Development of novel antimalarials targeting the plasmodial lactate transporter (PfFNT) through a fluorescence cross-correlation spectroscopy-based approach and functional assay

Drug resistance is a significant obstacle in the fight against malaria, prompting the exploration of new treatment approaches and drug targets. One potential target is the recently discovered plasmodial lactate transporter, PfFNT (short for Plasmodium falciparum formate-nitrite transporter). Several studies have shown that inhibiting this transporter can cause the accumulation of toxic levels of lactate within the parasite, leading to its death. Two compounds, BH296 and BH267.meta, have been developed to target both the PfFNT wild type (wt) and a relevant mutant, G107S. So far, these compounds have only been tested using a yeast-based functional assay, and biophysical characterization was missing. In this study, fluorescence cross-correlation spectroscopy (FCCS) measurements were performed to determine true Ki-values, as well as kon and koff rate constants for the binding of inhibitors to both the PfFNT wt and G107S mutant. Once the reliability of FCCS measurements had been confirmed, a compound library of 2,000 inhibitors was screened to identify novel scaffolds that have the potential to inhibit PfFNT. FCCS only allows the search for new inhibitors that displace the existing inhibitor, i.e., share the same binding pocket. To identify an alternative binding site, a functional screening assay with AZD3965 and Metformin was developed in this thesis.


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