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Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4651924
Author(s)
Xie, S. C.; Metcalfe, R. D.; Dunn, E.; Morton, C. J.; Huang, S. C.; Puhalovich, T.; Du, Y.; Wittlin, S.; Nie, S.; Luth, M. R.; Ma, L.; Kim, M. S.; Pasaje, C. F. A.; Kumpornsin, K.; Giannangelo, C.; Houghton, F. J.; Churchyard, A.; Famodimu, M. T.; Barry, D. C.; Gillett, D. L.; Dey, S.; Kosasih, C. C.; Newman, W.; Niles, J. C.; Lee, M. C. S.; Baum, J.; Ottilie, S.; Winzeler, E. A.; Creek, D. J.; Williamson, N.; Parker, M. W.; Brand, S.; Langston, S. P.; Dick, L. R.; Griffin, M. D. W.; Gould, A. E.; Tilley, L.
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.
