TY - JOUR
T1 - Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target
AU - Istvan, Eva S.
AU - Guerra, Francisco
AU - Abraham, Matthew
AU - Huang, Kuo Sen
AU - Rocamora, Frances
AU - Zhao, Haoshuang
AU - Xu, Lan
AU - Pasaje, Charisse
AU - Kumpornsin, Krittikorn
AU - Luth, Madeline R.
AU - Cui, Haissi
AU - Yang, Tuo
AU - Diaz, Sara Palomo
AU - Gomez-Lorenzo, Maria G.
AU - Qahash, Tarrick
AU - Mittal, Nimisha
AU - Ottilie, Sabine
AU - Niles, Jacquin
AU - Lee, Marcus C. S.
AU - Llinas, Manuel
AU - Kato, Nobutaka
AU - Okombo, John
AU - Fidock, David A.
AU - Schimmel, Paul
AU - Gamo, Francisco Javier
AU - Goldberg, Daniel E.
AU - Winzeler, Elizabeth A.
N1 - Funding Information:
We thank B. Crespo for support with speed of action studies. We thank C. Zhao at Cepter Biopartners for PvcIRS protein purification. E.A.W. was supported by a grant from the NIH (5 R01 AI152533-03). The Bill & Melinda Gates Foundation supported this work with grants to E.A.W., E.S.I., D.E.G., S.O., D.A.F., M.C.S.L., and M.L. (OPP1054480) and J.N. (OPP1132313). M.C.S.L. was supported by a grant from Wellcome (206194/Z/17/Z). M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences (T32 GM008666). F.G. was supported in part by a Ruth L. Kirschstein Institutional Research Award (T32 AI007036).
Copyright:
© 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2023/3/8
Y1 - 2023/3/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85149689930&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adc9249
DO - 10.1126/scitranslmed.adc9249
M3 - Article
C2 - 36888694
AN - SCOPUS:85149689930
SN - 1946-6234
VL - 15
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 686
M1 - eadc9249
ER -
