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

Jolyn E. Gisselberg, Zachary Herrera, Lindsey M. Orchard, Manuel Llinas, Ellen Yeh

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 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. Gisselberg et al. identified a non-bisphosphonate inhibitor of the bifunctional FPPS/GGPPS in malaria parasites. Using this inhibitor they uncover a new, highly selective small-molecule binding site in this validated antimalarial drug target, overcoming previous limitations to developing malaria-specific FPPS/GGPPS inhibitors.

Original languageEnglish (US)
Pages (from-to)185-193.e5
JournalCell Chemical Biology
Volume25
Issue number2
DOIs
StatePublished - Feb 15 2018

Fingerprint

Geranyltranstransferase
Farnesyltranstransferase
Diphosphonates
Antimalarials
Malaria
Parasites
Binding Sites
Molecules
Plasmodium
Falciparum Malaria
Diphosphates
Biosynthesis
Terpenes
Substrates
Enzymes
Human Activities
Biological Availability
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Gisselberg, Jolyn E. ; Herrera, Zachary ; Orchard, Lindsey M. ; Llinas, Manuel ; Yeh, Ellen. / Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site. In: Cell Chemical Biology. 2018 ; Vol. 25, No. 2. pp. 185-193.e5.
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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 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. Gisselberg et al. identified a non-bisphosphonate inhibitor of the bifunctional FPPS/GGPPS in malaria parasites. Using this inhibitor they uncover a new, highly selective small-molecule binding site in this validated antimalarial drug target, overcoming previous limitations to developing malaria-specific FPPS/GGPPS inhibitors.",
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Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site. / Gisselberg, Jolyn E.; Herrera, Zachary; Orchard, Lindsey M.; Llinas, Manuel; Yeh, Ellen.

In: Cell Chemical Biology, Vol. 25, No. 2, 15.02.2018, p. 185-193.e5.

Research output: Contribution to journalArticle

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