Principal Investigator (PI)
The Structural Genomics Consortium, Structural and Chemical Parasitology lab (Oxford and Toronto).
The Foundation is providing £189,618 in support.
Dr. Cynthia Tallant
The focus of the project will be the exploration of new antimalarial targets involved in parasite transcriptional regulation, such as the histone methyltransferase (HMT) SET1, and protein biosynthesis pathways controlled by the ribosomal translation elongation factor 2 (eEF2).
A number of histone methyltransferase inhibitors have been shown to inhibit parasite growth in the intraerythrocytic cycle in both P. falciparum and P. vivax ex vivo experiments. Concomitantly, these same compounds were shown to reduce H3K4me3 methylation levels in parasites. Additional genetic studies in P. falciparum showed that some of these genes are essential for the parasite in the asexual blood stage. Recently, a novel antimalarial compound DDD107498 has been discovered and publicly discosed. This compound has excellent drug-like properties and exhibits a potent activity profile against multiple life-cycle stages of the parasite. Its molecular target has been identified as the translation elongation factor 2 (eEF2) using whole genome sequencing of resistant cell lines treated with DDD107498. This finding nominates PfEF2 as a novel antimalarial target. Together, the proposal aims to identify chemically diverse compounds targeting these two classes of enzymes, with activity against resistant mutants and inert to the human orthologues.