Affiliated Programme based at the University of Glasgow

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Programme Leader:

IMAG0758

 

Research Overview

 

The overall focus of our research is to work closely with the pharmaceutical industry and academic collaborators to apply novel pharmacological and chemical probes, biochemical and cell biology techniques together with genetic and chemical genetic animal models to define the mechanisms of drug efficacy and adverse/toxic responses.

 

The primary question addressed by my group is that by understanding basic biological processes within the context of human disease, and the action of drugs on these processes can a rational design strategy be employed that increases drug efficacy whilst reducing adverse/toxic outcomes.

 

My group aims to test this notion by focusing on two key areas:

 

The first is to work with industry and academic collaborators to generate new pharmacological and chemical tools to probe the function and druggability of G protein coupled receptors (GPCRs). By combining this with novel animal disease models and chemical genetic models we aim to reveal the signalling mechanisms that underlie the physiological role of GPCRs and the action of drugs that target GPCRs. In this way we plan to define the signalling pathways that mediate therapeutically beneficial GPCR-responses and differentiate these from pathways that lead to adverse/toxic outcomes. We are currently testing the notion that GPCR ligands can be designed to channel receptor activity towards those pathways with therapeutic benefit and away from pathways leading to adverse/toxic responses. The overall aim is to define a knowledge framework that will allow for rational design of GPCR drugs that show increased efficacy and reduced toxicity.

 

The second focus of the group is by working in collaboration with GlaxoSmithKline, MRC-Technology, Medicines for Malaria Venture, MRC Unit the Gambia and a number of leading academic laboratories we are applying novel chemical probes, pharmacological inhibitors and chemical genetic models to define the essential phospho-signalling pathways in the human malarial parasite (Plasmodium falciparum) and to design next generation anti-malaria drugs that display clinical efficacy with reduced adverse/toxic outcomes. We are particularly focused on exploiting the phylogenetic diversity of the malaria kinome to design protein kinase inhibitors that target selectively the essential parasite protein kinases but that show low levels of off-target toxicity in the human host. In these studies we are employing novel chemical genetic approaches and developing chemical tools to define the off and on-target action of protein kinase inhibitors. This is being combined with defining the toxicity profile of protein kinase inhibitors that will allow for assessment of the potential toxic liability of novel agents that are designed to target parasite protein kinases. We are also working closely with a consortium of laboratories defining the mechanisms of parasite resistance to front line anti-malarial drugs. The overall question being addressed here is to inform a rational strategy that can generate next generation anti-malarial drugs that have high therapeutic efficacy but that show low levels of adverse/toxic outcomes and that have reduced potential for the development of resistance.

 

Industrial/Academic Collaborators and Funding Agencies:

Targeting muscarinic receptors in neurological disease:
Eli Lilly (LARP Grant), Monash Institute of Pharmacological Sciences, Integrated Toxicology Training Programme PhD (ITTP)

Defining the role of free fatty acid receptors:
AstraZeneca, University of Glasgow, BBSRC Industrial Partnership Award, BBSRC Project Grant

Toxicity associated with activation of mGluR5:
Novartis BBSRC-CASE studentship

Targeting malaria protein kinases – defining off target toxicity:
GlaxoSmithKline (Open Lab Foundation Award), MRCT (Developmental Gap Fund), Centre for Translational Therapeutics, University of Leicester, MMV, Wellcome Trust Project grant)

Malaria drug resistance:
Consortium led by Columbia University (New York, USA)

Defining physiological signalling pathways down-stream of the M3-muscarinic receptor

The pathways in GREEN are down stream of heterotrimeric G-protein activation and the pathways in RED are downstream of arrestin/phosphorylation-dependent signalling.

