PROJECT
Drug discovery for neglected tropical diseases
Optimisation of a novel class of trypanosomacidal compounds towards new treatments for African Sleeping sickness and Chagas disease
Human African trypanosomiasis (HAT, African sleeping sickness) and Chagas disease are parasitic infections caused by the protozoans Trypanosoma brucei and T. cruzi, respectively. They are responsible for significant morbidity and mortality in some of the poorest parts of the world.
Existing treatments for both HAT and Chagas disease are associated with severe side-effects, are limited in their efficacy, and are too expensive for the majority of the afflicted. Alternative drugs are sorely needed.
This project, which was supported by the NHMRC and the pharmaceutical company GSK, has identified a class of potent, selective, broad spectrum trypanosome-killing small molecules.
The key challenge that needs to be overcome to achieve clinically useful compounds is to improve metabolic stability, and that will be a focus of ongoing research in this area. In addition, there is a great opportunity to identify the biomolecular target of this class of compounds.
This PhD project will involve the design and synthesis of analogues of the existing library of compounds, which will then be evaluated for trypanosomacidal activity, safety, metabolic stability and drug-likeness by our collaborators. In addition, through analysis of structure activity relationships we will design molecular probes that might allow the protein target of this class of compound to be isolated and identified.
- Suggested readings
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- Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides Stephanie Russell, Raphaël Rahmani, Amy J. Jones, Harriet L. Newson, Kevin Neilde, Ignacio Cotillo, Marzieh Rahmani Khajouei, Lori Ferrins, Sana Qureishi, Nghi Nguyen, Maria S. Martínez-Martínez, Donald F. Weaver, Marcel Kaiser, Jennifer Riley, John Thomas, Manu De Rycker, Kevin D Read, Gavin R. Flematti, Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides”, Stephanie Russell, Raphaël Rahmani, Amy J. Jones, Harriet L. Newson, Kevin Neilde, Ignacio Cotillo, Marzieh Rahmani Khajouei, Lori Ferrins, Sana Qureishi, Nghi Nguyen, Maria S. Martínez-Martínez, Donald F. Weaver, Marcel Kaiser, Jennifer Riley, John Thomas, Manu De Rycker, Kevin D Read, Gavin R. Flematti, Eileen Ryan, Scott Tanghe, Ana Rodriguez, Susan A. Charman, Albane Kessler, Vicky M. Avery, Jonathan B. Baell, and Matthew J. Piggott. Journal of Medicinal Chemistry, 2016, 59, 9686−9720.
- Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi Swapna Varghese, Raphaël Rahmani, Stephanie Russell, Girdhar Singh Deora, Lori Ferrins, Arthur Toynton, Amy Jones, Melissa Sykes, Albane Kessler, Amanda Eufrásio, Artur Torres Cordeiro, Julian Sherman, Ana Rodriguez, Vicky M. Avery, Matthew Piggott, Jonathan B. Baell, ACS Medicinal Chemistry Letters, 2019, ASAP
Project goals
Through ligand-based drug design, improve metabolic stability while maintaining potency and selectivity, thereby identifying a drug candidate
Affinity labelling to identify the protein target of this class of compounds
Research team leader: Associate Professor Matthew Piggott
I am a synthetic organic chemist and I love designing and synthesising new compounds. Sometimes this is done with a practical application in mind; for example, with the aim of discovering new drugs (medicinal chemistry), to study complex biological systems (chemical biology), or as molecular components of electronic circuits or machines. Sometimes, strategy and methodology are the focus: how can we make a complex, biologically active natural product as efficiently as possible? And, sometimes, the driving force is about pushing the boundaries. We can design molecules with unprecedented, beautiful structures – can we make them? In all cases, the creativity and logic of organic synthesis is immensely intellectually rewarding.
Collaborations and funding
Past funding:
- Hit to Lead Optimization for kinetoplastid diseases: single agents for Chagas and HAT, Tres Cantos Open Lab Foundation (GSK-sponsored), 2015
- Discovery of single agents to treat Chagas disease and human African trypanosomiasis, NHMRC, APP1079351, 2015–17
External collaborators:
- Professor Jonathan Baell, Monash Institute of Pharmaceutical Science
- Professor Vicky Avery, Griffith University
How to apply
Interested in becoming part of this project? Complete the following steps to submit your expression of interest:
Step 1 - Check criteria
General UWA PhD entrance requirements can be found on the Future Students website.
Requirements specific to this project include:
- Applicants should have a major in Chemistry and research experience in Synthetic Organic Chemistry.
- Some understanding of biology is desirable but not required
Step 2 - Submit enquiry to research team leader
Step 3 - Lodge application
After you have discussed your project with the research team leader, you should be in a position to proceed to the next step of the UWA application process: Lodge an application. Different application procedures apply to domestic and international students.
Scholarships
- Domestic students
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All domestic students may apply for Research Training Program and University Postgraduate Awards (UPA) scholarships
- International students
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A range of scholarships are available from international organisations and governments. The full list, organised by country, is available on the Future Students website.
In addition, all international students may apply for International Research Training Program scholarships.
- Indigenous students
- Indigenous students are encouraged to apply for Indigenous Postgraduate Research Supplementary Scholarships.
- Forrest Foundation scholarships
- All international and Australian students who wish to study towards the degree of Doctor of Philosophy (PhD) at The University of Western Australia may apply for Forrest Scholarships.
