Aminoacyl tRNA synthetases (aaRSs) are attractive drug targets.  We found that class I and II aaRSs are 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 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 tRNA synthetase (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.

Reaction-hijacking of aminoacyl tRNA synthetases as a new anti-infectives strategy

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