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

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

Su W, Nguyen W, Siddiqui G, Dziekan JM, Marapana D, Penington JS, Mehra S, Razook Z, McCann K, Ngo A, Jarman KE, Barry AE, Papenfuss AT, Gilson PR, Creek DJ, Cowman AF, Sleebs BE, Dans MG. Deconvolution of the On-Target Activity of Plasmepsin V Peptidomimetics in Plasmodium falciparum Parasites. ACS Infectious Diseases. 2025;:10.1021/acsinfecdis.5c00742

Mao EY, Nguyen W, Jana GP, Maity BC, Pazicky S, Giannangelo C, Reader J, Famodimu MT, Birkholtz L-M, Delves MJ, Creek DJ, Bozdech Z, Laleu B, Burrows JN, Sleebs BE, Gancheva MR, Wilson DW. Characterizing the quick-killing mechanism of action of azithromycin analogs against malaria parasites. Antimicrobial Agents and Chemotherapy. 2025;69(9):10.1128/aac.01783-24

Nguyen W, Boulet C, Dans MG, Loi K, Jarman KE, Barnes CBG, Yeo T, Sheth T, Mukherjee P, Chakraborty A, Famodimu MT, Delves MJ, Pollard H, Sutherland CJ, Coyle R, Sevilleno N, Boonyalai N, Lee MCS, Rabie T, Birkholtz L-M, Baud D, Brand S, Chowdury M, de Koning-Ward TF, Fidock DA, Gilson PR, Sleebs BE. Optimization and Characterization of the Antimalarial Activity of N‑Aryl Acetamides that are Susceptible to Mutations in ROM8 and CSC1. Journal of Medicinal Chemistry. 2025;68(15):10.1021/acs.jmedchem.5c01471

Mao EY, Page SW, Sleebs BE, Gancheva MR, Wilson DW. A review of natural products as a source of next-generation drugs against apicomplexan parasites. npj Antimicrobials and Resistance. 2025;3(1):10.1038/s44259-025-00119-x

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

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

Shanley HT, Wang T, Taki AC, Byrne JJ, Chang BCH, Sleebs BE, Gasser RB. Advances in Anthelmintic Target Identification. International Journal of Molecular Sciences. 2025;26(8):10.3390/ijms26083738

Taki AC, Kapp L, Hall RS, Byrne JJ, Sleebs BE, Chang BCH, Gasser RB, Hofmann A. Prediction and Prioritisation of Novel Anthelmintic Candidates from Public Databases Using Deep Learning and Available Bioactivity Data Sets. International Journal of Molecular Sciences. 2025;26(7):10.3390/ijms26073134

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