Hughes & Northfield laboratory: Drug design

Researcher

Research Overview

The Drug Discovery Laboratory uses chemical biology approaches to develop novel peptide compounds for use against a range of therapeutic targets. Following design of the compounds, the candidate molecules are synthesised in our laboratory and evaluated using appropriate in vitro and in vivo assays. Data from these assays is then used to hone the design process, with the goal of producing more active compounds that are specific to the drug target, thus limiting potential off-target effects. The laboratory is excellently equipped to carry out the peptide synthesis and purification required to supply the peptides for this project, as well as to contribute to the subsequent in vitro assay and in vivo studies.

Our current work is focused on developing peptide mimetics of loops in neurotrophin proteins, specifically brain-derived neurotrophin factor (BDNF) and neurotrophin-3. These BDNF peptide mimetics are being applied as chemical biology tools to study neurotrophin signaling related to the growth of myelin in the peripheral and central nervous systems. Most recently the two lead compounds in our lab have been published demonstrating the ability to selectively promote myelination in either the peripheral or central nervous system (CNS), following a demyelinating injury. In the context of the CNS myelination, this may have implications for future treatment of multiple sclerosis.

Tony Hughes

As co-head of the Drug Design Laboratory in the Department of Pharmacology & Therapeutics, A/Prof Hughes has a long-standing interest in the design and development of small molecule mimetics of proteins as potential therapeutics. This requires an interdisciplinary approach, combining computational chemistry and structure-based drug design, peptide synthesis, pharmacology and neuroscience.

A/Prof Hughes designed the only two reported peptide mimetics of BDNF that are structural and functional mimetics of the BDNF neurotrophin. The first is cyclo(pAKKKR), which has been shown to promote myelination of peripheral nerves; and the second is TDP6, which has been shown to be a TrkB agonist and promotes remyelination in vivo of demyelinated nerves.

A/Prof Hughes has over 60 career publications, including 49 peer reviewed articles, with over 1600 citations, including publications in high impact journals (Journal of Biological Chemistry, four papers) and other highly ranked discipline journals (Journal of Medicinal Chemistry, two papers; Molecular Pharmacology).

Susan Northfield

Dr Susan Northfield is a peptide and medicinal chemist. She received her PhD in medicinal chemistry from Monash University in 2013, then spent two years as a postdoctoral researcher in the lab of Professor David Craik at the University of Queensland. In 2014 she joined the Department of Pharmacology & Therapeutics at the University of Melbourne and is currently the Joint Head of the Drug Design Laboratory.

Susan has two main research interests: (1) development of peptides that mimic loops from proteins/receptors, which may be developed as chemical biology tools and/or therapeutic leads, and (2) studying the pharmacokinetics of peptides, including enhancing their ability to cross cellular membranes. She has notably published her work in PNAS, the European Journal of Medicinal Chemistry, and Angewandte Chemie.

Staff

Current staff and students

Ms Qingqing Lin, PhD Student

Ms Denham Hopper, Masters Student

Ms Haoyue Zhang, undergraduate student volunteer

Alumni

Mr Jordan Sfyris Qoon, Masters Student (2016 – 2018)

Ms Zihan Shen, undergraduate research student (2018)

Mr Richard Cassar, Honours Student (2015)

Dr Kade Roberts

Dr Jordan Fletcher

Dr Paul O’Leary

Collaborators

Dr Simon Murray, Department of Anatomy and Neuroscience

Dr Junhua Xiao, Department of Anatomy and Neuroscience

Associate Professor Ross Bathgate, Howard Florey Institute

Associate Professor Akhter Hossain, Howard Florey Institute

Professor Alastair Stewart, Department of Pharmacology and Therapeutics

Professor Stephen O’Leary, Otolaryngology, The University of Melbourne

Professor Philip Thompson, Monash Institute of Pharmaceutical Sciences, Monash University

Professor David Craik, Institute for Molecular Bioscience, The University of Queensland

Professor John Wade, Howard Florey Institute

Professor Erica Fletcher, Department of Anatomy and Neuroscience

Funding

NHMRC Multiple Sclerosis Research Australia (MS Research Australia)

The CASS Foundation

University of Melbourne Early Career Research Grant (Northfield)

Melbourne Neuroscience Institute (Fellowship: Northfield; Seed-funding Grant: Hughes/Northfield)

The Michael Hirshorn Medical Research Commercialisation Fund

Research Outcomes

“MS and new ways of regenerating our brain's insulation", published in Pursuit, 28 August, 2018.

