Prof Patrick Sexton - Researcher Profile

Patrick Sexton

Address

Monash Institute of Pharmaceutical Sciences
381 Royal Parade

Contact Details

Tel: +61 3 990 39069

Fax: +61 3 9903 9581

Email: Patrick.Sexton@monash.edu

Web: http://www.pharm.monash.edu.au/research/mips/ddb/index.html


Biography

Position

Professor of Pharmacology
Faculty of Pharmacy and Pharmaceutical Sciences

Theme Leader - Drug Discovery Biology
Monash Institute of Pharmaceutical Sciences

A cellular revolution

In the last five years Professor Patrick Sexton and colleagues have begun unravelling the complexities of drug action that could revolutionise pharmaceutical drug design. Their profound new knowledge of the complex interactions occurring on the surface of the body's cells challenges traditional views of how medicines work, and could lead to treatments so precise they can be tailored to individual patients.

 

Working within the Monash Institute of Pharmaceutical Science, Patrick is uncovering the secrets of the largest family of cell surface receptors: G protein-coupled receptors (GPCRs). These receptors allow communication between what moves around the body to inside cells, and are the largest drug target family in the human genome.

The established approach to drug design was based on a belief that all pathways activated by a receptor would be affected equally by drugs, with investigations of drug action limited to a single signalling pathway.

However, Patrick's research has discovered there is far more going on at the cell surface. Receptor activity is far broader than previously understood. Most receptors are now known to activate multiple pathways. Further complicating the process, individual drugs acting at the same receptor cause different activity.

This understanding creates the potential to develop drugs that selectively activate beneficial pathways and don't activate signals that are less beneficial and lead to side-effects.

"Traditionally held views of why drugs work are changing," Patrick says. "It is only recently that we have begun to understand why some drugs work better for some diseases versus others.

"A very significant element of that comes back to the fact that we didn’t really mechanistically understand what these drugs were doing. Yes, we could get drugs to market but we were not necessarily predicting therapeutic effects in the way that we potentially could, and we were not directing the drugs to particular therapeutic end points as well as we could.

"These things are very important in whether we can actually create better medicines - medicines that could potentially be personalised to a patient, that target unmet medical needs and reduce side-effects."

Patrick's research has uncovered a whole new field of pharmacology.

However, traditional methods of understanding these complex cellular interactions no longer offer sufficient insight, and Patrick's team have produced a new ‘chemical toolbox’ to use in their work.

"We don’t have a lot of information that tells about the relative importance of one pathway versus another, and we really haven’t had the tools required to probe that," Patrick says. "So one thing we are trying to do is create that chemical toolbox, identify spectrums of behaviour of molecules and then be able to take those and move them into a physiological context and test the combinations of pathways to use.

"This information is critically important to progressing this field, but it is information that is lacking. We are working hard on it. We are constantly making new discoveries."

The goal at the end of all this hard work is producing better treatments for a range of neuropsychiatric diseases - such as schizophrenia and Alzheimer’s - and metabolic diseases, including type-2 diabetes.

Their knowledge of previously unused chemical pathways means researchers could also potentially rescue the function of severely damaged cells. By creating drugs that bind at different, newly discovered, parts of the receptor Patrick's team believe they can actually resume communications with cells previously thought unreachable and attack the core elements of disease in patients that have traditionally been deemed beyond treatment.

Keywords

Drug discovery, pharmacology , allosteric modulation, biased agonism, bivalent ligand, drug discovery, functional selectivity, rec, structure function of receptors, family B G protein-coupled receptors

Qualifications

PHD - MEDICINE, DENTISTRY & HEALTH SCIENCES
Institution: The University of Melbourne
Year awarded: 1988
BACHELOR OF SCIENCE (HONS)
Institution: The University of Melbourne
Year awarded: 1985

Publications

Book Chapters

Sexton, P.M., Poyner, D.R., Simms, J., Christopoulos, A., Hay, D.L., 2012, RAMPs as drug targets, in RAMPs, eds W.S. Spielman, & N. Parameswaran, Springer Science+Business Media, USA, pp. 61-74.

