Target indicators and mechanistic function of epidrugs with activity against multiple stages of Plasmodium falciparum parasites

Abstract

Resistance to the most widely used drugs in the treatment of malaria, those in artemisinin-based combination therapies, has emerged, most recently in Africa. Development of new drugs that exploit unique structures with new modes of action (MoA) is therefore critical. There is also a need for the development of compounds with transmission-blocking activity, in addition to the clearance of symptom-causing stages associated with drugs currently part of the chemotherapeutic toolbox. A promising avenue of research in this regard is into epigenetic drugs (“epidrugs”), which target epigenetic mechanisms of transcriptional control, resulting in parasite death through perturbation of gene expression. A selection of compounds with demonstrated epigenetic perturbation in human cancer cell lines have shown favourable inhibitory profiles against Plasmodium falciparum parasites. For a number of these compounds, the specific mode of action remained to be elucidated and characterised. This dissertation has contributed to our understanding of these compounds’ modes of action, demonstrating perturbation of histone post-translational modifications, and revealing possible binding modes to putative targets through in silico predictions. Findings confirmed histone deacetylase inhibition for both Scriptaid and Sirtinol, with histone deacetylase 1 (PfHDAC1) and sirtuin 2A (PfSir2A), respectively, indicated as the targets of these compounds through in silico docking studies. ML324 was found to exhibit histone demethylase activity in P. falciparum late-stage gametocytes, with PfJmj3 indicated as the target of this compound. Finally, the potential of these compounds as transmission-blocking drugs has been revealed through exflagellation inhibition assays and confirmed with standard membrane-feeding assays. These results underscore the potential of epigenetic transcriptional control as a targetable biology, and of epidrugs to contribute towards addressing the development of drug resistance by P. falciparum. The findings demonstrated in this dissertation may lay the groundwork for future drug development efforts for which the epigenetic drugs discussed here may serve as chemical scaffolds.