In this Webinar, You Will Learn:
• Cutting-edge models for characterising antimalarials at an early stage of development
• Approaches for identifying the mechanism of action of antimalarials
• Antimalarial drug targets essential for regulating Na+ homeostasis
About this Webinar:
Malaria, caused by the Plasmodium parasite, remains a serious global health threat. The emergence of drug resistance raises concerns that the current arsenal of clinically approved artemisinin-based combination therapies and experimental drug candidates may not be sufficient for disease elimination. This highlights the urgent need to continuously develop new antimalarial compounds to expand the clinical portfolio.
To support the global effort to treat and eliminate malaria, we screened libraries of drug-like small molecules against the asexual blood stage of P. falciparum, identifying hit classes with diverse chemical scaffolds. These hit classes demonstrated potent antiplasmodial activity without exhibiting cytotoxic effects on human cell lines, making them promising candidates for antimalarial development.
This presentation explores the optimisation and characterisation of multistage antimalarial activity while investigating the mechanisms of action of two exemplar hit classes. Through forward genetics, we identified the molecular targets of these novel antimalarials, which were validated via cross-resistance assays and reverse genetics. The optimised compounds displayed multistage efficacy and showed effectiveness in mosquito transmission models and asexual mouse models, underscoring their potential as multistage antimalarial therapies.
About the Brad Sleebs, PhD:
Dr Sleebs is a Laboratory Head in the New Medicines and Diagnostics Division at the Walter and Eliza Hall Institute. His past research includes the development of anxiolytics in collaboration with Bionomics, as well as agents targeting the BH3 family of proteins for the treatment of blood cancers in collaboration with Genentech and AbbVie. His current research focuses on developing small-molecule probes to better understand biological processes that are essential to the survival of parasites that impact both human and animal health. In parallel, Dr Sleebs leads drug discovery programs to design new therapeutics to treat parasitic diseases in collaboration with academic and industry partners, including Janssen Pharmaceuticals, Medicines for Malaria Venture, and MSD.
Selected Publications
[1]. 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 LM, 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. J Med Chem. 2025.
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[2]. 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. J Med Chem. 2025, 68(8), 8933-8966.
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[3]. 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. J Med Chem. 2024, 67(16), 14493-14523.
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[4]. Ashton TD, Dans MG, Favuzza P, Ngo A, Lehane AM, Zhang X, Qiu D, Chandra Maity B, De N, Schindler KA, Yeo T, Park H, Uhlemann AC, Churchyard A, Baum J, Fidock DA, Jarman KE, Lowes KN, Baud D, Brand S, Jackson PF, Cowman AF, Sleebs BE. Optimization of 2,3-Dihydroquinazolinone-3-carboxamides as Antimalarials Targeting PfATP4. J Med Chem. 2023, 66(5), 3540-3565.
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[5]. 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 WH, Sleebs BE, Gilson PR. Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1. Nat Commun. 2024, 15(1), 5219.
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