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Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.
- Xie, Stanley;
- Metcalfe, Riley;
- Dunn, Elyse;
- Morton, Craig;
- Huang, Shih-Chung;
- Puhalovich, Tanya;
- Du, Yawei;
- Wittlin, Sergio;
- Nie, Shuai;
- Luth, Madeline;
- Ma, Liting;
- Kim, Mi-Sook;
- Pasaje, Charisse;
- Kumpornsin, Krittikorn;
- Giannangelo, Carlo;
- Houghton, Fiona;
- Churchyard, Alisje;
- Famodimu, Mufuliat;
- Barry, Daniel;
- Gillett, David;
- Dey, Sumanta;
- Kosasih, Clara;
- Newman, William;
- Niles, Jacquin;
- Lee, Marcus;
- Baum, Jake;
- Ottilie, Sabine;
- Winzeler, Elizabeth;
- Creek, Darren;
- Williamson, Nicholas;
- Parker, Michael;
- Brand, Stephen;
- Langston, Steven;
- Dick, Lawrence;
- Griffin, Michael;
- Gould, Alexandra;
- Tilley, Leann
- et al.
Published Web Location
https://doi.org/10.1126/science.abn0611Abstract
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.
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