Cytoplasmic Isoleucyl tRNA synthetase as an attractive Multi-stage antimalarial drug target

• Published in: Science translational medicine 2023-03, Vol.15 (686), p.eadc9249-eadc9249
• Main Authors: Istvan, Eva S., Guerra, Francisco, Abraham, Matthew, Huang, Kuo-Sen, Rocamora, Frances, Zhao, Haoshuang, Xu, Lan, Pasaje, Charisse, Kumpornsin, Krittikorn, Luth, Madeline R., Cui, Haissi, Yang, Tuo, Diaz, Sara Palomo, Gomez-Lorenzo, Maria G., Qahash, Tarrick, Mittal, Nimisha, Ottilie, Sabine, Niles, Jacquin, Lee, Marcus C. S., Llinas, Manuel, Kato, Nobutaka, Okombo, John, Fidock, David A., Schimmel, Paul, Gamo, Francisco Javier, Goldberg, Daniel E., Winzeler, Elizabeth A.
• Format: Article
• Language: English
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.adc9249

Development of antimalarial compounds into clinical candidates remains costly and arduous without detailed knowledge of the target. As resistance increases and treatment options at various stages of disease are limited, it is critical to identify multi-stage drug targets that are readily interrogated in biochemical assays. Whole-genome sequencing of 18 parasite clones evolved using thienopyrimidine compounds with submicromolar, rapid-killing, pan-lifecycle antiparasitic activity showed that all had acquired mutations in the P. falciparum cytoplasmic isoleucyl tRNA synthetase (cIRS). Engineering two of the mutations into drug-naïve parasites recapitulated the resistance phenotype and parasites with conditional knockdowns of cIRS became hypersensitive to 2 thienopyrimidines. Purified recombinant P. vivax cIRS inhibition, cross resistance and biochemical assays indicated a novel, non-competitive, allosteric binding site that is distinct from that of known cIRS inhibitors mupirocin and reveromycin A. Our data show that Plasmodium cIRS is an important chemically and genetically validated target for next-generation medicines for malaria. Whole genome sequencing of evolved resistant clones and biochemical assays identified and validated Plasmodium falciparum cIRS as a promising antimalarial target.