Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site.

ABSTRACT: The bifunctional farnesyl/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key branchpoint enzyme in isoprenoid biosynthesis in Plasmodium falciparum (malaria) parasites. PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit FPPS and GGPPS enzymes by acting as a diphosphate substrate analog show poor bioavailability and selectivity for PfFPPS/GGPPS. We identified a new non-bisphosphonate compound, MMV019313, which is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes of inhibition. Molecular docking indicated tha

SUBMITTER: Gisselberg JE 

PROVIDER: S-EPMC5820002 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature