Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis.

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Wong W, Bai XC, Sleebs BE, Triglia T, Brown A, Thompson JK, Jackson KE, Hanssen E, Marapana DS, Fernandez IS, Ralph SA, Cowman AF, Scheres SHW, Baum J

Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis.

Nat Microbiol. 2017 Mar 13;2:17031. doi: 10.1038/nmicrobiol.2017.31.

PubMed ID
28288098 [ View in PubMed
]
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 A 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.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Mefloquine80S ribosomal subunitGroupPlasmodium falciparum
Yes
Binder
Details
Polypeptides
NameUniProt ID
60S ribosomal protein L4Q8I431Details
60S ribosomal protein L3Q8IJC6Details
60S ribosomal protein L2Q8I3T9Details
60S ribosomal protein L27Q8IKM5Details
60S ribosomal protein L24, putativeQ8IEM3Details
60S ribosomal protein L23Q8IE82Details
60S ribosomal protein L17, putativeQ8IDI5Details
60S ribosomal protein L10, putativeQ8ILV2Details
Ubiquitin-60S ribosomal protein L40Q8ID50Details
60S ribosomal protein L30e, putativeQ8IJK8Details
60S ribosomal protein L21Q8ILK3Details
60S ribosomal protein L14, putativeQ8ILE8Details