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

Aminoacyl tRNA synthetases (aaRSs) are attractive drug targets. Here we show that class I and II aaRSs are previously unrecognized targets for AMP-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate, via a reaction-hijacking mechanism. We identified adenosine 5′-sulfamate (AMS) as a broad specificity compound that hijacks a range of aaRSs; and ML901 as a specific reagent that hijacks a single aaRSs in the malaria parasite, Plasmodium falciparum, namely, tyrosine RS (PfYRS). ML901 exerts whole-of-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.