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.

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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

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

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;:10.1111/febs.70038

Ashton TD, Calic PPS, Dans MG, Ooi ZK, Zhou Q, Loi K, Jarman KE, Palandri J, Qiu D, Lehane AM, Maity B, De N, Famodimu MT, Delves MJ, Mao EY, Gancheva MR, Wilson DW, Chowdury M, de Koning‐Ward TF, Baud D, Brand S, Jackson PF, Cowman AF, Sleebs BE. Lactam Truncation Yields a Dihydroquinazolinone Scaffold with Potent Antimalarial Activity that Targets PfATP4. ChemMedChem. 2024;19(24):10.1002/cmdc.202400549

Awalt JK, Su W, Nguyen W, Loi K, Jarman KE, Penington JS, Ramesh S, Fairhurst KJ, Yeo T, Park H, Uhlemann A-C, Maity BC, De N, Mukherjee P, Chakraborty A, Churchyard A, Famodimu MT, Delves MJ, Baum J, Mittal N, Winzeler EA, Papenfuss AT, Chowdury M, de Koning-Ward TF, Maier AG, van Dooren GG, Baud D, Brand S, Fidock DA, Jackson PF, Cowman AF, Dans MG, Sleebs BE. Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b. European Journal of Medicinal Chemistry. 2024;280:10.1016/j.ejmech.2024.116921

Calic PPS, Ashton TD, Mansouri M, Loi K, Jarman KE, Qiu D, Lehane AM, Roy S, Rao GP, Maity B, Wittlin S, Crespo B, Gamo F-J, Deni I, Fidock DA, Chowdury M, de Koning-Ward TF, Cowman AF, Jackson PF, Baud D, Brand S, Laleu B, Sleebs BE. Optimization of pyrazolopyridine 4-carboxamides with potent antimalarial activity for which resistance is associated with the P. falciparum transporter ABCI3. European Journal of Medicinal Chemistry. 2024;276:10.1016/j.ejmech.2024.116677

Dans MG, Boulet C, Watson GM, Nguyen W, Dziekan JM, Evelyn C, Reaksudsan K, Mehra S, Razook Z, Geoghegan ND, Mlodzianoski MJ, Goodman CD, Ling DB, Jonsdottir TK, Tong J, Famodimu MT, Kristan M, Pollard H, Stewart LB, Brandner-Garrod L, Sutherland CJ, Delves MJ, McFadden GI, Barry AE, Crabb BS, de Koning-Ward TF, Rogers KL, Cowman AF, Tham W-H, Sleebs BE, Gilson PR. Author Correction: Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1. Nature Communications. 2024;15(1):10.1038/s41467-024-52849-7

Ashton TD, Calic PPS, Dans MG, Ooi ZK, Zhou Q, Palandri J, Loi K, Jarman KE, Qiu D, Lehane AM, Maity BC, De N, Giannangelo C, MacRaild CA, Creek DJ, Mao EY, Gancheva MR, Wilson DW, Chowdury M, de Koning-Ward TF, Famodimu MT, Delves MJ, Pollard H, Sutherland CJ, Baud D, Brand S, Jackson PF, Cowman AF, Sleebs BE. Property and Activity Refinement of Dihydroquinazolinone-3-carboxamides as Orally Efficacious Antimalarials that Target PfATP4. Journal of Medicinal Chemistry. 2024;67(16):10.1021/acs.jmedchem.4c01241

McConville R, Krol JMM, Steel RWJ, O’Neill MT, Davey BK, Hodder AN, Nebl T, Cowman AF, Kneteman N, Boddey JA. Flp/FRT-mediated disruption of ptex150 and exp2 in Plasmodium falciparum sporozoites inhibits liver-stage development. Proceedings of the National Academy of Sciences of the United States of America. 2024;121(28):10.1073/pnas.2403442121

Dans MG, Boulet C, Watson GM, Nguyen W, Dziekan JM, Evelyn C, Reaksudsan K, Mehra S, Razook Z, Geoghegan ND, Mlodzianoski MJ, Goodman CD, Ling DB, Jonsdottir TK, Tong J, Famodimu MT, Kristan M, Pollard H, Stewart LB, Brandner-Garrod L, Sutherland CJ, Delves MJ, McFadden GI, Barry AE, Crabb BS, de Koning-Ward TF, Rogers KL, Cowman AF, Tham W-H, Sleebs BE, Gilson PR. Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1. Nature Communications. 2024;15(1):10.1038/s41467-024-49491-8