Activity-based protein profiling of human and plasmodium serine hydrolases and interrogation of potential antimalarial targets
More about Open Access at the CrickAbstract
Malaria remains a global health issue requiring the identification of novel therapeutic targets to combat drug resistance. Metabolic serine hydrolases are druggable enzymes playing essential roles in lipid metabolism. However, very few have been investigated in malaria-causing parasites. Here, we used fluorophosphonate broad-spectrum activity-based probes and quantitative chemical proteomics to annotate and profile the activity of more than half of predicted serine hydrolases in P. falciparum across the erythrocytic cycle. Using conditional genetics, we demonstrate that the activities of four serine hydrolases, previously annotated as essential (or important) in genetic screens, are actually dispensable for parasite replication. Of importance, we also identified eight human serine hydrolases that are specifically activated at different developmental stages. Chemical inhibition of two of them blocks parasite replication. This strongly suggests that parasites co-opt the activity of host enzymes and that this opens a new drug development strategy against which the parasites are less likely to develop resistance.
Journal details
Journal iScience
Volume 25
Issue number 9
Pages 104996
Available online
Publication date
Full text links
Publisher website (DOI) 10.1016/j.isci.2022.104996
Europe PubMed Central 36105595
Pubmed 36105595
Keywords
Related topics
Type of publication