Leach, K., Simms, J., Sexton, P.M., Christopoulos, A., 2012, Structure-function studies of muscarinic acetylcholine receptors, in Muscarinic Receptors - Handbook of Experimental Pharmacology 208, eds AD Fryer, A Christopoulos, & NM Nathanson, Springer Science+Business Media, USA, pp. 29-48.

Wootten, D., Simms, J.W., Hay, D.L., Christopoulos, A., Sexton, P., 2010, Receptor activity modifying proteins and their potential as drug targets, in Progress in Molecular Biology and Translational Science, eds CA Lunn, Academic Press, UK, pp. 53-79.

Simms, J.W., Hall, N.E., Lam, P.H., Christopoulos, A., Abagyan, R., Sexton, P., 2009, Homology Modeling of GPCRs, in Methods in Molecular Biology - G Protein-Coupled Receptors in Drug Delivery, eds Wayne R Leifert, Humana Press, USA, pp. 97-113.

Journal Articles

Abdul Ridha, A., Lane, J.R.D., Sexton, P., Canals, M., Christopoulos, A., 2013, Allosteric modulation of a chemogenetically modified g protein-coupled receptor, Molecular Pharmacology [P], vol 83, issue 2, American Society for Pharmacology and Experimental Therapeutics, USA, pp. 521-530.

Wootten, D.L., Savage, E.E., Valant, C., May, L.T., Sloop, K.W., Ficorilli, J., Showalter, A.D., Willard, F.S., Christopoulos, A., Sexton, P.M., 2012, Allosteric modulation of endogenous metabolites as an avenue for drug discovery, Molecular Pharmacology [P], vol 82, issue 2, American Society for Pharmacology and Experimental Therapeutics, USA, pp. 281-290.

Lane, J.R.D., Sexton, P.M., Christopoulos, A., 2012, Bridging the gap: bitopic ligands of G-protein-coupled receptors, Trends in Pharmacological Sciences [P], vol E-pub, Elsevier Ltd * Trends Journals, UK, pp. 1-8.

Furness, S.G.B., Wootten, D.L., Christopoulos, A., Sexton, P.M., 2012, Consequences of splice variation on secretin family G protein-coupled receptor function, British Journal of Pharmacology [P], vol 166, issue 1, Wiley-Blackwell, Malden USA, pp. 98-109.

Harikumar, K.G., Wootten, D.L., Pinon, D.I., Koole, C.R., Ball, A.M., Furness, S.G., Graham, B., Dong, M., Christopoulos, A., Miller, L.J., Sexton, P.M., 2012, Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery, Proceedings Of The National Academy Of Sciences Of The United States Of America [P], vol 109, issue 45, National Academy of Sciences, USA, pp. 18607-18612.

Leach, K., Wen, C., Davey, A.E., Sexton, P.M., Conigrave, A.D., Christopoulos, A., 2012, Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor , Endocrinology [P], vol 153, issue 9, The Endocrine Society, USA, pp. 4304-4316.

Dong, M., Xu, X., Ball, A.M., Makhoul, J.A., Lam, P.C., Pinon, D.I., Orry, A., Sexton, P.M., Abagyan, R., Miller, L.J., 2012, Mapping spatial approximations between the amino terminus of secretin and each of the extracellular loops of its receptor using cysteine trapping, Faseb Journal [P], vol 26, issue 12, Federation of American Societies for Experimental Biology, USA, pp. 5092-5105.

Cawston, E.E., Lam, P.C.H., Harikumar, K.G., Dong, M., Ball, A.M., Augustine, M., Akgun, E., Portoghese, P.S., Orry, A., Abagyan, R., Sexton, P.M., Miller, L.J., 2012, Molecular basis for binding and subtype selectivity of 1,4-benzodiazepine antagonist ligands of the cholecystokinin receptor, Journal Of Biological Chemistry [P], vol 287, issue 22, American Society for Biochemistry and Molecular Biology Inc, USA, pp. 18618-18635.

