Journal
CELL CHEMICAL BIOLOGY
Volume 25, Issue 2, Pages 185-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2017.11.010
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Funding
- Stanford Consortium for Innovation, Design, Evaluation and Action (C-IDEA)
- NIH [1K08AI097239, 1DP5OD012119]
- Burroughs Wellcome Fund Career Award for Medical Scientists
- Burroughs Wellcome Fund Investigators in Pathogenesis of Infectious Disease (PATH) Award [1007041]
- Stanford School of Medicine Dean's Postdoctoral Fellowship
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [K08AI097239] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [DP5OD012119] Funding Source: NIH RePORTER
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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 that MMV019313 did not bind previously characterized substrate sites in PfFPPS/GGPPS. Our finding uncovers a new, selective small-molecule binding site in this important antimalarial drug target with superior druggability compared with the known inhibitor site and sets the stage for the development of Plasmodium-specific FPPS/GGPPS inhibitors.
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