Dr Brad Sleebs, Lab Head | WEHI Researcher Profile

Q: Design of novel antimalarial agents.

Malaria is a devastating disease that results in 460,000 deaths annually. Our laboratory is contributing to the global effort to develop novel small molecule therapies to treat and eliminate malaria. Our team is currently optimising several small molecule classes identified from phenotypic screening of the malaria parasite. The antimalarial classes exert differential activity against multiple stages of the parasite’s lifecycle and therefore have potential as a prophylactic, a curative therapy or being used to eliminate malaria from endemic regions. We are also employing chemical biology and genetic techniques to identify the mechanism of action of the small molecule classes under development.

Q: Targeting aspartyl proteases in the malaria and cryptosporidium parasites.

The malaria parasite encodes ten cathepsin D-like and one viral aspartyl protease. Our laboratory is focused on developing small molecule tools and developing genetic models to help understand the essential role of these aspartyl proteases in malaria parasite survival. This research has established the essentiality of several malaria aspartyl proteases and therefore suggesting these are attractive antimalarial drug targets. In the next phase of our research, we have identified drug-like starting points independently targeting several essential aspartyl proteases of the malaria and the closely related cryptosporidium parasite. Our team is currently developing these small molecule classes as potential therapeutics to treat malaria and cryptosporidiosis.

Q: Development of nematicides to treat human and animal helminthiases.

Parasitic worms (helminths) infect 50% of the human population and represent a major socioeconomic burden i due to the helminthiases that they cause in agriculture. Treatment failures and evidence of anthelmintic resistance are limiting treatment options, such that there is an unmet need for new treatment strategies. Using molecular techniques and high throughout put screening, we have identified multiple small molecule classes with nematicide activity. Our aim is to use medicinal chemistry methods to optimise potency of these small molecules to achieve improve efficacy against nematode worms in vitro and ultimately in mouse models. A secondary aim is to use genomic and proteomic methods to understand the mechanism by which the small molecules under development kill nematodes.

About

Our laboratory focuses on chemical biology approaches at a basic research level to identify and understand new biological mechanisms. We also concentrate on harnessing medicinal chemistry methods to target biological processes with the aim to develop new small molecules therapeutics.

We have strong collaborations with researchers both within our institute and externally, across a variety of disciplines, including:

high throughput screening
structural biology
parasitology
oncology

Our team works closely with industry partners in several drug discovery programs dedicated to developing new therapeutics in the cancer and infectious disease fields.

Our laboratory has interests in:

Design of small molecule inhibitors of aspartyl proteases to understand their role in the malaria and cryptosporidiosis.
Design of small molecules to target SH2 domain proteins to investigate their role in inflammation and cancer.
Identification of the mechanism of action of small molecule antimalarials currently under optimisation in our laboratory.
Development of small molecule therapies to treat human and animal helminthiasis.

Education

Joint appointments

Grants and funding

Publications

Selected publications from Dr Brad Sleebs

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;:10.1021/acs.jmedchem.5c00614

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

Duffy S, Sleebs BE, Avery VM. An adaptable, fit-for-purpose screening approach with high-throughput capability to determine speed of action and stage specificity of anti-malarial compounds. Antimicrobial Agents and Chemotherapy. 2024;68(10):10.1128/aac.00746-24

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

Shanley HT, Taki AC, Nguyen N, Wang T, Byrne JJ, Ang C-S, Leeming MG, Williamson N, Chang BCH, Jabbar A, Sleebs BE, Gasser RB. Comparative structure activity and target exploration of 1,2-diphenylethynes in Haemonchus contortus and Caenorhabditis elegans. International Journal for Parasitology Drugs and Drug Resistance. 2024;25:10.1016/j.ijpddr.2024.100534

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