Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Science translational medicine, Volume: 15, Issue: 686
March 8, 2023
Eva S Istvan ES, Francisco Guerra F, Matthew Abraham M, Kuo-Sen Huang KS, Frances Rocamora F, Haoshuang Zhao H, Lan Xu L, Charisse Pasaje C, Krittikorn Kumpornsin K, Madeline R Luth MR, Haissi Cui H, Tuo Yang T, Sara Palomo Diaz S, Maria G Gomez-Lorenzo MG, Tarrick Qahash T, Nimisha Mittal N, Sabine Ottilie S, Jacquin Niles J, Marcus C S Lee MCS, Manuel Llinas M, Nobutaka Kato N, John Okombo J, David A Fidock DA, Paul Schimmel P, Francisco Javier Gamo FJ, Daniel E Goldberg DE, Elizabeth A Winzeler EA

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 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 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 cIRS is an important chemically and genetically validated target for next-generation medicines for malaria.

Courtesy of the U.S. National Library of Medicine