Clark Lab - Peptide chemical biology

We are interested in studying the role of naturally occurring bioactive peptides in a broad range of human diseases. Peptides have a diverse range of functions in human biology including acting as hormones, neuro-regulators and in the protection against pathogens. Our work in this area is focused on understanding the molecular mechanism that these peptide use to elicit a biological response with the hope of using this knowledge to develop new drug leads.

The study of endogenous human peptides and proteins and the isolation and characterisation of bioactive peptides from natural sources has generated huge interest in the development of these molecules for the treatment of a broad range of human diseases. Although there are many advantages of using peptides as therapeutics, there are still a number of hurdles that need to be overcome before this source of promising drug leads fulfill their vast potential. Our goal is to create potent and selective drug leads based on naturally occurring peptides for the treatment of human diseases and to develop novel strategies to provide these molecules with the ability to resist the body’s natural degradation pathways so they are able to reach their biological target.

For information on available PhD and Honours projects please contact Dr Richard Clark.

A selection of the projects that we currently work on are shown below.

A new GPCR target for conotoxins

This project aims to characterise the interaction between conotoxins and the GABA(B) receptor, discover new conotoxins that target this receptor and design new ligands for related receptors that are also involved in nerve signalling. This involves undertaking structure/activity studies, screening venom extracts, mechanistic studies using receptor constructs and assays and functional studies in cell-based systems and native tissue. This will provide us with an intimate understanding of the effect of conotoxins on this novel receptor that will underpin the future development of new drug leads for treating neurological diseases including pain, anxiety, depression, epilepsy and drug addiction.

A new GPCR target for conotoxins

The design and development of peptides to modulate iron homeostasis

Hepcidin is the major peptide hormone in the body regulating iron levels. There are a number of diseases associated with the dysregulation of hepcidin levels in humans, including haemochromatosis (iron overload) and anaemia (low iron levels). The overall objective of this project is to develop stabilised peptides to modulate iron homeostasis by altering circulating hepcidin levels. These molecules will be potential drug leads for the treatment of iron-related disorders.

Hepcidin

New peptide drugs for the treatment of chronic pain

Chronic pain affects up to 1 in 5 Australians and subsequently has a major effect on people’s quality of life and impacts on both the health system and industry. Conotoxins, with their exquisite specificity and potency have recently created much excitement as drug leads for the treatment of chronic pain. For example, the conotoxin MVIIA (also known as Ziconotide or Prialt) has been approved for use in the U.S. and Europe for the treatment of pain and several other conotoxins have entered clinical trials. In addition, a number of conotoxins have played a critical role in dissecting the molecular mechanisms of ion channel and transporter functions in the nervous system. However, like most peptides, their beneficial activities are largely undermined by susceptibility to proteolysis in vivo. This research project seeks to use peptide engineering approaches to greatly improve their bioavailability and resistance to proteolytic degradation while maintaining their full potency.

Peptide drugs

Discovery and development of peptides for the treatment of inflammation and infection

This project involves the discovery of novel peptides from nature that modulate the immune response to prevent inflammation or infection by pathogens. Using peptide engineering we can modify these leads to understand how they mechanism of action, improve their drug-like properties, and develop therapies that are targeted to one location in the body.

Peptide engineering

Discovery, synthesis and characterization of novel antimicrobial peptides from insects

Increasing pathogen resistance against commonly used antibacterial drugs is an escalating health threat and there is an urgent need for novel lead molecules to target these organisms. Insects, making up ~80% of all living organisms, are populating a diverse range of ecological spaces and thus have evolved a complex immune system involving numerous antimicrobial peptides. The project seeks to discover novel bioactive peptides from ant species using state-of-the-art techniques such as transcriptome mining combined with mass spectrometry based peptidomics. Solid phase peptide synthesis will be used to generate sufficient amounts of peptides for bioactivity studies and structural characterization. This project is led by Dr Johannes Koehbach.

Ants

Carstens BB, Berecki G, Daniel JT, Lee HS, Jackson KAV, Tae H, Sadeghi M, Castro J, O’Donnell T, Deiteren A, Brierley SM, Craik DJ, Adams DJ, Clark RJ. Structure-Activity Studies of Cysteine-Rich a-Conotoxins that Inhibit High Voltage-Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif. Angew. Chem. Int. Ed. (2016) 55, 4692-4696.

Grishin AA*, Cuny H*, Hung A*, Clark RJ*, Brust A, Akondi K, Alewood PF, Craik DJ, Adams DJ, Identifying key amino acid residues that affect alpha-conotoxin AuIB inhibition of alpha3beta4 nicotinic acetylcholine receptors, J. Biol. Chem. (2013) 288, 34428-34442.

Clark RJ#, Tan C, Preza GC, Nemeth E, Ganz T, Craik DJ, Understanding the structure/activity relationships of the iron regulatory peptide hepcidin. Chem. Biol. (2011) 18, 336-343.

Clark RJ, Jensen J, Nevin ST, Callaghan BP, Adams DJ and Craik DJ, The engineering of an orally active conotoxin for the treatment of neuropathic pain. Angewandte Chemie (2010) 49, 6545-6548

Clark R J, Daly N L, Craik D J. Structural plasticity of the cyclic cystine knot framework: implications for biological activity and drug design. Biochemical J (2006) 394, 85-93

*Clark R J, Fischer H, Dempster L, Daly N L, Rosengren K J, Nevin S T, Daly N L, Meunier F A, Adams D J, Craik D J. Engineering stable peptide toxins by means of backbone cyclisation: stabilisation of the a-conotoxin MII. Proc. Nat. Acad. Sci. (2005) 102, 13767-13772.

Rosengren KJ, Clark RJ, Daly NL, Göransson U, Jones A, Craik DJ. Microcin J25 has a threaded sidechain-to-backbone. JACS (2003) 125, 12464-12474.

View full publication list

Lab head

Staff

Students

Local

Dr Johan Rosengren
School of Biomedical Sciences
University of Queensland

Dr Christian Gruber
School of Biomedical Sciences
University of Queensland

A/Prof. Trent Woodruff
School of Biomedical Sciences
University of Queensland

Professor David Craik
Institute for Molecular Biosciences
University of Queensland

Professor Nathan Subramaniam and Dr Daniel Wallace
Institute of Health and Biomedical Innovation
Queensland University of Technology

A/Prof. Jason Mulvenna
QIMR Berghofer Medical Research Institute

National

Prof. David Adams
Illawarra Health and Medical Research Intitute
University of Wollongong

Prof. Des Richardson
Department of Pathology and Bosch Institute
University of Sydney

Prof. Norelle Daly
Australian Institute of Tropical Health and Medicine
James Cook University

A/Prof. Stuart Brierley
School of Medicine
Flinders University

A/Prof. John Miles
Australian Institute of Tropical Health and Medicine
James Cook University

International

Prof. Ulf Göransson
Department of Medicinal Chemistry
Uppsala University, Sweden

Prof. Tomas Ganz
David Geffen School of Medicine
UCLA, USA

Prof. Elizabeta Nemeth
Center for Iron Disorders
UCLA, USA

Find out more about our research environment and how to apply to do a short or long-term research project with us.