Potent reaction hijacking inhibitors of Plasmodium falciparum asparagine tRNA synthetase.

4-aminoquinazoline sulfonamides show nanomolar potency against blood-stage Plasmodium falciparum, with up to 300-fold selectivity and reaction-hijacking inhibition of Pf AsnRS.

• Why it matters: Rising resistance to existing antimalarials threatens malaria control, creating a need for new drugs with distinct mechanisms and low resistance risk.
• What they did: The authors tested 4AQS compounds against blood and transmissible P. falciparum stages, used targeted mass spectrometry to identify reaction hijacking of aminoacyl tRNA synthetases, and confirmed target preference via selective aaRS knockdown and tolerance selection.
• The result: Subtle scaffold changes shift the main target from Pf ThrRS to cytoplasmic Pf AsnRS, linked to increased potency and amino acid starvation response, while recombinant assays show Pf AsnRS is more susceptible than human AsnRS.

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