Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines

The inhibition of Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) by a novel series of bicyclic azetidines has shown the potential to prevent malaria transmission, provide prophylaxis, and offer single-dose cure in animal models of malaria. To date, however, the molecular basis of Plasmodium cFRS inhibition by bicyclic azetidines has remained unknown. Here, we present structural and biochemical evidence that bicyclic azetidines are competitive inhibitors of L-Phe, one of three substrates required for the cFRS-catalyzed aminoacylation reaction that underpins protein synthesis in the parasite. Critically, our co-crystal structure of a PvcFRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct subsites within the PvcFRS catalytic site. The ligand occupies the L-Phe site along with an auxiliary cavity and traverses past the ATP binding site. Given that BRD1389 recognition residues are conserved amongst apicomplexan FRSs, this work lays a structural framework for the development of drugs against both Plasmodium and related apicomplexans.

Automated summary

The novel series of bicyclic azetidines has shown potential in inhibiting Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) and could serve as competitive inhibitors of L-Phe, providing a structural framework for drug development against both Plasmodium and related apicomplexans. The co-crystal structure of a PvcFRS-BRD1389 complex reveals how the bicyclic azetidine ligand binds to distinct subsites within the PvcFRS catalytic site, offering insights into its mechanism of action.