ABSTRACT
Malaria is a mosquito-borne infectious disease, with its most severe form caused by the protozoan parasite Plasmodium falciparum. The rapid emergence and spread of drug‑resistant parasites demand new therapeutic strategies. As an obligate intracellular pathogen, P. falciparum invades and proliferates within human erythrocytes. To ensure the development and survival, the parasite needs to modify host molecules to make the host cells habitable. Increasing evidence indicates that host kinases within the erythrocytes are activated upon parasite infection, suggesting a potential role for host signal transduction in the parasite life cycle. This raises the possibility of targeting host kinases as a host-directed antimalarial strategy that offers key advantages. These include a reduced likelihood of resistance development by targeting host-encoded factors rather than parasite proteins, as well as the opportunity to repurpose the extensive libraries of kinase inhibitors developed for other diseases such as cancer, thereby accelerating and reducing the costs of antimalarial drug discovery.

During my PhD, I investigated the therapeutic potential of host kinases involved in the Akt/PI3K and MAPK signalling pathways during P. falciparum infection. Multiple host kinases associated with these pathways were found to be modulated upon parasite infection. In addition, inhibitors corresponding to several of these kinases exhibited activity against both asexual blood-stage parasites and sexual-stage gametocytes, suggesting potential dual-stage efficacy with both curative and transmission-blocking properties. However, subsequent mechanistic investigations provided limited evidence that the observed antimalarial activity was mediated through host-directed mechanisms, instead indicating parasite-encoded targets. Although host kinases of these pathways seem not to be an effective target to fight malaria, I have identified various inhibitors that kill the parasite directly with sub-micromolar efficacy. This represents an exciting avenue for the future development of novel antimalarial therapies.

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