Cowman Lab

Plasmodium falciparum, the deadliest malaria-causing parasite, invades and multiplies within human red blood cells. The parasite first attaches to the red blood cell and its proteins bind to the receptors on the red blood cell surface.
We try to understand the interactions between the parasite and the host cell that lead to successful invasion. Targeted protein depletion or antibody-mediated blocking of these interactions prevents the parasite from entering the red blood cell. Hence, it provides an attractive target for vaccine development.

Project resource: https://youtu.be/274N1V5Wucc
Video of malaria parasites (blue) invading red blood cells (purple) and a Ca2+ signalling event (yellow), captured by lattice light sheet microscopy. Credit Cindy Evelyn.

Once inside the red blood cell, the parasite modifies it so that the cell can provide a safe environment for parasite growth and replication. To achieve this, the parasite produces a huge number of proteins which are then delivered to various destinations within the red blood cell. Inhibition of this protein trafficking kills the parasite, so we try to understand the mechanisms of this process and how we can stop it.

New treatments for malaria are urgently needed due to rapidly developing resistance to existing medications. Our research team, in collaboration with Merck & Co., Inc., has identified a novel class of drug-like molecules that prevent malaria parasites growing in human red blood cells, known as dual plasmepsin IX/X inhibitors. With the support of a $4.6 million grant from the Wellcome Trust we have been working to improve these molecules and to test them against all parasite lifecycle stages. By characterising the drug targets, identifying their mode of action at all stages of the parasite lifecycle and studying their resistance profile, we can better understand the biology of the malaria parasite and how to kill it effectively with these new treatments. Our dual plasmepsin inhibitors have been shown to robustly kill parasites at multiple stages of the parasite lifecycle and have a high barrier to resistance, making them ideal antimalarial drug candidates. As a result, our lead drug candidate is currently undergoing Phase I clinical trials in humans, and has the potential to become a new antimalarial drug, with the hope of contributing to the eradication of malaria.

Malaria-causing parasites are transmitted by mosquitoes that have fed on the blood of infected individuals. The mosquito is infected with parasite gametocytes, which undergo sexual reproduction inside the mosquito and give rise to sporozoites. Sporozoites reside in the salivary gland of the mosquito and are able to invade human hepatocytes when the mosquito feeds again. Our lab tries to understand these processes and how to block them. We have identified enzymes required for sporozoite formation and are now trying to understand their function. We are also interested in innovative ways to limit malaria transmission. WEHI’s mosquito insectary enables us to conduct research on malaria transmission. Team members: Tup Reaksudsan, Julie Healer, Melissa Hobbs

Protein degradation, rather than inhibition, is a potent strategy for disrupting protein function. PROTACs are drugs that hijack the cell’s own ubiquitination machinery to degrade pathogenic proteins. Using malaria parasite specific PROTACs and by improving our understanding of the parasites own protein degradation system, we aim to destabilise functions essential for parasite survival in humans. By their unique mechanism of action, PROTACs can also bypass traditional drug resistance pathways.

To achieve these aims we will be using a combination of cutting-edge CRISPR/Cas9 mediated gene-editing of human malaria parasites, chemical biology, and structural biology.

To better understand core processes regulating malaria parasite transmission to mosquitoes and its development at the host-vector interface we use functional proteomics approaches, including Thermal Proteome Profiling (TPP) and Limited Proteolysis Mass Spectrometry (Lip-MS). TPP and Lip-MS allow proteome-wide readout of protein stability, which is influenced by protein interactions with diverse physiological ligands, other proteins or structural modifications.

We further leverage these orthogonal approaches for drug target-identification studies and characterisation of the mechanism of action of transmission-blocking antimalarials.