Davey, A.E., Leach, K., Valant, C., Conigrave, A.D., Sexton, P.M., Christopoulos, A., 2012, Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor, Endocrinology [P], vol 153, issue 3, The Endocrine Society, USA, pp. 1232-1241.

Valant, C., Felder, C.C., Sexton, P.M., Christopoulos, A., 2012, Probe dependence in the allosteric modulation of a G protein-coupled receptor: implications for detection and validation of allosteric ligand effects, Molecular Pharmacology [P], vol 81, issue 1, American Society for Pharmacology and Experimental Therapeutics, USA, pp. 41-52.

Koole, C.R., Wootten, D.L., Simms, J., Savage, E.E., Miller, L.J., Christopoulos, A., Sexton, P.M., 2012, Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) differentially regulates orthosteric but not allosteric agonist binding and function, Journal Of Biological Chemistry [P], vol 287, issue 6, American Society for Biochemistry and Molecular Biology Inc, Bethesda USA, pp. 3659-3673.

Koole, C.R., Wootten, D.L., Simms, J.W., Miller, L.J., Christopoulos, A., Sexton, P., 2012, Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor activation, Journal Of Biological Chemistry [P], vol 287, issue 6, The American Society for Biochemistry and Molecular Biology, Inc., Bethesda USA, pp. 3642-3658.

Willard, F.S., Wootten, D.L., Showalter, A.D., Savage, E.E., Ficorilli, J., Farb, T.B., Bokvist, K., Alsina-Fernandez, J., Furness, S.G., Christopoulos, A., Sexton, P.M., Sloop, K.W., 2012, Small molecule allosteric modulation of the glucagon-like Peptide-1 receptor enhances the insulinotropic effect of oxyntomodulin, Molecular Pharmacology [P], vol 82, issue 6, American Society for Pharmacology and Experimental Therapeutics, USA, pp. 1066-1073.

Gregory, K.J., Sexton, P.M., Tobin, A.B., Christopoulos, A., 2012, Stimulus bias provides evidence for conformational constraints in the structure of a G protein-coupled receptor, Journal Of Biological Chemistry [P], vol 287, issue 44, American Society for Biochemistry and Molecular Biology Inc., USA, pp. 37066-37077.

Valant, C., Aurelio, L., Devine, S.M., Ashton, T.D., White, J.M., Sexton, P.M., Christopoulos, A., Scammells, P.J., 2012, Synthesis and characterization of novel 2-amino-3-benzoylthiophene derivatives as biased allosteric agonists and modulators of the adenosine A1 receptor, Journal of Medicinal Chemistry [P], vol 55, issue 5, American Chemical Society, USA, pp. 2367-2375.

Canals, M., Lane, J., Wen, A., Scammells, P., Sexton, P., Christopoulos, A., 2011, A Monod-Wyman-Changeux mechanism can explain G protein-coupled receptor (GPCR) allosteric modulation, Journal Of Biological Chemistry [P], vol 287, issue 1, American Society for Biochemistry and Molecular Biology, Inc., United States, pp. 650-659.

Canals, M., Sexton, P., Christopoulos, A., 2011, Allostery in GPCRs: 'MWC' revisited, Trends In Biochemical Sciences [P], vol 36, issue 12, Elsevier Science London, UK, pp. 663-672.

Suratman, N.S., Leach, K., Sexton, P., Felder, C.C., Loiacono, R., Christopoulos, A., 2011, Impact of species variability and "probe-dependence" on the detection and in vivo validation of allosteric modulation at the M(4) muscarinic acetylcholine receptor, British Journal of Pharmacology [P], vol 162, issue 7, John Wiley & Sons Ltd, UK, pp. 1659-1670.

Wootten, D., Simms, J., Koole, C., Woodman, O., Summers, R., Christopoulos, A., Sexton, P., 2011, Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids, Journal Of Pharmacology And Experimental Therapeutics [P], vol 336, issue 2, Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic fl, AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, pp. 540-550.

