Targeting epigenetic regulators for antimalarial development

Malaria, caused by Plasmodium parasites, remains a global health issue, with 249 million new cases in 2022. Plasmodium falciparum, the deadliest species, shows growing drug resistance, threatening control efforts. This project investigates how epigenetic mechanisms, changes in gene expression without altering DNA, control the parasite's life cycle and survival. Unlike many organisms, P. falciparum has few transcription factors, relying heavily on epigenetic regulation, such as histone modifications, to manage gene activity. These modifications, including acetylation and methylation, are added or removed by proteins called writers, erasers, and readers. This study focuses on four key proteins, PfMYST, PfBDP6, PfSET3, and PfBDP1, believed essential for parasite survival based on prior genetic screens.

The aims are to confirm these proteins' importance, explore their potential as drug targets, and understand their roles in gene regulation. Using CRISPR gene editing, conditional knockouts will test if these proteins are vital for the parasite. Chemical probes, compounds that inhibit similar proteins in humans, will be tested against P. falciparum to identify effective inhibitors. The project will also assess how genetic and chemical changes affect parasite growth, life cycle transitions, and immune evasion genes using lab assays and sequencing. Methods include growing parasites in human blood, editing their genes, and testing drug responses over 72 hours. The goal is to provide new insights into the biology of the malaria parasite, which may in turn lead to the identification of targets for future treatments, addressing the urgent need for novel therapies as resistance to current drugs like artemisinin rises.