Associate Professor Mark Smythe

Principal Research Fellow

Institute for Molecular Bioscience
m.smythe@imb.uq.edu.au
+61 7 334 62977

Overview

Research Interests

  • Combinatorial Chemistry and Molecular Design
    The approach is to combine protein structural information with combinatorial chemistry, resulting in the design and synthesis of molecules that mimic protein structure, ultimately leading to the discovery of compounds that mimic protein function. We are actively pursuing small molecules for cytokine and G-protein coupled receptors.
  • Protein-protein interactions
    Many biological processes are carried out, or regulated, through protein-protein interactions. Despite their physiological significance, they remain one of the most difficult molecular recognition events to inhibit or mimic. We have developed molecular design processes that successfully identify small molecular candidates which modulate the function of protein-protein interactions. We currently have several lead molecules against numerous protein-protein interaction targets.
  • Molecular design
    We have developed an integrated design platform for library design and structure-based design of molecules that modulate protein-protein interactions. This approach includes a set of unique biological descriptors for library design, a purpose-built virtual screening of virtual library platform and databases comprising large virtual libraries of compounds. Using these methodologies we design and synthesise arrays of molecules that sample biologically relevant diversity space for primary screening, as well as arrays of molecules specifically targetted for a therapeutic protein of interest.
  • Combinatorial chemistry
    Current strategies in library design involve the calculation of hundreds of potential descriptors that define various chemical characteristics, and selecting a diverse set of compounds in this descriptor space. With hundreds of available descriptors it is difficult to know which descriptors, if any, are important or essential for describing biological activity. Consequently such procedures result in the optimisation of libraries in chemical descriptor space, which has little impact on biologically relevant regions of that space. To overcome this we have developed a series of biologically-relevant descriptors that are used in library design. As a consequence, we aim to identify the biologically-relevant structural regions of chemical diversity and design and synthesise arrays of molecules that match this diversity space. We have developed new linkers and auxiliaries to aid combinatorial synthesis and a molecular design platform to achieve these objectives. We have synthesised various constrained cyclic peptide libraries (molecular toolkit libraries) and libraries of macrocycles and heterocycles. We have a particular focus on the discovery and exploitation of privileged structures.

Qualifications

  • Bachelor of Science Honours, James Cook University
  • Bachelor of Science, James Cook University
  • PhD, University of Melbourne

Publications

  • Barkan, David T., Cheng, Xiao-Li, Celino, Herodion, Tran, Tran T., Bhandari, Ashok, Craik, Charles S., Sali, Andrej and Smythe, Mark L. (2016) Clustering of disulfide-rich peptides provides scaffolds for hit discovery by phage display: application to interleukin-23. BMC Bioinformatics, 17 481: . doi:10.1186/s12859-016-1350-9

  • Ranganath, Sheila, Bhandari, Ashok, Avitahl-Curtis, Nicole, McMahon, Jaimee, Wachtel, Derek, Zhang, Jenny, Leitheiser, Christopher, Bernier, Sylvie G., Liu, Guang, Tran, Tran T., Celino, Herodion, Tobin, Jenny, Jung, Joon, Zhao, Hong, Glen, Katie E., Graul, Chris, Griffin, Aliesha, Schairer, Wayne C., Higgins, Carolyn, Reza, Tammi L., Mowe, Eva, Rivers, Sam, Scott, Sonya, Monreal, Alex, Shea, Courtney, Bourne, Greg, Coons, Casey, Smith, Adaline, Tang, Kim, Mandyam, Ramya A., Masferrer, Jaime, Liu, David, Patel, Dinesh V., Fretzen, Angelika, Murphy, Craig A., Milne, G. Todd, Smythe, Mark L. and Carlson, Kenneth E. (2015) Discovery and characterization of a potent interleukin-6 binding peptide with neutralizing activity in vivo. PLoS One, 10 11: 1-19. doi:10.1371/journal.pone.0141330

