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Efficacy and mechanism of action of cipargamin as an antibabesial drug candidate
Open accessPublished version of a preprint
Abstract
Babesiosis is a disease brought on by intraerythrocytic parasites of the genus Babesia . Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs against Babesia . Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainly Plasmodium and Toxoplasma . This study evaluated the growth-inhibiting properties of CIP against Babesia spp. and investigated the mechanism of CIP on B. gibsoni . The half inhibitory concentration (IC 50 ) values of CIP against the in vitro growth of B. bovis and B. gibsoni were 20.2 ± 1.4 and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth of B. microti and B. rodhaini in vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3- and 2.4-fold decrease in BgATP4 L921V and BgATP4 L921I , respectively, compared to that of BgATP4 WT . An in silico investigation revealed reductions in affinity for CIP binding to BgATP4 L921V and BgATP4 L921I compared to BgATP4 WT . Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in IC 50 values. Combining CIP with TQ effectively eliminated B. microti infection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.
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Metadata
- Authors
- Li, H., Ji, S., Ariefta, N. R., Galon, E. M. S., El-Sayed, S. A., Do, T., Jia, L., Sakaguchi, M., Asada, M., Nishikawa, Y., Qin, X., Liu, M., & Xuan, X.
- Affiliations
- National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine (JP)
- Yanbian University (CN)
- Cavite State University (PH)
- Mansoura University (EG)
- Nagasaki University (JP)
- Hubei University of Arts and Science (CN)
- Corresponding author
- Liu, Mingming
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2025-06-19
- Volume
- 13
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W4411436402
- Cited by
- 1
- References
- 55
- Citations by year
- 2026: 1
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- creativecommons.org/licenses/by/4.0/ (vor)
- creativecommons.org/licenses/by/4.0/ (am)
- creativecommons.org/licenses/by/4.0/ (tdm)
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (22H0250906)
- Ministry of Agriculture, Forestry and Fisheries (JPJ008837)
- Topics
- Life Sciences › Immunology and Microbiology › Parasitology › Vector-borne infectious diseases
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Keywords
- cipargamin, Babesia, babesiosis, drug resistance, tafenoquine, combination therapy, Babesia microti, Babesia gibsoni, Babesia bovis, Babesia rodhaini, antiparasitic drug efficacy
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- Li, H., Ji, S., Ariefta, N. R., Galon, E. M. S., El-Sayed, S. A., Do, T., Jia, L., Sakaguchi, M., Asada, M., Nishikawa, Y., Qin, X., Liu, M., & Xuan, X. (2025). Efficacy and mechanism of action of cipargamin as an antibabesial drug candidate. eLife. https://doi.org/10.7554/elife.101128.4
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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