Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis.
Article Details
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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
Drug Target Kind Organism Pharmacological Action Actions Mefloquine 80S ribosomal subunit Group Plasmodium falciparum YesBinderDetails - Polypeptides
Name UniProt ID 60S ribosomal protein L4 Q8I431 Details 60S ribosomal protein L3 Q8IJC6 Details 60S ribosomal protein L2 Q8I3T9 Details 60S ribosomal protein L27 Q8IKM5 Details 60S ribosomal protein L24, putative Q8IEM3 Details 60S ribosomal protein L23 Q8IE82 Details 60S ribosomal protein L17, putative Q8IDI5 Details 60S ribosomal protein L10, putative Q8ILV2 Details Ubiquitin-60S ribosomal protein L40 Q8ID50 Details 60S ribosomal protein L30e, putative Q8IJK8 Details 60S ribosomal protein L21 Q8ILK3 Details 60S ribosomal protein L14, putative Q8ILE8 Details