A/Prof 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 A/Prof Brad Sleebs

Taki AC, Sleebs BE, Wells TNC, Keiser J, Gasser RB. Early-stage anthelmintic discovery: Integrating phenotype, target and mechanism. Biotechnology Advances. 2026;93:10.1016/j.biotechadv.2026.109008

Yek K, Apolloni FL, Xu B, Nguyen NH, Ziegler AR, Scott NE, Sleebs BE, Edgington‐Mitchell LE. Integration of Chemical Probes and Degradomics Reveals That Cathepsin B Functions Primarily as a Dipeptidyl Carboxypeptidase in Macrophages. ChemMedChem. 2026;21(21):10.1002/cmdc.70530

Sleebs BE. Plasmepsins as Antimalarial Drug Targets—Then, Now, and the Future. Medicinal Research Reviews. 2026;46(6):10.1002/med.70065

Kaethner M, Young ND, Sleebs BE, Lee EF, Fairlie WD, Gasser RB. Comparative reconstruction of intrinsic apoptosis in clade V nematodes reveals a conserved execution module and heterogeneous regulatory architecture. Computational and Structural Biotechnology Journal. 2026;:10.34133/csbj.0239

Adams G, Dans MG, Zhou Q, Su W, Ngo A, Jarman KE, Fawaz MV, Kelly MJ, McCauley JA, Olsen DB, Boddey JA, Cowman AF, Sleebs BE. Activity Refinement and Property Assessment of Peptidomimetics with Potent Antimalarial Activity That Target Plasmepsin V. ACS Infectious Diseases. 2026;12(9):10.1021/acsinfecdis.6c00314

Kaethner M, Young ND, Lee EF, Fairlie WD, Sleebs BE, Chang BCH, Gasser RB. Intrinsic apoptosis in nematodes: Evolutionary plasticity and biotechnological opportunities. Biotechnology Advances. 2026;90:10.1016/j.biotechadv.2026.108911

Favuzza P, Dans MG, Su W, Thompson JK, Hodder AN, Ngo A, Penington JS, Marapana DS, Dziekan JM, Papenfuss AT, de Lera Ruiz M, Coyle R, Lee MCS, McCauley JA, Lowes K, Olsen DB, Sleebs BE, Cowman AF. Dual plasmepsin IX and X inhibitors are refractory to development of resistance. PLOS Pathogens. 2026;22(9):10.1371/journal.ppat.1014068

Dans M, Awalt JK, Nguyen N, Palandri J, Ngo A, Jarman KE, Jeon JH, Yeo T, Park H, Uhlemann A-C, Mao EY, Gancheva MR, Wilson DW, Mukherjee P, Chakraborty A, Kristan M, Stewart L, Sutherland CJ, Baud D, Brand S, Fidock DA, Jackson PF, Cowman AF, Sleebs BE. 2‑Amino-3,4-Dihydroquinazolines Exhibit Potent Antimalarial Activity by Targeting Plasmepsin X. ACS Infectious Diseases. 2026;12(8):10.1021/acsinfecdis.6c00258

Barnes CB, Schneider MP, Ventura OD, Razook Z, McCann K, Boulet C, Literski AH, Barry AE, Sleebs BE, Crabb BS, Gilson PR, Bullen HE. Unpacking boxes: identification of novel inhibitors of malaria parasite invasion. International Journal for Parasitology Drugs and Drug Resistance. 2026;31:10.1016/j.ijpddr.2026.100647

Shen Y, Young ND, Song J, Sleebs BE, Chang BCH, Lee EF, Fairlie WD, Gasser RB. Genome-wide reconstruction of the intrinsic apoptosis pathway in Haemonchus contortus. BMC Genomics. 2026;27(1):10.1186/s12864-026-12596-z