Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target-Reference-Cited by-同舟云学术

Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target

Published:2023-03-08 Issue:686 Volume:15 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Istvan Eva S.¹^ORCID,Guerra Francisco²^ORCID,Abraham Matthew²^ORCID,Huang Kuo-Sen³^ORCID,Rocamora Frances²^ORCID,Zhao Haoshuang³^ORCID,Xu Lan⁴,Pasaje Charisse⁵^ORCID,Kumpornsin Krittikorn⁶^ORCID,Luth Madeline R.²^ORCID,Cui Haissi⁷^ORCID,Yang Tuo²,Palomo Diaz Sara⁸^ORCID,Gomez-Lorenzo Maria G.⁸^ORCID,Qahash Tarrick⁹¹⁰^ORCID,Mittal Nimisha²^ORCID,Ottilie Sabine²^ORCID,Niles Jacquin⁵^ORCID,Lee Marcus C. S.⁶^ORCID,Llinas Manuel⁹¹⁰¹¹^ORCID,Kato Nobutaka⁴^ORCID,Okombo John¹²^ORCID,Fidock David A.¹²¹³^ORCID,Schimmel Paul⁷^ORCID,Gamo Francisco Javier⁸^ORCID,Goldberg Daniel E.¹^ORCID,Winzeler Elizabeth A.²^ORCID

Affiliation:

1. Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63130, USA.

2. Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

3. Cepter Biopartners, Nutley, NJ 07110, USA.

4. Global Health Drug Discovery Institute, Tsinghua University, 30 Shuangqing Rd, Haidian District, Beijing, China.

5. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

6. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.

7. Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA.

8. Global Health Medicines, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos 28760, Spain.

9. Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.

10. Huck Center for Malaria Research, Pennsylvania State University, University Park, PA 16802, USA.

11. Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA.

12. Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.

13. Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

Link

https://www.science.org/doi/pdf/10.1126/scitranslmed.adc9249

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