@article{88a2335e054441b99a3962c9ea59d31c,
title = "Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy",
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 mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.",
keywords = "malaria, drug resistance, drug discovery, transporter, mitochondria",
author = "Xie, {Stanley C.} and Metcalfe, {Riley D.} and Elyse Dunn and Morton, {Craig J.} and Huang, {Shih Chung} and Tanya Puhalovich and Yawei Du and Sergio Wittlin and Shuai Nie and Luth, {Madeline R.} and Liting Ma and Kim, {Mi Sook} and Pasaje, {Charisse Flerida A.} and Krittikorn Kumpornsin and Carlo Giannangelo and Houghton, {Fiona J.} and Alisje Churchyard and Famodimu, {Mufuliat T.} and Barry, {Daniel C.} and Gillett, {David L.} and Sumanta Dey and Kosasih, {Clara C.} and William Newman and Niles, {Jacquin C.} and Lee, {Marcus C. S.} and Jake Baum and Sabine Ottilie and Winzeler, {Elizabeth A.} and Creek, {Darren J.} and Nicholas Williamson and Parker, {Michael W.} and Stephen Brand and Langston, {Steven P.} and Dick, {Lawrence R.} and Griffin, {Michael D. W.} and Gould, {Alexandra E.} and Leann Tilley",
note = "Funding Information: 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) Copyright: {\textcopyright} 2022 American Association for the Advancement of Science. All rights reserved.",
year = "2022",
month = jun,
day = "3",
doi = "10.1126/science.abn0611",
language = "English",
volume = "376",
pages = "1074--1079",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6597",
}