title: Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis.
abstract: Malaria control is heavily dependent on chemotherapeutic agents for disease prevention and drug treatment. Defining the mechanism of action for licensed drugs, for which no target is characterized, is critical to the development of their second-generation derivatives to improve drug potency towards inhibition of their molecular targets. Mefloquine is a widely used antimalarial without a known mode of action. Here, we demonstrate that mefloquine is a protein synthesis inhibitor. We solved a 3.2 Å cryo-electron microscopy structure of the Plasmodium falciparum 80S ribosome with the (+)-mefloquine enantiomer bound to the ribosome GTPase-associated centre. Mutagenesis of mefloquine-binding residues generates parasites with increased resistance, confirming the parasite-killing mechanism. Furthermore, structure-guided derivatives with an altered piperidine group, predicted to improve binding, show enhanced parasiticidal effect. These data reveal one possible mode of action for mefloquine and demonstrate the vast potential of cryo-electron microscopy to guide the development of mefloquine derivatives to inhibit parasite protein synthesis.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
authors.forename: Wilson
authors.initials: W
authors.lastname: Wong
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Xiao-Chen
authors.initials: XC
authors.lastname: Bai
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
authors.forename: Brad E
authors.initials: BE
authors.lastname: Sleebs
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Triglia
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Brown
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Thompson
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Jackson
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Hanssen
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
authors.forename: Danushka S
authors.initials: DS
authors.lastname: Marapana
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Israel S
authors.initials: IS
authors.lastname: Fernandez
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Ralph
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Sjors H W
authors.initials: SHW
authors.lastname: Scheres
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.|Department of Life Sciences, Imperial College London, South Kensington, London, SW7 2AZ, UK.
authors.forename: Jake
authors.initials: J
authors.lastname: Baum
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D015767:Mefloquine / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012270:Ribosomes / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D011500:Protein Synthesis Inhibitors; D015767:Mefloquine