Synopsis

Malaria is a devastating disease caused by the Plasmodium parasite. Due to the threat of emerging drug resistance, the current arsenal of clinically used artemisinin combination therapies and drug candidates undergoing clinical assessment may not be sufficient in eliminating the disease. Thus, novel chemotypes that target multiple stages of the parasite lifecycle are required to continually populate the antimalarial clinical portfolio.

To contribute to the global effort to treat and eliminate malaria we have performed a high throughput screen of the Janssen Jumpstarter library of 80,000 drug-like small molecules against the asexual stage of P. falciparum parasite. Several hit classes with unique scaffolds were identified and shown to exhibit sub-micromolar EC₅₀ values against asexual P. falciparum and did not display cytotoxicity towards human cell lines highlighting their attractiveness as starting points for antimalarial development.

This presentation will focus on the optimisation and characterisation of the multistage antimalarial activity of two unique hit scaffolds. The molecular target of the novel scaffolds was established using forward genetic studies, phenotypic models, and drug resistant clinical strains. The optimised scaffolds clear parasitaemia in transmission and asexual mouse models demonstrating their potential for inclusion in a curative or population control antimalarial therapy.

Biography

Dr Sleebs is a Laboratory Head in the Chemical Biology Division at the Walter and Eliza Hall Institute. His past research includes the development of anxiolytics and agents that target the BH3 family of proteins for the treatment of blood cancers. His current research focuses on developing small molecule probes to better understand biological processes that are essential to the survival of the malaria parasite and the progression of cancer malignancies. In parallel, Dr Sleebs leads drug discovery programs in both oncology and infectious diseases in collaboration with institute colleagues and with industry partners.