1. Investigating the mode of action of 1,3,4- oxadiazoles against malaria parasites
- Author
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Rai, Anjana
- Subjects
- malaria, drug discovery, drug resistance, novel drug target
- Abstract
Malaria, caused by Plasmodium parasites, is one of the world’s most significant infectious diseases. Nearly half of the world’s population is at risk of infection and in 2021 there were >200 million clinical cases of malaria and >600,000 malaria associated deaths. Plasmodium falciparum is responsible for most malaria-related morbidity and mortality, which occurs mainly in sub-Saharan Africa. There is no highly effective vaccine available for malaria, so treatment and prophylaxis rely heavily on antimalarial drugs. Unfortunately, malaria parasite resistance to all clinically used antimalarial drugs, including the gold-standard Artemisinin Combination Therapies (ACTs), is a significant issue and means that new drugs are needed, particularly those with different modes of action to current drugs. Previous work in this laboratory screening the CSIRO Compound Library for antiparasitic agents identified a series of 1,3,4-oxadiazoles (termed CSIRO-96A) as a new anti-plasmodial chemotype with a slow-action phenotype different to known antimalarial drugs. Representative compounds CSIRO-96A-1 and CSIRO-96A-3 were used to select for in vitro resistant P. falciparum parasites, sub-clones of which were found to have mutations in a gene encoding a putative palmitoyltransferase protein belonging to DHHC-CRD S-acyltransferase protein family (PfDHHC7). While the essentiality of pfdhhc7 in the asexual development stage of P. falciparum parasite is not clear, it is known to be expressed in P. falciparum schizonts and merozoites and localises to the rhoptry organelles that are involved in invasion, this protein is otherwise uncharacterised in Plasmodium parasites. Two independent non-synonymous mutations were identified as being associated with resistance to CSIRO-96A compounds, a tyrosine to serine change in amino acid 168 (Y168S) and a glycine to aspartic acid change at 380 (G380D). This led to the working hypothesis investigated in this thesis project, that PfDHHC7 is involved in the anti-plasmodial mode of action (MoA) or resistance mechanism of CSIRO-96A compounds. [...]
- Published
- 2023