GPCR summary

  1. Zindel, D., Butcher, A. J., Al-Sabah, S., Lanzerstorfer, P., Weghuber, J., Tobin, A. B., Bünemann, M. & Krasel, C. Engineered hyperphosphorylation of the beta2-adrenoceptor prolongs arrestin-3 binding and induces arrestin internalization. Molecular pharmacology 87, 349-362 (2015).
  1. Doerig, C., Rayner, J. C., Scherf, A. & Tobin, A. B. Post-translational protein modifications in malaria parasites. Nature reviews. Microbiology (2015).
  1. Prihandoko, R. & Tobin, A. B. Challenges of assigning protein kinases to in vivo phosphorylation events. Focus on “Use of LC-MS/MS and Bayes’ theorem to identify protein kinases that phosphorylate aquaporin-2 at Ser256”. American journal of physiology. Cell physiology 307, C121-122 (2014).
  1. Kern, S. Agarwal, S., Huber, K., Gehring, A. P., Strödke, B., Wirth, C. C., Brügl, T., Abodo, L. O., Dandekar, T., Doerig, C., Fischer, R., Tobin, A. B., Alam, M. M., Bracher, F. & Pradel, G. Inhibition of the SR protein-phosphorylating CLK kinases of Plasmodium falciparum impairs blood stage replication and malaria transmission. PloS one 9, e105732 (2014).
  1. Graciotti, M., Alam, M., Solyakov, L., Schmid, R., Burley, G., Bottrill, A. R., Doerig, C., Cullis, P. & Tobin, A. B. Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation. PloS one 9, e85391 (2014).
  1. Butcher, A.J., Huson, B. D., Shimpukade, B., Alvarez-Curto, E., Prihandoko, R., Ulven, T., Milligan, G. & Tobin, A. B. Concomitant Action of Structural Elements and Receptor Phosphorylation Determines Arrestin-3 Interaction with the Free Fatty Acid Receptor FFA4. The Journal of biological chemistry 289, 18451-18465 (2014).
  1. Bradley, S. J., Riaz, S. A. & Tobin, A. B. Employing novel animal models in the design of clinically efficacious GPCR ligands. Current opinion in cell biology 27, 117-125 (2014).
  1. Hudson, B.D., Shipmukade, B., Mackenzie, A. E., Butcher, A. J., Pediani, J. D., Christiansen, E., Heathcote, H., Tobin, A. B., Ulven, T. & Milligan, G. The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Molecular pharmacology 84, 710-725 (2013).
  1. Dorin-Semblat, D., Bottrill, A. R., Solyakov, L., Tobin, A. & Doerig, C. Experimental tools for the study of protein phosphorylation in Plasmodium. Methods in molecular biology 923, 241-257 (2013).
  1. Gregory, K. J., Sexton, P. M., Tobin, A. B., and Christopoulos, A. Stimulus bias provides evidence for conformational constraints in the structure of a G protein-coupled receptor.  The Journal of Biological Chemistry 287, 37066-77 (Joint Corresponding Author) (2012)
  1. Butcher, A. J., Kong, K. C., Prihandoko, R., and Tobin, A. B. Physiological role of G-protein coupled receptor phosphorylation.  Handbook of Experimental Pharmacology, 79-94 (2012)
  1. Talevich, E., Tobin, A. B., Kannan, N., and Doerig, C. An evolutionary perspective on the kinome of malaria parasites.  Philosophical Transactions of the Royal Society London B Biological Sciences 367, 2607-2618 (2012)
  1. Lasonder, E., Treeck, M., Alam, M., and Tobin, A. B. Insights into the Plasmodium falciparum schizont phospho-proteome. Microbes Infect 14, 811-819 (2012)
  1. Hopp, C. S., Flueck, C., Solyakov, L., Tobin, A., and Baker, D. A. Spatiotemporal and Functional Characterisation of the Plasmodium falciparum cGMP-Dependent Protein Kinase. PLoS One 7, e48206 (2012)
  1. Guttery, D. S., Poulin, B., Ferguson, D. J., Szoor, B., Wickstead, B., Carroll, P. L., Ramakrishnan, C., Brady, D., Patzewitz, E. M., Straschil, U., Solyakov, L., Green, J. L., Sinden, R. E., Tobin, A. B., Holder, A. A., and Tewari, R. A Unique Protein Phosphatase with Kelch-Like Domains (PPKL) in Plasmodium Modulates Ookinete Differentiation, Motility and Invasion.  PLoS Pathog 8, e1002948 (2012)
  1. Guttery, D. S., Ferguson, D. J., Poulin, B., Xu, Z., Straschil, U., Klop, O., Solyakov, L., Sandrini, S. M., Brady, D., Nieduszynski, C. A., Janse, C. J., Holder, A. A., Tobin, A. B., and Tewari, R. A putative homologue of CDC20/CDH1 in the malaria parasite is essential for male gamete development. PLoS Pathog 8, e1002554 (2012)
  1. Solyakov, L., Halbert, J., Alam, M. M., Semblat, J. P., Dorin-Semblat, D., Reininger, L., Bottrill, A. R., Mistry, S., Abdi, A., Fennell, C., Holland, Z., Demarta, C., Bouza, Y., Sicard, A., Nivez, M. P., Eschenlauer, S., Lama, T., Thomas, D. C., Sharma, P., Agarwal, S., Kern, S., Pradel, G., Graciotti, M., Tobin, A. B., and Doerig, C. Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum. Nat Commun 2, 565 (Joint Corresponding Author) (2011)
  1.    Poulin, B., Butcher, A., McWilliams, P., Bourgognon, J. M., Pawlak, R., Kong, K. C., Bottrill, A., Mistry, S., Wess, J., Rosethorne, E. M., Charlton, S. J., and Tobin, A. B. The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner. Proc Natl Acad Sci U S A 107, 9440-9445 (2010)
  1. Doerig, C., and Tobin, A. B. Parasite protein kinases: at home and abroad. Cell Host Microbe 8, 305-307 (2010)
  1. Kong, K. C., Butcher, A. J., McWilliams, P., Jones, D., Wess, J., Hamdan, F. F., Werry, T., Rosethorne, E. M., Charlton, S. J., Munson, S. E., Cragg, H. A., Smart, A. D., and Tobin, A. B. M3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1. Proc Natl Acad Sci U S A 107, 21181-21186 (2010)
  1. Gregory, K. J., Hall, N. E., Tobin, A. B., Sexton, P. M., and Christopoulos, A. Identification of orthosteric and allosteric site mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias. J Biol Chem 285, 7459-7474 (2010)
  1. Solyakov, L., Sayan, E., Riley, J., Pointon, A., and Tobin, A. B. Regulation of p53 expression, phosphorylation and subcellular localization by a G-protein-coupled receptor. Oncogene 28, 3619-3630 (2009)
  1. Butcher, A. J., Torrecilla, I., Young, K. W., Kong, K. C., Mistry, S. C., Bottrill, A. R., and Tobin, A. B. N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptors in cerebellar granule neurons. J Biol Chem 284, 17147-17156 (2009)
  1. Tobin, A. B., Butcher, A. J., and Kong, K. C. Location, location, location…site-specific GPCR phosphorylation offers a mechanism for cell-type-specific signalling. Trends Pharmacol Sci 29, 413-420 (2008)
  1. Doerig, C., Billker, O., Haystead, T., Sharma, P., Tobin, A. B., and Waters, N. C. Protein kinases of malaria parasites: an update. Trends Parasitol 24, 570-577 (2008)
  1. Torrecilla, I., Spragg, E. J., Poulin, B., McWilliams, P. J., Mistry, S. C., Blaukat, A., and Tobin, A. B. Phosphorylation and regulation of a G protein-coupled receptor by protein kinase CK2. J Cell Biol 177, 127-137 (2007)

Tobin Group