Anti-plasmodial compound screening & deciphering the mode of action of a putative PI3K inhibitor

Host: Rebecca Edgar

Venue:  Sir Kenneth & Lady Noreen Murray Seminar Room, CTIR 2.84

Malaria remains a major global health threat, killing one person every minute. As resistance to current antimalarial drugs emerge, new antimalarials rapidly need to be developed, with novel modes of action. Malaria symptoms are caused by Plasmodium parasites repeated invasion and lysis of red blood cells during the asexual blood stages (ABS). In addition to targeting symptomatic ABS, activity against sexual stages of Plasmodium, and hence, transmission‑blocking activity is also essential to sustainably control the disease. In an effort to discover new anti-plasmodial molecules, I have screened two libraries against P. falciparum ABS, taking two approaches: (1) leveraging the underexplored chemical diversity of natural products, and (2) re-purposing small molecules targeting various signalling pathways in human cells. (1) The Pierre Fabre Natural Extracts Library is composed of 800 extracts from plants originating from all over the world. I identified 7 extracts able to kill P. falciparum at low concentrations, including 3 never described in the literature previously. Cutting edge chromatography technologies will allow the identification and isolation of active molecules. (2) Upon screening a library of over 200 small molecules targeting human ubiquitination and ubiquitination-related pathways, I identified 24 molecules with submicromolar EC50 against the parasite. The most potent compound, BGT-226, is an inhibitor of human phosphatidylinositol 3’-kinase (PI3K). BGT-226 displays an impressive EC50 of 1.3 nM against the ABS, and it also impairs male gamete exflagellation. I am currently investigating this compound further to identify its precise target within the parasite, its mode of action, and characterise its drug-like properties. While in vitro selection of resistant parasites is underway (and no resistant population emerged so far), we are also using advance unbiased proteomics approach to identify target candidates of BGT-226. In parallel, I am testing the inhibition of PfPI3K by BGT-226 with several methods, including the use of reverse genetics.

Biography: After her bachelor and master degrees at EPFL in Lausanne (Switzerland), Coralie conducted her PhD in the lab of Dr Teresa Carvalho, in Melbourne (Australia). She investigated the relationships between the malaria parasite Plasmodium falciparum and its host red blood cell, in particular looking at eryptosis (red blood cell death), and investigating host-targeting compounds. She then continued her work on P. falciparum in the lab of Profs Paul Gilson and Brendan Crabb at the Burnet Institute, where she investigated the mode of action of antimalarial compounds from the MMV Pathogen Box. More recently, she came back to Europe to investigate ubiquitination pathways in P. falciparum, in the lab of Prof Mathieu Brochet at the University of Geneva (Switzerland). Throughout this research, she reconnected with her interest in discovering new antimalarial compounds and deciphering their modes of action.