Plasmepsin V inhibitors as antimalarial agents
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Infection and Immunity | .(JavaScript must be enabled to view this email address) |
Dr Brad Sleebs (Co-supervisor) |
Chemical Biology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Infection and Immunity | .(JavaScript must be enabled to view this email address) |
Details of project
Malaria parasites survive inside human red blood cells by renovating them. This is achieved by exporting hundreds of proteins into the erythrocyte to remodel it. These 200-300 exported proteins traffic through the parasite Endoplasmic Reticulum (ER) and possess an N-terminal export motif, termed the Plasmodium export element (PEXEL), which targets the proteins to the erythrocyte. In order for proteins to be correctly exported, the PEXEL motif (RxLxQ/E/D) must be cleaved by an ER-resident aspartic acid protease called Plasmepsin V (PMV). If cleavage does not take place, proteins accumulate inside the parasite and are not exported. We believe that small molecule inhibitors of PMV will block the export of these 200-300 proteins and result in the death of the parasite. Hence, PMV is considered to be a prime target for the development of new antimalarial drugs.
The main goal of this project is to design potent small molecule PMV inhibitors that will help to further probe the biology of the malaria parasite’s export pathway and, ultimately, to generate a new antimalarial drug. This project will comprise a variety of different aspects of drug discovery and malaria biology, including medicinal chemistry, in silico design and malaria protein trafficking. The medicinal chemistry component will involve the synthesis of a number of analogues and evaluation of their biological enzymatic activity. In silico design will aid in the medicinal chemistry optimisation process. The leading molecules designed in the process will be investigated in biological assays that characterise the effectiveness of the lead molecules as therapeutic treatments and to further dissect the biology of the protein export pathway in malaria.
This project is ideal for Honours and PhD students.
Project references
- Boddey JA, Hodder AN, Gunther S, Gilson PR, Patsiouras H, Kapp EA, Pearce JA, de Koning-Ward TF, Simpson RJ, Crabb BS, Cowman AF. An aspartyl protease directs malaria effector proteins to the host cell. Nature. 2010;463: 627-21. PMID: 20130643.
- deKoning-Ward TF, Gilson PR, Boddey JA, Rug M, Smith BJ, Papenfuss AT, Sanders PR, Lundie RJ, Maier AG, Cowman AF, Crabb BS. A newly discovered prtein export machine in malaria parasites. Nature. 2009;459: 945-9. PMID: 19536257.
- Boddey JA, Moritz RL, Simpson RJ, Cowman AF. Role of the Plasmodium export element in trafficking parasite proteins to the infected erythrocyte. Traffic. 2009;10(3):285-99. PMID: 19055692.
- Kappe, SHI; Vaughan, AM; Boddey, JA; Cowman, AF.That Was Then But This Is Now: Malaria Research in the Time of an Eradication Agenda. Science. 2010;328(5980): 862-866. PMID: 20466924.
Research interests
Chemical Biology Division: The Medicinal Chemistry laboratory conducts research aimed at developing new therapeutically useful molecules. Combining synthetic organic chemistry with a knowledge of structural biology and principles of drug design, we focus on small molecules and their biological applications.Projects in the laboratory currently focus on cancer and parasitic diseases such as malaria, human African trypanosomiasis, leishmaniasis and Chagas’ disease.
Infection and Immunity division: Our laboratory works predominantly on Plasmodium falciparum, the causative agent of the most severe form of malaria in humans. This disease causes millions of deaths and much suffering for people living in tropical and subtropical regions of the world. Our main aim is to understand how this parasite infects humans and the mechanisms it uses to evade host immune responses as this knowledge is critical in identifying and designing new treatments and vaccines urgently required for this disease.
Research theme
Infectious diseases
Scientific discipline
- Chemistry
- Medicinal Chemistry
- Structural Biology
Keywords
drug discovery, malaria, therapeutic, medicinal chemistry, crystal structure