Langmead Laboratory

Servier Drug Discovery Program

Molecular and Translational Drug Discovery

Chris Langmead

Dr Chris Langmead
Head, Servier Program in Drug Discovery
Lab Head
Email: chris.langmead@monash.edu
Project areas | Key publications | Collaborations | Lab members | Funding

Project areas

Research focus

G protein-coupled receptors (GPCRs) are the largest family of receptors and are responsible for regulating a range of physiological functions and pathology. As such, it is unsurprising that approximately 40% of marketed drugs target this receptor family. We utilize a variety of platforms, techniques and collaborations in order to progress our GPCR discovery projects towards clinical development.  Research in this laboratory covers a range of disciplines including molecular biology, molecular pharmacology, cellular & native tissue pharmacology and translational biology.

Servier Discovery Program: Our portfolio includes multiple GPCR projects at differing stages of the drug discovery process, ranging from target validation though to lead optimisation. Our primary therapeutic areas of interest are schizophrenia, Parkinson’s disease and metabolic disorders.

Additional Projects: The lab has a strong research interest in disorders associated with the basal ganglia in the CNS, including projects studying the role of the orphan GPCRs and muscarinic acetylcholine receptors in schizophrenia, cognitive disorders and addiction.

Molecular pharmacology

To probe molecular mechanisms of action, we utilise a range of biochemical, pharmacological and cell-signalling assays including radioligand binding, TR-FRET, calcium mobilization, cAMP accumulation, GTPγ35S binding, ERK1/2 phosphorylation and label-free technology. Additionally we develop and run cellular assays in 384-well format to enable high-throughput and primary SAR screening.

Positive (left) and negative (right) allosteric modulation of acetylcholine (ACh)-stimulated inositol phosphate accumulation in CHO cells expressing the muscarinic M5 receptor after treatment with the receptor alkylating agent, phenoxybenzamine (PBZ). Adapted from Berizzi et  al.  (2016)  Mol  Pharmacol.  (in  press).

Figure legend: Positive (top) and negative (bottom) allosteric modulation of acetylcholine (ACh)-stimulated inositol phosphate accumulation in CHO cells expressing the muscarinic M5 receptor after treatment with the receptor alkylating agent, phenoxybenzamine (PBZ). Adapted from Berizzi et  al., (2016) Mol Pharmacol. 90(4):427-36.

Cellular and native pharmacology

To better reflect the in vivo situation, we study GPCR pharmacology (using many of the assays above) in native tissue and cellular systems, including isolated brain tissue, primary cultured neurons, isolated primary blood cells and immortalized cell lines endogenously expressing GPCR targets.

Variation in chemotactic response in peripheral blood mononuclear cells (PBMCs) and monocyte-like cell lines (THP-1 and U937) with a range of chemoattractants.

Figure legend: Variation in chemotactic response in peripheral blood mononuclear cells (PBMCs) and a monocyte-like cell lines (THP-1 and U937) with a range of GPCR-targeting chemoattractants. Adapted from Riddy et al., (2018) PLOS One (https://doi.org/10.1371/journal.pone.0197177)

Figure legend: Expression profiling of the orphan receptor, Gpr52 (white), in the dorsal striatum of mouse brain using RNAscope fluorescent in situ hybridization. Gpr52 is primarily co-expressed with the dopamine D2 receptor (Drd2; red), but not the dopamine D1 receptor (Drd1; green), in medium spiny neurons

Figure legend: Expression profiling of the orphan receptor, Gpr52 (white), in the dorsal striatum of mouse brain using RNAscope fluorescent in situ hybridization. Gpr52 is primarily co-expressed with the dopamine D2 receptor (Drd2; red), but not the dopamine D1 receptor (Drd1; green), in medium spiny neurons (Sherie Ma).

Translational biology

To provide translation from recombinant and cellular studies to in vivo models and better understand drug mechanism of action, we utilise a range of translational approaches, including electrophysiology, in vivo neurobiology, obesity and metabolism models and PK-PD studies, often in collaboration with the Centre for Drug Candidate Optimisation at MIPS.

Figure legend: Atherosclerotic plaque from the aorta of a wild-type mouse fed a 60% high fat diet for 20 weeks.Figure legend: Atherosclerotic plaque from the aorta of a wild-type mouse fed a 60% high fat diet for 20 weeks, as imaged using Coherent Anti-Stokes Raman Scattering (CARS) microscopy (white = macrophages / lipids; green = collagen; Sanja Bosnyak-Gladovic & Cameron Nowell).

