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

  • Journal Article

Science (New York, N.Y.), Volume: 376, Issue: 6597
June 3, 2022
Stanley C Xie SC, Riley D Metcalfe RD, Elyse Dunn E, Craig J Morton CJ, Shih-Chung Huang SC, Tanya Puhalovich T, Yawei Du Y, Sergio Wittlin S, Shuai Nie S, Madeline R Luth MR, Liting Ma L, Mi-Sook Kim MS, Charisse Flerida A Pasaje CFA, Krittikorn Kumpornsin K, Carlo Giannangelo C, Fiona J Houghton FJ, Alisje Churchyard A, Mufuliat T Famodimu MT, Daniel C Barry DC, David L Gillett DL, Sumanta Dey S, Clara C Kosasih CC, William Newman W, Jacquin C Niles JC, Marcus C S Lee MCS, Jake Baum J, Sabine Ottilie S, Elizabeth A Winzeler EA, Darren J Creek DJ, Nicholas Williamson N, Michael W Parker MW, Stephen Brand S, Steven P Langston SP, Lawrence R Dick LR, Michael D W Griffin MDW, Alexandra E Gould AE, Leann 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 , namely tyrosine RS (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.

Courtesy of the U.S. National Library of Medicine