Prof Alan Cowman AC, Lab Head | WEHI Researcher Profile

Q: How do malaria parasites invade red blood cells?

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/274N1V5WuccVideo of malaria parasites (blue) invading red blood cells (purple) and a Ca2+ signalling event (yellow), captured by lattice light sheet microscopy. Credit Cindy Evelyn.

Q: How does the malaria parasite survive inside the red blood cell?

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.

Q: Development of novel antimalarial drugs

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.

Q: Parasite transmission into and from the mosquito

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

Q: Overcoming drug resistance in malaria parasites

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.

Q: Functional proteomics of malaria parasite

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.

About

Our research is aimed at understanding how Plasmodium falciparum, the parasite that causes the most severe form of malaria, infects humans and causes disease.

We focus on three major aspects of malaria:
– Understanding how the parasite invades human red blood cells. This will help us to develop a vaccine that prevents the parasite from infecting red blood cells.
– Studying how the parasite survives inside the red blood cell. This will help us to develop new treatments which will kill the parasite once it is present inside the human body.
– Combining our expertise in structural biology and chemistry, we develop novel antimalarial drugs in collaboration with pharmaceutical companies.

We are an interdisciplinary team, combining expertise in cell biology, imaging, structural studies and biological chemistry. We look for novel approaches and unconventional thinking to combat malaria.

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Selected publications from Prof Alan Cowman AC

2025;

Kongsomboonvech AK, Scally SW, Le Guen Y, Valissery P, Salinas ND, Cowman AF, Tolia NH, Egan ES. CD44 cross-linking promotes Plasmodium falciparum invasion. Nature Communications. 2025;:10.1038/s41467-025-67030-x

Favuzza P, Palandri J, de Lera Ruiz M, Bailey W, Boyce CW, Danziger A, Fawaz MV, Kelly M, Murgolo N, Robbins JA, Vavrek M, Zhao L, Lei Z, Guo Z, Reaksudsan K, Steel RWJ, Hodder AN, Ngo A, Dziekan JM, Thompson JK, Triglia T, Birkinshaw RW, Penington JS, Scally SW, Dans MG, Coyle R, Sevilleno N, Orban A, Feufack-Donfack LB, Popovici J, Lee MCS, Papenfuss A, Lowes KN, Sleebs BE, McCarthy JS, McCauley JA, Boddey JA, Olsen DB, Cowman AF. MK-7602: a potent multi-stage dual-targeting antimalarial. EBioMedicine. 2025;123:10.1016/j.ebiom.2025.106061

Anton L, Cheng W, Haile MT, Dziekan JM, Cobb DW, Zhu X, Han L, Li E, Nair A, Lee CL, Wang H, Ke H, Zhang G, Doud EH, Cowman AF, Ho C-M. Integrated structural biology of the native malarial translation machinery and its inhibition by an antimalarial drug. Nature Structural & Molecular Biology. 2025;32(11):10.1038/s41594-025-01632-3

Kongsomboonvech AK, Scally SW, Le Guen Y, Valissery P, Salinas ND, Cowman AF, Tolia NH, Egan ES. CD44 cross-linking promotes Plasmodium falciparum invasion. 2025;:10.1101/2025.07.30.667750

Marapana D, Cobbold SA, Pasternak M, Shami GJ, Ralph SA, Lopaticki S, Yousef J, Vaibhav V, Dagley LF, Komander D, Cowman AF. Functional characterisation of components in two Plasmodium falciparum Cullin-RING-Ligase complexes. Scientific Reports. 2025;15(1):10.1038/s41598-025-05342-0

Hodder AN, Sleebs BE, Adams G, Rezazadeh S, Ngo A, Jarman K, Scally S, Czabotar P, Wang H, McCauley JA, Olsen DB, Cowman AF. Structure–activity analysis of imino‐pyrimidinone‐fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors. The FEBS Journal. 2025;292(11):10.1111/febs.70038

Cowman A, Seager B, Lim P, Lai K-H, Feufack-Donfack L, Dass S, Xiao X, Jung N, Abraham A, Grigg M, Anstey N, William T, Sattabongkot J, Leis A, Longley R, Duraisingh M, Popovici J, Wilson D, Scally S. PTRAMP, CSS and Ripr form a conserved complex required for merozoite invasion of Plasmodium species into erythrocytes. 2025;:10.21203/rs.3.rs-6292540/v1

Awalt JK, Ooi ZK, Ashton TD, Mansouri M, Calic PPS, Zhou Q, Vasanthan S, Lee S, Loi K, Jarman KE, Penington JS, Qiu D, Zhang X, Lehane AM, Mao EY, Gancheva MR, Wilson DW, Giannangelo C, MacRaild CA, Creek DJ, Yeo T, Sheth T, Fidock DA, Churchyard A, Baum J, Famodimu MT, Delves MJ, Kristan M, Stewart L, Sutherland CJ, Coyle R, Jagoe H, Lee MCS, Chowdury M, de Koning-Ward TF, Baud D, Brand S, Jackson PF, Cowman AF, Dans MG, Sleebs BE. Optimization and Characterization of N‑Acetamide Indoles as Antimalarials That Target PfATP4. Journal of Medicinal Chemistry. 2025;68(8):10.1021/acs.jmedchem.5c00614

Seager BA, Lim PS, Lai KH, Feufack-Donfack LB, Dass S, Xiao X, Jung NC, Abraham A, Grigg MJ, Anstey NM, William T, Sattabongkot J, Leis A, Longley RJ, Duraisingh MT, Popovici J, Wilson DW, Scally SW, Cowman AF. PTRAMP, CSS and Ripr form a conserved complex required for merozoite invasion of Plasmodium species into erythrocytes. 2025;:10.1101/2025.03.25.644866

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Lab research projects

How do malaria parasites invade red blood cells?

How does the malaria parasite survive inside the red blood cell?

Development of novel antimalarial drugs

Parasite transmission into and from the mosquito

Overcoming drug resistance in malaria parasites

Functional proteomics of malaria parasite

Student research projects

Exploiting malarial invasion proteins for novel malaria vaccines

Honours/Masters by Coursework/PhD

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Exploiting malarial invasion proteins for novel malaria vaccines

Honours/Masters by Coursework/PhD

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View all student research projects

Prof Alan Cowman AC

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