Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy

SC Xie; RD Metcalfe; E Dunn; CJ Morton; SC Huang; T Puhalovich; Y Du; S Wittlin; S Nie; MR Luth; L Ma; MS Kim; CFA Pasaje; K Kumpornsin; C Giannangelo; FJ Houghton; A Churchyard; MT Famodimu; DC Barry; DL Gillett; S Dey; CC Kosasih; W Newman; JC Niles; MCS Lee; J Baum; S Ottilie; EA Winzeler; DJ Creek; N Williamson; MW Parker; S Brand; SP Langston; LR Dick; MDW Griffin; AE Gould; L Tilley

Journal article

Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy

SC Xie, RD Metcalfe, E Dunn, CJ Morton, SC Huang, T Puhalovich, Y Du, S Wittlin, S Nie, MR Luth, L Ma, MS Kim, CFA Pasaje, K Kumpornsin, C Giannangelo, FJ Houghton, A Churchyard, MT Famodimu, DC Barry, DL Gillett Show all

Science | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2022

DOI: 10.1126/science.abn0611

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Abstract

Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a ..

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University of Melbourne Researchers

Stanley Xie Author

Craig Morton Author

Nicholas Williamson Author

Michael Parker Author

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Grants

Awarded by National Institute of General Medical Sciences

Funding Acknowledgements

This work was funded by the following: the Global Health Innovative Technology Fund, Japan (H2019-104 to L.T., A.E.G., and S.B.); National Health and Medical Research Council (NHMRC, 1139884 to L.T.); Medicines for Malaria Venture (MMV RD/15/0007 to S.B., RD-08-2800 to J.B.); and Millennium Pharmaceuticals (to A.E.G. and S.P.L.), a wholly owned subsidiary of Takeda Pharmaceuticals Company Limited. J.B. is supported by an Investigator Award from Wellcome (100993/B/13/Z); M.W.P. is an NHMRC Research Fellow (APP1117183) and Investigator (APP1194263). The project was also supported by the Malaria Drug Accelerator (MalDA, BMGF OPP1054480 to M.R.L., S.O., K.K., M.C.S.L., J.C.N., and E.A.W.); L.T. was supported by an Australian Research Council Laureate Fellowship (FL150100106); M.R.L. was supported by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences (T32 GM008666); D.J.C. was supported by a NHMRC Synergy Grant (APP1185354)