Potent reaction hijacking inhibitors of Plasmodium falciparum asparagine tRNA synthetase
14 affiliations
- 1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
- 2Department of Biological Engineering, Massachusetts Institute of Technology
- 3Department of Microbiology and Immunology, Columbia University Medical Center
- 4Biological Chemistry and Drug Discovery, Faculty of Life Sciences, University of Dundee
- 5Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University
- 6Biotherapeutics Program CSIRO
- 7Department of Biochemistry, Genetics and Microbiology, University of Pretoria
- 8London School of Hygiene and Tropical Medicine
- 9Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
- 10Department of Pediatrics, School of Medicine, University of California San Diego
- 11Medicines for Malaria Venture
- 12Department of Biochemistry, Stellenbosch University
- 13Lgenia, Inc.
- 14Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center
Abstract
Malaria remains one of the major threats to human health. Breakthrough drugs with high potency and low resistance risk are needed to combat the ever-increasing resistance to currently deployed antimalarials. Here, we explore a series of 4-aminoquinazoline-based sulfonamides (4AQS), with a synthetically accessible scaffold. Exemplars exhibit nanomolar potency against blood stage Plasmodium cultures, with up to 300-fold selectivity compared with a mammalian cell line. The compounds are active against transmissible stages of Plasmodium falciparum and refractory to resistance development. Targeted mass spectrometry reveals that the 4AQS compounds act as reaction hijacking inhibitors targeting P. falciparum aminoacyl tRNA synthetases (aaRSs). Subtle changes to the chemical structure switch the main target from cytoplasmic threonine tRNA synthetase ( Pf ThrRS) to cytoplasmic asparagine tRNA synthetase ( Pf AsnRS), a change that is associated with increased potency against P. falciparum . The target preference was confirmed by selective knockdown of different P. falciparum aaRSs and by tolerance selection in a mutator line. Consistent with aaRS targets, exemplar compounds activate the amino acid starvation response. Recombinant enzyme inhibition and thermal stabilization assays confirm the susceptibility of Pf AsnRS to reaction hijacking and show that human AsnRS is less susceptible. A molecular model of Asn-tRNA-bound Pf AsnRS reveals that a potent hijacker adopts a pose similar to adenosine 5′-monophosphate (AMP). An AlphaFold model of the native Pf AsnRS dimer helps explain the tolerance-conferring effect of a mutation at the dimer interface.
IMPORTANCE: Every year, at least 200 million new malaria infections are diagnosed, causing more than 600,000 deaths in Africa and Southeast Asia. Ever-increasing levels of resistance to current antimalarials are leading to an impending crisis. Breakthrough drugs with new modes of action are much needed. Here, we explore a series of inhibitors that hijack critical malaria parasite enzymes. The target enzymes catalyze the formation of a bond between the hijackers and an enzyme substrate, forming a tight-binding compound that disrupts the malaria parasite’s protein translation machinery. The hijacking inhibitors exhibit high-level potency against the disease-causing stage of the malaria parasite and are also active against transmissible stages. They exhibit up to 300-fold selectivity compared with a mammalian cell line, possess drug-like chemical attributes, and are easily synthesized. Importantly, the compounds are refractory to resistance development.
