Journal article

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

Wilson Wong, Xiao-Chen Bai, Brad E Sleebs, Tony Triglia, Alan Brown, Jennifer K Thompson, Katherine E Jackson, Eric Hanssen, Danushka S Marapana, Israel S Fernandez, Stuart A Ralph, Alan F Cowman, Sjors HW Scheres, Jake Baum



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 resid..

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Awarded by National Health and Medical Research Council of Australia (NHMRC) Project Grant

Awarded by Human Frontier Science Program (HFSP)Young Investigator Program Grant

Awarded by UK Medical Research Council

Awarded by Wellcome Trust

Awarded by Australian Research Council (ARC)

Awarded by Medical Research Council

Funding Acknowledgements

The authors thank I. Lucet, J. Boddey, S. Herrmann, G. McFadden, J. Rayner, A. Ruecker, M. Delves, H. Baumann, G. Murshudov and P. Emsley for discussions and experimental assistance, S. Chen and C. Savva for help with microscopy, and J. Grimmett and T. Darling for help with computing. The experimental data were made possible by Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. The research was directly supported by a National Health and Medical Research Council of Australia (NHMRC) Project Grant (APP1024678 to J. B. and W.W.), the Australian Cancer Research Foundation, a Human Frontier Science Program (HFSP)Young Investigator Program Grant (RGY0071/2011, to J.B.) and grants from the UK Medical Research Council (MC_UPA0251013, to S.H.W.S.). W.W. is an Early Career Development Awardee (APP1053801) from the NHMRC and was in receipt of a travel award from OzEMalaR to visit MRC-LMB UK to conduct experiments. X.-C.B. is supported by an EU FP7 Marie Curie Postdoctoral Fellowship. A.B. and I.S.F. are supported by grants to V. Ramakrishnan from the Wellcome Trust (WT096570) and the UK Medical Research council (MC_U105184332). J.B. was supported by a Future Fellowship (FT100100112) from the Australian Research Council (ARC) and is currently supported by an Investigator Award from the Wellcome Trust (100993/Z/13/Z). Additional support for this work came from a Pathfinder Award from the Wellcome Trust (105686).