Dong, M., Lam, P., Pinon, D., Orry, A., Sexton, P., Abagyan, R., Miller, L., 2011, Molecular basis of secretin docking to its intact receptor using multiple photolabile probes distributed throughout the, Journal Of Biological Chemistry [P], vol 286, issue 27, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, USA, pp. 23888-23899.

Koole, C., Wootten, D., Simms, J., Valant, C., Miller, L., Christopoulos, A., Sexton, P., 2011, Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation, Molecular Pharmacology [P], vol 80, issue 3, American Society of Pharmacology & Experimental Therapeutics, USA, pp. 486-497.

Leach, K., Sexton, P., Christopoulos, A., 2011, Quantification of allosteric interactions at G protein-coupled receptors using radioligand binding assays, Current Protocols in Pharmacology [P], vol 1, issue Supp 52 (Unit 1.22), John Wiley & Sons, Inc., USA, pp. 1-41.

Miller, L.J., Chen, Q., Lam, P.C., Pinon, D.I., Sexton, P., Abagyan, R., Dong, M., 2011, Refinement of glucagon-like peptide 1 docking to its intact receptor using mid-region photolabile probes and molecular modeling, Journal Of Biological Chemistry [P], vol 286, issue 18, American Society for Biochemistry & Molecular Biology Inc, USA, pp. 15895-15907.

Qi, T., Ly, K., Poyner, D.R., Christopoulos, G., Sexton, P., Hay, D.L., 2011, Structure-function analysis of amino acid 74 of human RAMP1 and RAMP3 and its role in peptide interactions with adrenomedullin and calcitonin gene-related peptide receptors, Peptides [P], vol 32, issue 5, Elsevier Inc., USA, pp. 1060-1067.

Valant, C., Lane, J., Sexton, P., Christopoulos, A., 2011, The best of both worlds? Bitopic orthosteric/allosteric ligands of G protein - coupled receptors, Annual Review Of Pharmacology And Toxicology [P], vol 53, Annual Reviews, United States, pp. 153-178.

Leach, K., Davey, A.E., Felder, C.C., Sexton, P., Christopoulos, A., 2011, The role of transmembrane domain 3 (Tmiii) in the actions of orthosteric, allosteric and atypical agonists of the M4 muscarinic acetylcholine receptor, Molecular Pharmacology [P], vol 79, issue 5, American Society for Pharmacology & Experimental Therapeutics, USA, pp. 855-865.

Aurelio, L., Christopoulos, A., Flynn, B., Scammells, P., Sexton, P., Valant, C., 2011, The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A(1) adenosine receptor, Bioorganic & Medicinal Chemistry Letters [P], vol 21, issue 12, Pergamon-Elsevier Science Ltd, UK, pp. 3704-3707.

Koole, C., Wootten, D., Simms, J., Valant, C., Sridhar, R., Woodman, O., Miller, L., Summers, R., Christopoulos, A., Sexton, P.M., 2010, Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: Implications for drug screening, Molecular Pharmacology [P], vol 78, issue 3, American Society for Pharmacology and Experimental Therapeutics, USA, pp. 456-465.

Valant, C., Aurelio, L., Urmaliya, V., White, P., Scammells, P., Sexton, P., Christopoulos, A., 2010, Delineating the mode of action of adenosine A1 receptor allosteric modulators, Molecular Pharmacology [P], vol 78, issue 3, American Society for Pharmacology and Experimental Therapeutics, United States, pp. 444-455.

Stewart, G.D., Sexton, P., Christopoulos, A., 2010, Detection of novel functional selectivity at M3 muscarinic acetylcholine receptors using a Saccharomyces cerevisiae platform, Acs Chemical Biology [P], vol 5, issue 4, American Chemical Society, USA, pp. 365-375.

