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

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. Purifi

SUBMITTER: Istvan ES 

PROVIDER: S-EPMC10286833 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature