Plasmodium falciparum cytoplasmic prolyl-tRNA synthetase (PfProRS) (PfProRS)

Plasmodium falciparum cytoplasmic prolyl-tRNA synthetase (PfProRS) is a vital enzyme in the malaria parasite responsible for the aminoacylation of tRNA with proline, a critical step in protein biosynthesis [1, 4]. It belongs to the class II aminoacyl-tRNA synthetase family and is essential for the parasite's survival during both the liver and asexual blood stages of its life cycle [7, 8]. PfProRS has been validated as a high-priority drug target, notably as the molecular target of the natural product febrifugine and its synthetic derivative halofuginone [1, 7]. Inhibition of PfProRS triggers an amino acid starvation response in the parasite, effectively halting protein production and parasite replication [1, 12]. However, a major challenge in developing PfProRS inhibitors is achieving high selectivity over the human ortholog (HsProRS), as cross-reactivity can lead to significant host toxicity and adverse effects such as emesis and gastrointestinal distress [5, 6]. Recent research has focused on identifying allosteric inhibitors and triple-site ligands that offer improved selectivity and can overcome resistance mechanisms, such as the adaptive proline response or specific point mutations in the catalytic site [8, 13, 15].

Other names

Proline--tRNA ligaseProlyl-tRNA synthetaseProRSPfcPRSPf-cProRSPF3D7_1213800

Inhibition of the enzyme's catalytic activity prevents the charging of tRNA with proline, thereby halting protein synthesis and triggering an amino acid starvation response in the parasite [1, 7].