Aurelio, L., Valant, C., Flynn, B., Sexton, P., White, J., Christopoulos, A., Scammells, P., 2010, Effects of conformational restriction of 2-amino-3-benzoylthiophenes on A1 adenosine receptor modulation, Journal of Medicinal Chemistry [P], vol 53, American Chemical Society, United States, pp. 6550-6559.

Van Der Westhuizen, E., Christopoulos, A., Sexton, P., Wade, J., Summers, R., 2010, H2 relaxin is a biased ligand relative to H3 relaxin at the relaxin family peptide receptor 3 (RXFP3) [S], Molecular Pharmacology [P], vol 77, issue 5, American Society for Pharmacology and Experimental Therapeutics, United States, pp. 759-772.

Gregory, K.J., Hall, N., Tobin, A., Sexton, P., Christopoulos, A., 2010, Identification of orthosteric and allosteric site mutations in M 2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias, Journal Of Biological Chemistry [P], vol 285, issue 10, American Society for Biochemistry & Molecular Biology Inc, USA, pp. 7459-7474.

Harikumar, K.G., Ball, A.M., Sexton, P., Miller, L.J., 2010, Importance of lipid-exposed residues in transmembrane segment four for family B calcitonin receptor homo-dimerization, Regulatory Peptides [P], vol 164, issue 2-3, Elsevier BV, The Netherlands, pp. 113-119.

Leach, K., Loiacono, R.E., Felder, C.C., McKinzie, D.L., Mogg, A., Shaw, D.B., Sexton, P.M., Christopoulos, A., 2010, Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties, Neuropsychopharmacology [P], vol 35, issue 4, Nature Publishing Group, UK & USA, pp. 855-869.

Avlani, V.A., Langmead, C.J., Guida, E., Wood, M.D., Tehan, B.G., Herdon, H.J., Watson, J.M., Sexton, P., Christopoulos, A., 2010, Orthosteric and allosteric modes of interaction of novel selective agonists of the M1 muscarinic acetylcholine receptor, Molecular Pharmacology [P], vol 78, issue 1, American Society for Pharmacology & Experimental Therapeutics, USA, pp. 94-104.

Gregory, K., Sexton, P., Christopoulos, A., 2010, Overview of receptor allosterism, Current Protocols in Pharmacology [P], vol Chapter 1, issue Supp 51, John Wiley & Sons, Inc., USA, pp. 1.21-1-1.21-34.

Stewart, G.D., Sexton, P., Christopoulos, A., 2010, Prediction of functionally selective allosteric interactions at an M 3 muscarinic acetylcholine receptor mutant using Saccharomyces cerevisiae, Molecular Pharmacology [P], vol 78, issue 2, American Society for Pharmacology & Experimental Therapeutics, USA, pp. 205-214.

Dong, M., Lam, P.C., Pinon, D.I., Orry, A., Sexton, P., Abagyan, R., Miller, L.J., 2010, Secretin occupies a single protomer of the homodimeric secretin receptor complex: insights from photoaffinity labeling studies using dual sites of covalent attachment, Journal Of Biological Chemistry [P], vol 285, issue 13, American Society for Biochemistry & Molecular Biology Inc, USA, pp. 9919-9931.

Nawaratne, V., Leach, K., Felder, C.C., Sexton, P.M., Christopoulos, A., 2010, Structural determinants of allosteric agonism and modulation at the M 4 muscarinic acetylcholine receptor: Identification of ligand-specific and global activation mechanisms, Journal Of Biological Chemistry [P], vol 285, issue 25, American Society for Biochemistry & Molecular Biology Inc, USA, pp. 19012-19021.

Robinson, S.A., Loiacono, R., Christopoulos, A., Sexton, P., Malone, D.T., 2010, The effect of social isolation on rat brain expression of genes associated with endocannabinoid signaling, Brain Research [P], vol 1343, Elsevier BV, The Netherlands, pp. 153-167.