Research Publications

    • Fletcher, J. L.; Wood, R. J.; Nguyen, J.; Norman, E. M. L.; Jun, C. M. K.; Prawdiuk, A. R.; Biemond, M.; Nguyen, H. T. H.; Northfield, S. E.; Hughes, R. A.; Gonsalvez, D. G.; Xiao, J.; Murray, S. S. 2018, 38, 7088-7099.
    • Gonsalvez DG, Tran G, Fletcher J, Hughes RA, Hodgkinson S, Wood R, Yoo SW, De Silva M, Wong Agnes, McLean C, Kennedy P, Kilpatrick TJ, Murray SS, Xiao J. A brain-derived neurotrophic factor-based p75NTR peptide mimetic ameliorates experimental autoimmune neuritis induced axonal pathology and demyelination. eNeuro 2017; 4(3): e0142-17.
    • Wang CK, Northfield SE, Huang Y-H, Ramos MC, Craik DJ. Inhibition of tau aggregation using a naturally-occurring cyclic peptide scaffold. European Journal of Medicinal Chemistry2016;109: 342-349.
    • Northfield SE, Mountford SJ, Wielens J, Liu M, Zhang L, Herzog H, Holliday ND, Scanlon MJ, Parker MW, Chalmers DK, Thompson PE. Propargyloxyproline regio- and stereoisomers for click-conjugation of peptides: Synthesis and application in linear and cyclic peptides. Australian Journal of Chemistry 2015;68(9): 1365-1372.
    • Patil NA, Tailhades J, Hughes RA, Separovic F, Wade JD, Hossain MA. Cellular disulfide bond formation in bioactive peptides and proteins. International Journal of Molecular Sciences2015;16: 1791-1805.
    • Wang CK*, Northfield SE*, Swedberg JE, Colless B, Chaousis S, Craik DJ. Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability. European Journal of Medicinal Chemistry 2015;97: 202-213. *Indicates co-authorship
    • Wong AW, Giuffrida L, Wood R, Peckham H, Gonsalvez D, Murray SS, Hughes RA, Xiao J. TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination. Molecular and Cellular Neuroscience 2014;63: 132-140.
    • Wang CK*, Northfield SE*, Colless B, Chaousis S, Hamernig I, Lohman R-J, Nielsen D, Schroeder CI, Liras S, Price D, Fairlie D, Craik DJ. Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients. Proceedings of the National Academy of Science 2014;111(49): 17504-17509. *Indicates co-authorship
    • Northfield SE, Wang CK, Schroeder CI, Durek T, Kan M-W, Swedberg JE, Craik DJ. Disulfide-rich macrocyclic peptides as templates in drug design. European Journal of Medicinal Chemistry 2014;77: 248-257.
    • Xiao J, Hughes RA, Lim JY, Wong AW, Ivanusic JJ, Ferner AH, Kilpatrick TJ, Murray SS. A small peptide mimetic of brain-derived neurotrophic factor promotes peripheral myelination. Journal of Neurochemistry 2013;125: 386-398.
    • Bathgate RA, Zhang S, Hughes RA, Rosengren KJ, Wade JD. The structural determinants of insulin-like peptide 3 activity. Frontiers in Endocrinology 2012;3: 11.
    • Shabanpoor F, Zhang S, Hughes RA, Hossain MA, Layfield S, Ferraro T, Bathgate RAD, Separovic F, Wade JD. Design and development of analogues of dimers of insulin-like peptide 3 (INSL3) B-chain as high affinity antagonists of RXFP2. Biopolymers 2011;96: 81-87.
    • Shabanpoor F, Hughes RA, Zhang S, Bathgate RAD, Layfield S, Hossain MA, Tregear GW, Separovic F, Wade JD. Effect of helix-promoting strategies on the biological activity of novel analogues of the B-chain of INSL3. Amino Acids 2010;38: 121-131
    • Northfield SE, Roberts KD, Mountford SJ, Hughes RA, Kaiserman D, Mangan M, Pike RN, Bird PI, Thompson PE. Synthesis of ‘Difficult’ Fluorescence Quenched Substrates of Granzyme-C. International Journal of Peptide Research and Therapeutics 2010;16(3): 159-165.

Research Projects



Faculty Research Themes

Neuroscience

School Research Themes

Biomedical Neuroscience, Therapeutics & Translation



Key Contact

For further information about this research, please contact Joint Heads of Laboratory Associate Professor Tony Hughes & Dr Susan Northfield

Department / Centre

Pharmacology and Therapeutics

Unit / Centre

Hughes & Northfield laboratory: Drug design

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