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 Llinás; Ellen Yeh

doi:10.1016/j.chembiol.2017.11.010

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

Cell Chem Biol. 2018 Feb 15;25(2):185-193.e5. doi: 10.1016/j.chembiol.2017.11.010. Epub 2017 Dec 21.

Authors

Jolyn E Gisselberg¹, Zachary Herrera¹, Lindsey M Orchard², Manuel Llinás³, Ellen Yeh⁴

Affiliations

¹ Department of Biochemistry, Stanford Medical School, Stanford University, Stanford, CA 94305, USA.
² Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA; Huck Center for Malaria Research, Pennsylvania State University, University Park, PA 16802, USA.
³ Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA; Huck Center for Malaria Research, Pennsylvania State University, University Park, PA 16802, USA; Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA.
⁴ Department of Biochemistry, Stanford Medical School, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford Medical School, Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford Medical School, Stanford University, Stanford, CA 94305, USA. Electronic address: ellenyeh@stanford.edu.

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.

Keywords: drug discovery; farnesyl/geranylgeranyl diphosphate synthase; high-throughput screening; malaria; non-bisphosphonate inhibitor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites / drug effects
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Farnesyltranstransferase / antagonists & inhibitors*
Farnesyltranstransferase / metabolism
Geranyltranstransferase / antagonists & inhibitors*
Geranyltranstransferase / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology
Plasmodium falciparum / metabolism
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*

Substances

Enzyme Inhibitors
Small Molecule Libraries
Geranyltranstransferase
Farnesyltranstransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding