Abstract
The post-translational farnesylation of proteins serves to anchor a subset of intracellular proteins to membranes in eukaryotic organisms and also promotes protein-protein interactions. Inhibition of protein farnesyltransferase (PFT) is lethal to the pathogenic protozoa Plasmodium falciparum. Parasites were isolated that were resistant to BMS-388891, a tetrahydroquinoline (THQ) PFT inhibitor. Resistance was associated with a 12-fold decrease in drug susceptibility. Genotypic analysis revealed a single point mutation in the beta subunit in resistant parasites. The resultant tyrosine 837 to cysteine alteration in the beta subunit corresponded to the binding site for the THQ and peptide substrate. Biochemical analysis of Y837C-PFT demonstrated a 13-fold increase in BMS-388891 concentration necessary for inhibiting 50% of the enzyme activity. These data are consistent with PFT as the target of BMS-388891 in P. falciparum and suggest that PFT inhibitors should be combined with other antimalarial agents for effective therapy.
Highlights
Malaria causes about 300 million infections annually.1 Approximately 90% of the deaths occur in Africa, with falciparum malaria a major contributor
We have been able to demonstrate that low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFT inhibitors (PFTIs) inhibit P. falciparum protein farnesyltransferase (PFT) (PfPFT) and are cytotoxic to parasites both in vitro and in vivo
BMS-388891-resistant P. falciparum Clones Can Be Selected—Earlier studies demonstrated that P. falciparum 3D7 was highly sensitive to growth inhibition by the THQ PFTI, BMS-388891, with an ED50 of 7.0 nM.3
Summary
Zyme protein farnesyltransferase (PFT) is a viable drug target for pathogenic protozoa, including the malaria parasite Plasmodium falciparum (4 – 8).. PFT inhibitors (PFTIs) have been developed by the pharmaceutical industry because of their anti-cancer properties (9 –11) Utilizing this existing resource, we have been able to demonstrate that low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT (PfPFT) and are cytotoxic to parasites both in vitro and in vivo.. Because of the enzymatic nature of the drug target, we have begun to investigate potential P. falciparum resistance to PFTIs. The THQ PFTI used in this work, BMS-388891 (Fig. 1), is a potent inhibitor of parasite proliferation and causes severe defects in maturation.. Using the solved crystal structure of the mammalian protein farnesyltransferase, we created a model for the P. falciparum PFT enzyme that explains the THQ-PFT binding interactions and explains the molecular mechanism of resistance (15–18) to better facilitate drug development. The location of the primer relative to the start is given in parentheses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
