Anti-plasmodial activity of proteasome inhibitors against various Plasmodium species: a preclinical evaluation
9 affiliations
- 1Department of Tropical Medicine, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do, Republic of Korea
- 2Department of Infectious Diseases, 103 Military Hospital, Hanoi, Vietnam
- 3Institute of Clinical Infectious Diseases, 108 Military Central Hospital, Hanoi, Vietnam
- 4Department of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, Republic of Korea
- 5Department of Physiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea
- 6Department of Pharmacology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea
- 7Chemical and Structural Biology of Pathogens, Discovery Biology, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea
- 8School of Basic Medical Sciences & School of Public Health, Faculty of Medicine, Yangzhou University, Yangzhou, China
- 9Department of Infection Biology, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, United Kingdom
Abstract
The discovery of novel anti-malarial drugs has become urgent due to increasing drug resistance. Our previous work identified ONX-0914, which targets parasite proteolytic systems, as promising against Plasmodium falciparum. This study aims to further evaluate the antiplasmodial activity of ONX-0914 and related proteasome inhibitors (PIs) against various Plasmodium strains. The in vitro antimalarial activity of the inhibitors was evaluated against the Plasmodium knowlesi A1H1 strain and compared with that against the chloroquine (CQ)-sensitive P. falciparum 3D7 strain. Potent synergistic interactions between compounds and artemisinin (ART) were analyzed against PkA1H1 and ART-resistant PfDd2R539T(+) using an isobologram. To explore the mode of action, the disruption of the ubiquitin-proteasome system (UPS) in PkA1H1 and Pf3D7 was investigated. In vivo efficacy of ONX-0914 was further validated against CQ-resistant Plasmodium yoelii. PIs significantly inhibited PkA1H1 proliferation with low-nanomolar IC50 values; ONX-0914 and LU-005i were more potent against PkA1H1 than Pf3D7, and effectively blocked multiple blood stages. Inhibition of parasite growth correlated with potent disruption of UPS at nanomolar concentrations (IC50 < 50 nM). ONX-0914 demonstrated strong synergistic activity with ART and other PIs (∑FIC50 < 0.8). In vivo, ONX-0914 significantly suppressed P. yoelii infection, improving lifespan, with ⁓84% efficacy at an intraperitoneal (IP) dose of 20 mg/kg, and ⁓90% in combination with artemisinin at a dose of 10 mg/kg (IP). Further optimization of the structure and dosing regimen is able to enhance the therapeutic potential of PIs as potential antimalarial drug candidates.
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BibTeX
@article{truong2026antiplasmodial,
title = {{Anti-plasmodial activity of proteasome inhibitors against various Plasmodium species: a preclinical evaluation}},
author = {Nguyen Van Truong and Tuyet-Kha Nguyen and Nguyen Sy Thau and Thi-Thanh Hang Chu and Jin-Hee Han and Sung-Hun Na and Won-Sun Park and Wan-Joo Chun and Joo Hwan No and Feng Lu and Robert W. Moon and Eun-Taek Han},
journal = {Antimicrobial Agents and Chemotherapy},
year = {2026},
month = sep,
doi = {10.1128/aac.00382-26},
url = {https://doi.org/10.1128/aac.00382-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Anti-plasmodial activity of proteasome inhibitors against various Plasmodium species: a preclinical evaluation
AU - Nguyen Van Truong
AU - Tuyet-Kha Nguyen
AU - Nguyen Sy Thau
AU - Thi-Thanh Hang Chu
AU - Jin-Hee Han
AU - Sung-Hun Na
AU - Won-Sun Park
AU - Wan-Joo Chun
AU - Joo Hwan No
AU - Feng Lu
AU - Robert W. Moon
AU - Eun-Taek Han
PY - 2026
DA - 2026/09/30
JO - Antimicrobial Agents and Chemotherapy
DO - 10.1128/aac.00382-26
UR - https://doi.org/10.1128/aac.00382-26
AB - The discovery of novel anti-malarial drugs has become urgent due to increasing drug resistance. Our previous work identified ONX-0914, which targets parasite proteolytic systems, as promising against Plasmodium falciparum. This study aims to further evaluate the antiplasmodial activity of ONX-0914 and related proteasome inhibitors (PIs) against various Plasmodium strains. The in vitro antimalarial activity of the inhibitors was evaluated against the Plasmodium knowlesi A1H1 strain and compared with that against the chloroquine (CQ)-sensitive P. falciparum 3D7 strain. Potent synergistic interactions between compounds and artemisinin (ART) were analyzed against PkA1H1 and ART-resistant PfDd2R539T(+) using an isobologram. To explore the mode of action, the disruption of the ubiquitin-proteasome system (UPS) in PkA1H1 and Pf3D7 was investigated. In vivo efficacy of ONX-0914 was further validated against CQ-resistant Plasmodium yoelii. PIs significantly inhibited PkA1H1 proliferation with low-nanomolar IC50 values; ONX-0914 and LU-005i were more potent against PkA1H1 than Pf3D7, and effectively blocked multiple blood stages. Inhibition of parasite growth correlated with potent disruption of UPS at nanomolar concentrations (IC50 < 50 nM). ONX-0914 demonstrated strong synergistic activity with ART and other PIs (∑FIC50 < 0.8). In vivo, ONX-0914 significantly suppressed P. yoelii infection, improving lifespan, with ⁓84% efficacy at an intraperitoneal (IP) dose of 20 mg/kg, and ⁓90% in combination with artemisinin at a dose of 10 mg/kg (IP). Further optimization of the structure and dosing regimen is able to enhance the therapeutic potential of PIs as potential antimalarial drug candidates.
SN - 0066-4804
SN - 1098-6596
ER -