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BibTeX
@article{ye2026potent,
title = {{Potent reaction hijacking inhibitors of Plasmodium falciparum asparagine tRNA synthetase}},
author = {Xi Ye and Lisl Y. Esherick and Nutpakal Ketprasit and Sunil K. Narwal and Luiz C. Godoy and Nonlawat Boonyalai and Con Dogovski and Craig J. Morton and Tayla Rabie and Mufuliat T. Famodimu and Chia-Wei Tai and Tomas Yeo and Owain Donnelly and Lily V. Orta and Isla Anderson and Jin H. Jeon and Lena H. M. Le and Michael G. Leeming and Mariana Laureano De Souza and Elodie Chenu and Darren J. Creek and Michael J. Delves and Lyn-Marie Birkholtz and James Duffy and Karen Lobb and Greg Durst and Marcus C. S. Lee and David A. Fidock and Jacquin C. Niles and Miles G. Siegel and Leann Tilley and Stanley C. Xie},
journal = {mBio},
year = {2026},
month = oct,
doi = {10.1128/mbio.01884-26},
url = {https://journals.asm.org/doi/10.1128/mbio.01884-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Potent reaction hijacking inhibitors of Plasmodium falciparum asparagine tRNA synthetase
AU - Xi Ye
AU - Lisl Y. Esherick
AU - Nutpakal Ketprasit
AU - Sunil K. Narwal
AU - Luiz C. Godoy
AU - Nonlawat Boonyalai
AU - Con Dogovski
AU - Craig J. Morton
AU - Tayla Rabie
AU - Mufuliat T. Famodimu
AU - Chia-Wei Tai
AU - Tomas Yeo
AU - Owain Donnelly
AU - Lily V. Orta
AU - Isla Anderson
AU - Jin H. Jeon
AU - Lena H. M. Le
AU - Michael G. Leeming
AU - Mariana Laureano De Souza
AU - Elodie Chenu
AU - Darren J. Creek
AU - Michael J. Delves
AU - Lyn-Marie Birkholtz
AU - James Duffy
AU - Karen Lobb
AU - Greg Durst
AU - Marcus C. S. Lee
AU - David A. Fidock
AU - Jacquin C. Niles
AU - Miles G. Siegel
AU - Leann Tilley
AU - Stanley C. Xie
PY - 2026
DA - 2026/10/30
JO - mBio
DO - 10.1128/mbio.01884-26
UR - https://journals.asm.org/doi/10.1128/mbio.01884-26
AB - Malaria remains one of the major threats to human health. Breakthrough drugs with high potency and low resistance risk are needed to combat the ever-increasing resistance to currently deployed antimalarials. Here, we explore a series of 4-aminoquinazoline-based sulfonamides (4AQS), with a synthetically accessible scaffold. Exemplars exhibit nanomolar potency against blood stage Plasmodium cultures, with up to 300-fold selectivity compared with a mammalian cell line. The compounds are active against transmissible stages of Plasmodium falciparum and refractory to resistance development. Targeted mass spectrometry reveals that the 4AQS compounds act as reaction hijacking inhibitors targeting P. falciparum aminoacyl tRNA synthetases (aaRSs). Subtle changes to the chemical structure switch the main target from cytoplasmic threonine tRNA synthetase ( Pf ThrRS) to cytoplasmic asparagine tRNA synthetase ( Pf AsnRS), a change that is associated with increased potency against P. falciparum . The target preference was confirmed by selective knockdown of different P. falciparum aaRSs and by tolerance selection in a mutator line. Consistent with aaRS targets, exemplar compounds activate the amino acid starvation response. Recombinant enzyme inhibition and thermal stabilization assays confirm the susceptibility of Pf AsnRS to reaction hijacking and show that human AsnRS is less susceptible. A molecular model of Asn-tRNA-bound Pf AsnRS reveals that a potent hijacker adopts a pose similar to adenosine 5′-monophosphate (AMP). An AlphaFold model of the native Pf AsnRS dimer helps explain the tolerance-conferring effect of a mutation at the dimer interface. IMPORTANCE: Every year, at least 200 million new malaria infections are diagnosed, causing more than 600,000 deaths in Africa and Southeast Asia. Ever-increasing levels of resistance to current antimalarials are leading to an impending crisis. Breakthrough drugs with new modes of action are much needed. Here, we explore a series of inhibitors that hijack critical malaria parasite enzymes. The target enzymes catalyze the formation of a bond between the hijackers and an enzyme substrate, forming a tight-binding compound that disrupts the malaria parasite’s protein translation machinery. The hijacking inhibitors exhibit high-level potency against the disease-causing stage of the malaria parasite and are also active against transmissible stages. They exhibit up to 300-fold selectivity compared with a mammalian cell line, possess drug-like chemical attributes, and are easily synthesized. Importantly, the compounds are refractory to resistance development.
SN - 2150-7511
ER -