Year: 2024
Type: article
Abstract: Parasites, such as the malaria parasite P. falciparum, are critically dependent on host nutrients. Interference with nutrient uptake can lead to parasite death and, therefore, serve as a successful treatment strategy. P. falciparum parasites cannot synthesise cholesterol, and instead source this lipid from the host. Here, we tested whether cholesterol uptake pathways could be 'hijacked' for optimal drug delivery to the intracellular parasite. We found that fluorescent cholesterol analogues were delivered from the extracellular environment to the intracellular parasite. We investigated the uptake and inhibitory effects of conjugate compounds, where proven antimalarial drugs (primaquine and artesunate) were attached to steroids that mimic the structure of cholesterol. These conjugated antimalarial drugs improved the inhibitory effects against multiple parasite lifecycle stages, multiple parasite species, and drug-resistant parasites, whilst also lowering the toxicity to human host cells. Steroids with introduced peroxides also displayed antimalarial activity. These results provide a proof-of-concept that cholesterol mimics can be developed as a drug delivery system against apicomplexan parasites with the potential to improve drug efficacy, increase therapeutic index, and defeat drug resistance.
Source: EMBO Molecular Medicine
Authors: Merryn Fraser, Blake Curtis, Patrick Phillips, Patrick A Yates, Kwong Sum Lam, Otto Netzel, Giel G van Dooren, Alyssa Ingmundson, Kai Matuschewski, Malcolm D McLeod, Alexander G Maier
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,890
Funders: Australian Government, Australian National University, Deutsche Forschungsgemeinschaft, Department of Health and Aged Care, Australian Government, Department of Education and Training, Department of Education, Skills and Employment, Australian Government, Medical Research Council, Australian Research Council, National Health and Medical Research Council
OpenAlex ID: W4399542270