune physiological responses, and the ability to engender signal pathway bias. The detection and quantification of allosteric drug candidates remain an ongoing challenge, but the development of novel analytical approaches for quantifying allostery is enriching structure-activity and structure-function studies of the phenomenon. Very recent breakthroughs in both structural and computational biology of GPCRs are also beginning to unravel the mechanistic basis of allosteric modulation at the molecular level. © 2013 Elsevier Ltd.


Velkov T.,Monash Institute of Pharmaceutical Sciences
PPAR Research | Year: 2013

Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPARα. This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPARαLBD. The role of L-FABP in the delivery of ligands directly to PPARα via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed. © 2013 Tony Velkov.


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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