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. Given the broad range of processes in which these receptors are implicated, it is unsurprising that approximately 30% 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 hit-to-lead chemistry. Our primary therapeutic areas of interest are schizophrenia 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 in schizophrenia and cognitive disorders and the muscarinic M5 receptor in 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, CREB and GSK3ß phosphorylation and label-free technology (xCELLigence). Additionally we develop and run cellular assays in 384-well format to enable high-throughput and primary SAR screening as well as evaluation of biased agonism.

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) with a range of chemoattractants.
Figure legend: Phenotypic evaluation of primary human osteoclasts derived from blood monocytes as defined by number of nuclei (DAPI; blue; A-C), calcitonin receptor expression (yellow; A), TRAP expression (ELF-97; green; B), actin ring (Phalloidin-AlexaFluor647; red; C) and bone resorption  (clear  unstained  regions;  D).Figure legend: Phenotypic evaluation of primary human osteoclasts derived from blood monocytes as defined by number of nuclei (DAPI; blue; A-C), calcitonin receptor expression (yellow; A), TRAP expression (ELF-97; green; B), actin ring (Phalloidin-AlexaFluor647; red; C) and bone resorption  (clear  unstained  regions;  D).

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, cognition and metabolism models and PK-PD-receptor occupancy studies, often in collaboration with the Centre for Drug Candidate Optimisation at MIPS.

Figure legend: Inhibition of cortically evoked excitatory post-synaptic currents (EPSCs) in mouse striatal medium spiny neurons (top).Figure legend: Recording of cortically evoked excitatory post-synaptic currents (EPSCs) in mouse striatal medium spiny neurons (A and B). The inhibition of evoked EPSCs by a test drug is shown in (C).

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Collaborations

Servier

  • Dr Catherine Rochat, Alliance Management
  • Dr Jean-Philippe Stephan and Dr Celine Legros , Biotechnology
  • Dr Elizabeth Harley & Dr Philippe Delerive, Metabolism Innovation Pole
  • Dr Mark Millan, Dr Elisabeth Mocaer and Dr Clotilde Mannoury la Cour, CNS Innovation Pole
  • Dr Philippe Pastoureau & Dr Massimo Sabatini, Immuno-inflammation Innovation Pole
  • Dr Anne-Marie Chollet, Dr Arnaud Le Tiran and 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

Key publications

Research papers

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. Anal Biochem. 2017, 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.  Mol Pharmacol. 2017, 91(2):87-99. Erratum in: Mol Pharmacol. 2017, 91(3):263.

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.  J Pharmacol Exp Ther. 2016, 359(2):354-365.

Berizzi A, Gentry PR, Rueda P, den Hoedt S, Sexton PM, Langmead CJ, Christopoulos A. Molecular mechanisms of action of M5 muscarinic acetylcholine receptor allosteric modulators. Mol Pharmacol. 2016, 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. Murine GPRC6A mediates cellular responses to L-amino acids, but not osteocalcin variants. PLoS ONE. 2016. 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. Mol Pharmacol. 2015, 88:779-90

Reviews

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. International Union of Basic and Clinical Pharmacology. XC. Multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol Rev. 2014; 66:918-47

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

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

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

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

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Lab members

Dr Patricia Rueda
Research Fellow and Project Lead

Darren Riddy
Research Fellow and Project Lead

Dr Greg Stewart
Research Fellow and Project Lead

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

Alice Berizzi
PhD Student (with Professor Christopulos)

Jen-Yin Goh
PhD Student

Matt Basile
Honours Student

Cassie Hatzipantelis
Honours Student

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Funding

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