Q1 · CROSS-FIELD
Article
Author: Winzeler, Elizabeth A. ; Gould, Alexandra E. ; Churchyard, Alisje ; Wittlin, Sergio ; Puhalovich, Tanya ; Morton, Craig J. ; Metcalfe, Riley D. ; Barry, Daniel C. ; Williamson, Nicholas ; Griffin, Michael D.W. ; Houghton, Fiona J. ; Gillett, David L. ; Baum, Jake ; Dick, Lawrence R. ; Brand, Stephen ; Kim, Mi-Sook ; Ottilie, Sabine ; Nie, Shuai ; Creek, Darren J. ; Lee, Marcus C. S. ; Kumpornsin, Krittikorn ; Xie, Stanley C. ; Parker, Michael W. ; Kosasih, Clara C. ; Dey, Sumanta ; Dunn, Elyse ; Newman, William ; Famodimu, Mufuliat T. ; Tilley, Leann ; Giannangelo, Carlo ; Ma, Liting ; Pasaje, Charisse Flerida A. ; Huang, Shih-Chung ; Du, Yawei ; Niles, Jacquin C. ; Luth, Madeline R. ; Langston, Steven P.
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 that hijacks a single aaRS in the malaria parasite
Plasmodium falciparum
, namely tyrosine RS (
Pf
YRS). 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.