Aurelio, L., Valant, C., Figler, H., Flynn, B.L., Linden, J., Sexton, P., Christopoulos, A., Scammells, P.J., 2009, 3- and 6-substituted 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines as A1 adenosine receptor allosteric modulators and antagonists, Bioorganic & Medicinal Chemistry [P], vol 17, issue 20, Pergamon, UK, pp. 7353-7361.

van der Westhuizen, E.T., Wade, J.D., Sexton, P.M., Summers, R.J., 2009, Addition of a carboxy-terminal green fluorescent protein does not alter the binding and signaling properties of relaxin family peptide receptor 3, Annals of the New York Academy of Sciences [P], vol 1160, Wiley-Blackwell Publishing, Inc., USA, pp. 105-107.

Aurelio, L., Valant, C., Flynn, B.L., Sexton, P.M., Christopoulos, A., Scammells, P.J., 2009, Allosteric modulators of the adenosine A1 receptor: Synthesis and pharmacological evaluation of 4-substituted 2-amino-3-benzoylthiophenes, Journal of Medicinal Chemistry [P], vol 52, issue 14, American Chemical Society, USA, pp. 4543-4547.

Stewart, G.D., Valant, C., Dowell, S.J., Mijaljica, D., Devenish, R.J., Scammells, P.J., Sexton, P., Christopoulos, A., 2009, Determination of adenosine A1 receptor agonist and antagonist pharmacology using Saccharomyces cerevisiae: Implications for ligand screening and functional selectivity, Journal Of Pharmacology And Experimental Therapeu..., vol 331, issue 1, American Society for Pharmacology and Experimental Therapeutics, USA, pp. 277-286.

Gao, F., Harikumar, K.G., Dong, M., Lam, P.C., Sexton, P.M., Christopoulos, A., Bordner, A., Abagyan, R., Miller, L.J., 2009, Functional importance of a structurally distinct homodimeric complex of the family B G protein-coupled secretin receptor, Molecular Pharmacology [P], vol 76, issue 2, American Society of Pharmacology and Experimental Therapeutics, USA, pp. 264-274.

Sexton, P.M., Poyner, D.R., Simms, J.W., Christopoulos, A., Hay, D.L., 2009, Modulating receptor function through RAMPs: can they represent drug targets in themselves?, Drug Discovery Today, vol 14, issue 7-8, Elsevier Ltd, UK, pp. 413-419.

Other

Scammells, P.J., Aurelio, L., Christopoulos, A., Sexton, P., Valant, C., Flynn, B.L., Linden, J., 2009, A1 adenosine receptor allosteric enhancers, USA, AU.

Teaching Commitment

  • Lectures to BSc students in the Faculty of Medicine, Nursing, and Health Sciences
  • Lectures to BPharmSci students in the Faculty of Pharmacy and Pharmaceutical Sciences
  • Supervision of Honours students in Drug Discovery Biology
  • Supervision of PhD students in Drug Discovery Biology

    • Activities

    Affiliations with institutes

    Theme Leader
    Drug Discovery Biology
    Monash Institute of Pharmaceutical Sciences

    Grants

    Title:
    Molecular characterisation of the glucagon-like peptide 1 receptor.
    Investigators:
    Sexton, P, Simms, J, Canals, M
    Funding:
    (2011 - 2014). National Health & Medical Research Council (NHMRC).
    (2011 - 2015). National Health & Medical Research Council (NHMRC).
    Title:
    Subtype selectivity and functional bias of VPAC receptor positive allosteric modulators (PAMs) for understanding models of pulmonary disease.
    Investigators:
    Sexton, P, Christopoulos, A, Meutermans, W, Le, G
    Funding:
    (2012 - 2016). Alchemia.
    (2012 - 2016). Australian Research Council (ARC).
    Title:
    Understanding G Protein-coupled receptors (GPCRs): Accelerating discovery from concept to clinic.
    Investigators:
    Sexton, P, Christopoulos, A, Summers, R
    Funding:
    (2009 - 2013). National Health & Medical Research Council (NHMRC).
    (2011 - 2015). National Health & Medical Research Council (NHMRC).