Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target

Eva S. Istvan, Francisco Guerra, Matthew Abraham, Kuo Sen Huang, Frances Rocamora, Haoshuang Zhao, Lan Xu, Charisse Pasaje, Krittikorn Kumpornsin, Madeline R. Luth, Haissi Cui, Tuo Yang, Sara Palomo Diaz, Maria G. Gomez-Lorenzo, Tarrick Qahash, Nimisha Mittal, Sabine Ottilie, Jacquin Niles, Marcus C.S. Lee, Manuel LlinasNobutaka Kato, John Okombo, David A. Fidock, Paul Schimmel, Francisco Javier Gamo, Daniel E. Goldberg, Elizabeth A. Winzeler

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 multistage 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–life cycle 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 two thienopyrimidines. Purified recombinant P. vivax cIRS inhibition, cross-resistance, and biochemical assays indicated a noncompetitive, 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.

Original languageEnglish (US)
Article numbereadc9249
JournalScience Translational Medicine
Volume15
Issue number686
DOIs
StatePublished - Mar 8 2023

All Science Journal Classification (ASJC) codes

  • General Medicine

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