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Collaborations

Servier

  • Dr Catherine Rochat, R&D Alliance Management
  • Dr Jean-Philippe Stephan, Dr Celine Legros & Dr Loubna Chadli, CPCB
  • Dr Elizabeth Harley & Dr Philippe Delerive, Metabolism Centre for Therapeutic Innovation
  • Dr Stefano Chimenti & Dr Michel Feletou, Cardiovascular Centre for Therapeutic Innovation
  • Dr Mark Millan, Dr Ross Jeggo & Dr Clotilde Mannoury la Cour, CNS Centre for Therapeutic Innovation
  • Dr Philippe Pastoureau & Dr Massimo Sabatini, Immuno-inflammation Centre for Therapeutic Innovation
  • Dr Anne-Marie Chollet, Dr Arnaud Le Tiran & Dr Philippe Gloanec, Medicinal Chemistry

Monash Institute of Pharmaceutical Sciences

Other collaborations

  • Professor David Spanswick, Biomedicine Discovery Institute, Monash University
  • Professor Michael Cowley and Dr Stephanie Simmonds, Biomedicine Discovery Institute, Monash University
  • Professor Andrew Lawrence, Florey Institute of Neuroscience and Mental Health
  • Dr Jess Nithianantharajah, Florey Institute of Neuroscience and Mental Health
  • Associate Professor Andrew Murphy & Dr Hélène Kammoun, Baker IDI
  • Associate Professor Alex Fornito, Monash Biomedical Imaging, Monash University
  • Professor Andrew Tobin & Dr Sophie Bradley, University of Glasgow, UK
  • Professor Craig Lindsley, Vanderbilt Centre for Neuroscience Drug Discovery, USA

Recent publications

Research papers

Riddy DM, Goy E, Delerive P, Summers RJ, Sexton PM, Langmead CJ.  Comparative genotypic and phenotypic analysis of human peripheral blood monocytes and surrogate monocyte-like cell lines commonly used in metabolic disease research (2018) PLoS ONE e0197177;  doi: 10.1371/journal.pone.0197177.

Diepenhorst NA, Leach K, Keller AN, Rueda P, Cook AE, Pierce TL, Nowell CJ, Pastoureau P, Sabatini M, Summers RJ, Charman WN, Sexton PM, Christopoulos A, Langmead CJ.  Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity. (2018) Br J Pharmacol; doi: 10.1111/bph.14344.

Berizzi AE, Perry CJ, Shackleford DM, Lindsley CW, Jones CK, Chen NA, Sexton PM, Christopoulos A, Langmead CJ, Lawrence AJ.  Muscarinic M5 receptors modulate ethanol seeking in rats. (2018) Neuropsychopharmacol; doi: 10.1038/s41386-017-0007-3.

Bradley SJ, Molloy C, Bundgaard C, Mogg AJ, Thompson KJ, Dwomoh L, Sanger HE, Crabtree MD, Brooke SM, Sexton PM, Felder CC, Christopoulos A, Broad LM, Tobin AB, Langmead CJ. Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes. (2018) Mol Pharmacol; doi: 10.1124/mol.118.111872.

Berizzi AE, Bender AM, Lindsley CW, Conn PJ, Sexton PM, Langmead CJ, Christopoulos A.  Structure-activity relationships of pan-Gaq/11 coupled muscarinic acetylcholine receptor positive allosteric modulators. (2018) ACS Chem Neurosci; doi: 10.1021/acschemneuro.8b00136.

Bender AM, Cho  HP, Nance KD, Lingenfelter KS, Luscombe VB, Gentry PR, Voigtritter K, Berizzi AE, Sexton PM, Langmead CJ, Christopoulos A, Locuson CW, Bridges TM, Chang S, O'Neill JC, Zhan X, Niswender CM, Jones CK, Conn PJ, Lindsley CW. (2018) Discovery and optimization of potent and CNS penetrant M5-preferring positive allosteric modulators derived from a novel, chiral N-(indanyl)piperidine amide scaffold. (2018) ACS Chem Neurosci; doi: 10.1021/acschemneuro.8b00126.

Diepenhorst NA, Nowell CJ, Rueda P, Henriksen K, Pierce T, Cook AE, Pastoureau P, Sabatini M, Charman WN, Christopoulos A, Summers RJ, Sexton PM, Langmead CJ.  High throughput quantitative analysis of human osteoclast differentiation and activity (2017) Anal Biochem 519:51-56.

