1. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy
- Author
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Xie, SC, Metcalfe, RD, Dunn, E, Morton, CJ, Huang, S-C, Puhalovich, T, Du, Y, Wittlin, S, Nie, S, Luth, MR, Ma, L, Kim, M-S, Pasaje, CFA, Kumpornsin, K, Giannangelo, C, Houghton, FJ, Churchyard, A, Famodimu, MT, Barry, DC, Gillett, DL, Dey, S, Kosasih, CC, Newman, W, Niles, JC, Lee, MCS, Baum, J, Ottilie, S, Winzeler, EA, Creek, DJ, Williamson, N, Parker, MW, Brand, S, Langston, SP, Dick, LR, Griffin, MDW, Gould, AE, Tilley, L, Xie, SC, Metcalfe, RD, Dunn, E, Morton, CJ, Huang, S-C, Puhalovich, T, Du, Y, Wittlin, S, Nie, S, Luth, MR, Ma, L, Kim, M-S, Pasaje, CFA, Kumpornsin, K, Giannangelo, C, Houghton, FJ, Churchyard, A, Famodimu, MT, Barry, DC, Gillett, DL, Dey, S, Kosasih, CC, Newman, W, Niles, JC, Lee, MCS, Baum, J, Ottilie, S, Winzeler, EA, Creek, DJ, Williamson, N, Parker, MW, Brand, S, Langston, SP, Dick, LR, Griffin, MDW, Gould, AE, and Tilley, L
- 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.
- Published
- 2022