WEHI PhD Completion Seminar hosted by Dr Madeline Dans

Wenyin Su

PhD Student – Sleebs and Cowman Laboratories

ACRF Chemical Biology division – New Medicines & Advanced Technologies Theme

Infectious Diseases & Immune Defence division – Infection, Inflammation & Immunity Theme

WEHI

Chemical genetics of plasmepsin V and cytochrome b

 

Davis Auditorium

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Including Q&A session

Malaria is caused by the Plasmodium parasite and causes more than 600,000 deaths worldwide annually. The emergence of resistance against almost all antimalarial drugs has now become an obstacle to eliminating the disease. To address the issue, there is an urgent need for the discovery and development of new antimalarials with novel mechanisms of action. This research seminar describes the application of chemo-genetic and chemo-proteomic methods to independently investigate the mechanism of action of two antimalarial classes.

Plasmepsin V (PMV) is an aspartyl protease that is essential for processing the N-terminal PEXEL motif of proteins licensing them for export to the host red blood cell during the asexual segment of malaria parasite’s lifecycle. Small molecule peptidomimetics mimicking the PEXEL motif have been previously developed as potent inhibitors of PMV. The peptidomimetics have been shown to block protein export and kill the malaria parasite, although confirmation of their on-target activity was required. During my PhD, after resistance selection and genome sequencing revealed a mutation in PMV, I reversed engineered parasites to confirm the mutation in PMV. I also applied biased and unbiased chemo-proteomics to demonstrate on-target engagement of PMV in P. falciparum parasites, definitively showing that the peptidomimetics kill the parasite by targeting PMV.

Separately, to uncover new starting points for antimalarial development, a phenotypic screen of the Janssen Jumpstarter library against the asexual stage parasite uncovered the cyclopropyl carboxamide hit class. I performed forward genetics to identify the mechanism of action of the hit class. Whole genome sequencing of cyclopropyl carboxamide-resistant parasites uncovered mutations in the Qo site of cytochrome b, which is an essential component of the mitochondrial electron transport chain. Cytochrome b was confirmed as the molecular target by evaluating cyclopropyl carboxamide analogs against cytochrome b resistant parasite lines, and in a mitochondrial functional assay supporting this antimalarial class targeting cytochrome b.

All welcome!