Riddy DM, Cook AE, Diepenhorst NA, Bosnyak S, Brady R, Mannoury la Cour C, Mocaer E, Summers RJ, Charman WN, Sexton PM, Christopoulos A, Langmead CJ.  Isoform-specific biased agonism of histamine H3 receptor agonists.  (2017) Mol Pharmacol 91(2):87-99.

Choy KH, Shackleford DM, Malone DT, Mistry SN, Patil RT, Scammells PJ, Langmead CJ, Pantelis C, Sexton PM, Lane JR, Christopoulos A.  Positive allosteric modulation of the muscarinic M1 receptor improves efficacy of antipsychotics in mouse glutamatergic deficit models of behavior. (2016) J Pharmacol Exp Ther 359(2):354-365.

Berizzi AE, Gentry PR, Rueda P, den Hoedt S, Sexton PM, Langmead CJ, Christopoulos A. Molecular mechanisms of action of M5 muscarinic acetylcholine receptor allosteric modulators. (2016) Mol Pharmacol 90(4):427-36.

Rueda P, Harley E, Lu Y, Stewart GD, Fabb S, Diepenhorst NA, Cremers B, Rouillon M-H, Wehrle I, Geant A, Lamarche G, Leach K, Charman WN, Christopoulos A, Summers RJ, Sexton PM, Langmead CJ (2016) Murine GPRC6A mediates cellular responses to L-amino acids, but not osteocalcin variants. PLoS ONE; e0146846.

Riddy DM, Valant C, Rueda P, Charman WN, Sexton PM, Summer RJ, Christopoulos A, Langmead CJ. Label-free kinetics: exploiting functional hemi-equilibrium to derive rate constants for muscarinic receptor antagonists. (2015) Mol Pharmacol. 88:779-90.

Reviews

Riddy DM, Delerive P, Summers RJ, Sexton PM, Langmead CJ. G protein-coupled receptors targeting insulin resistance, obesity and type 2 diabetes mellitus. (2018) Pharmacol Rev 70(1): 39-67 (doi: 10.1124/pr.117.014373).

Diepenhorst NA, Rueda P, Cook AE, Pastoureau P, Sabatini M, Langmead CJ. G protein-coupled receptors as anabolic drug targets in osteoporosis. (2018) Pharmacol Ther 184:1-12 (doi: 10.1016/j.pharmthera.2017.10.015).

Christopoulos A, Changeux J-P, Catterall WA, Fabbro D, Burris TP,  Cidlowski JA, Olsen RW, Peters JA, Neubig RR, Pin J-P, Sexton PM, Kenakin TP, Ehlert FJ, Spedding M, Langmead CJ. (2014) International Union of Basic and Clinical Pharmacology. XC. Multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol Rev 66:918-47.

Langmead CJ, Christopoulos, A.  Functional and structural perspectives on allosteric modulation of GPCRs. (2014) Curr Opin Cell Biol 27, 94-101.

Langmead CJ, Christopoulos A. (2013) Supra-physiological efficacy at GPCRs: superstition or super agonists? Br J Pharmacol 169:353-356.

Langmead CJ, Watson J, Reavill C (2008) Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther 117(2):232-43.

Langmead CJ, Christopoloulos A. (2006) Allosteric agonists of 7TM receptors: Expanding the pharmacological toolbox. Trends Pharmacol Sci 27(9): 475-81.

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Lab members

Dr Patricia Rueda
Research Fellow & Project Leader

Darren Riddy
Research Fellow & Project Leader

Dr Greg Stewart
Research Fellow & Project Leader

Dr Sherie Ma
Research Fellow

Dr Sheng Ang
Research Fellow

Alice Berizzi
Research Fellow

Dr Sanja Bosnyak-Gladovic
Research Fellow

Dr Rocio De La Fuente
Research Fellow

Dr Natalie Diepenhorst
Research Fellow

Dr Stewart Fabb
Research Fellow

Dr Monica Langiu
Research Fellow

Dr Cherry Mao
Research Fellow

Dr Jon Merlin
Research Fellow

Dr Tracie Pierce
Research Fellow

Dr Mohsin Sarwar
Research Fellow

Yao (Jackie) Lu
Research Assistant

Jen-Yin Goh
PhD Student

Jimmy Tao
Honours Student

Michela Vermeulen
Honours Student

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Funding

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