  • Long, Stephen M., Tran, Tran T., Adams, Peter, Darwen, Paul and Smythe, M. L. (2011) Conformational searching using a population-based incremental learning algorithm. Journal of Computational Chemistry, 32 8: 1541-1549. doi:10.1002/jcc.21732

View all Publications

Supervision

  • (2012) Doctor Philosophy

  • (2008) Doctor Philosophy

  • (2005) Doctor Philosophy

View all Supervision

Publications

Book Chapter

  • Bourne, Gregory T., Nielson, Jonathon L., Coughlan, Justin F., Darwen, Paul, Campitelli, Marc R., Horton, Douglas A., Rhumann, Andreas, Love, Stephen G., Tran, Tran T. and Smythe, Mark L. (2005). A convenient method for the synthesis of cyclic peptide libraries. In John Howl (Ed.), Peptide synthesis and applications (pp. 151-166) Clifton, NJ, USA: Humana Press.

Journal Article

Conference Publication

  • Kulis, C., Bourne, G., Kellie, S. and Smythe, M. (2010). Design, synthesis and evaluation of inhibitors targeting the SHP-1 catalytic domain. In: Abstracts of EPS 2010: The 31st European Peptide Symposium. EPS 2010: The 31st European Peptide Symposium, Copenhagen, Denmark, (103-103). 5-9 September 2010. doi:10.1002/psc.1303

  • Schroeder, CI, Nielsen, KJ, Adams, DA, Loughnan, M, Thomas, L, Bourne, GT, Smythe, ML, Alewood, PF, Craik, DJ and Lewis, RJ (2004). From Omega-Conotoxins to Macrocycle Mimetics. In: Journal of Peptide Science. , , (95-95). .

  • Hamwood, T., Kobe, B., Smythe, M. L. and Hume, D. A. (2002). Clues to interaction between CSF-1 and CSF-1R from specificity and structure. In: Australian Society of Immunologists Meeting. Australian Society of Immunologists Meeting, Brisbane, ((Poster)). 1-5 December, 2002.

  • Battersby, B. J., Bryant, D. E., Meutermans, W. and Smythe, M. L. (2001). Colloidal barcoding in combinatorial chemistry. In: Innovation and Perspectives in Solid Phase Synthesis and Combinatorial Libraries. Innovation & Perspectives in Solid Phase Synthesis & Combinatl, York, England, (199-202). 31 Aug - 4 Sept, 1999.

  • Bourne, G. T., Cassidy, P.J., Meutermans, W., Campitelli, M.R. and Smythe, M.L. (2001). Incorporation of a cis-amide bond isostere in the synthesis of cyclic tetrapeptides. In: Peptides: The wave of the future. Peptides: The wave of the future, San Diego, (). 9-14/6/01.

  • Meutermans, W., Golding, S., Campitelli, M.R., Horton, D., Bourne, G. T. and Smythe, M. L. (2001). Privilege structures: New strategies for the synthesis of cyclic tetrapepties. In: 17th Australian Peptide Conference. 17th AFS, San Diego, (). 9-15th June, 2001.

  • Golding, S.W., Bourne, G.T., Meutermans, W.D.F., Jones, A. and Smythe, M.L. (2001). The use of a novel safety catch linker for BOC-based assembly of cyclic peptide libraries. In: Proceedings of the 17th Australian Peptide Conference. 17th Australian Peptide Conference, San Diego, Calafornia, (). 9-14 June, 2001.

Edited Outputs

Grants (Administered at UQ)

PhD and MPhil Supervision

Completed Supervision

  • (2012) Doctor Philosophy — Principal Advisor

    Other advisors:

  • (2008) Doctor Philosophy — Principal Advisor

  • (2005) Doctor Philosophy — Principal Advisor

    Other advisors:

  • (2007) Doctor Philosophy — Associate Advisor

  • (2004) Doctor Philosophy — Associate Advisor

    Other advisors: