Structure of Plasmodium vivax N-myristoyltransferase with inhibitor IMP-1088: exploring an NMT inhibitor for antimalarial therapy
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Plasmodium vivax is responsible for the most widespread form of malaria and approximately 2.5 billion people, or over one-third of the world's population, are at risk of P. vivax infection (Battle et al., 2019[Battle, K. E., Lucas, T. C. D., Nguyen, M., Howes, R. E., Nandi, A. K., Twohig, K. A., Pfeffer, D. A., Cameron, E., Rao, P. C., Casey, D., Gibson, H. S., Rozier, J. A., Dalrymple, U., Keddie, S. H., Collins, E. L., Harris, J. R., Guerra, C. A., Thorn, M. P., Bisanzio, D., Fullman, N., Huynh, C. K., Kulikoff, X., Kutz, M. J., Lopez, A. D., Mokdad, A. H., Naghavi, M., Nguyen, G., Shackelford, K. A., Vos, T., Wang, H., Lim, S. S., Murray, C. J. L., Price, R. N., Baird, J. K., Smith, D. L., Bhatt, S., Weiss, D. J., Hay, S. I. & Gething, P. W. (2019). Lancet, 394, 332-343.]). In humans, P. vivax can enter a dormant liver phase, which allows it to survive in various climates, including tropical and temperate regions, and contributes to its extensive geographical prevalence (Battle et al., 2019[Battle, K. E., Lucas, T. C. D., Nguyen, M., Howes, R. E., Nandi, A. K., Twohig, K. A., Pfeffer, D. A., Cameron, E., Rao, P. C., Casey, D., Gibson, H. S., Rozier, J. A., Dalrymple, U., Keddie, S. H., Collins, E. L., Harris, J. R., Guerra, C. A., Thorn, M. P., Bisanzio, D., Fullman, N., Huynh, C. K., Kulikoff, X., Kutz, M. J., Lopez, A. D., Mokdad, A. H., Naghavi, M., Nguyen, G., Shackelford, K. A., Vos, T., Wang, H., Lim, S. S., Murray, C. J. L., Price, R. N., Baird, J. K., Smith, D. L., Bhatt, S., Weiss, D. J., Hay, S. I. & Gething, P. W. (2019). Lancet, 394, 332-343.]). P. vivax infection significantly impacts the quality of life of infected individuals, causing cyclical episodes of fever and weakness, representing a substantial burden in endemic countries due to treatment costs and productivity loss. P. vivax can persist in human hosts as hypnozoites in the liver that can cause relapses that can extend over several months or years (Flannery et al., 2022[Flannery, E. L., Kangwanrangsan, N., Chuenchob, V., Roobsoong, W., Fishbaugher, M., Zhou, K., Billman, Z. P., Martinson, T., Olsen, T. M., Schäfer, C., Campo, B., Murphy, S. C., Mikolajczak, S. A., Kappe, S. H. I. & Sattabongkot, J. (2022). Mol. Ther. Methods Clin. Dev. 26, 427-440.]). Curing vivax malaria requires antimalarial drugs that are effective against both the blood and liver stages. Unfortunately, the sole licensed antimalarial with P. vivax activity, primaquine, has the drawback of inducing severe hemolysis in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, representing approximately 15% of the population in P. vivax endemic regions (Douglas et al., 2023[Douglas, N. M., Piera, K. A., Rumaseb, A., Ley, B., Anstey, N. M. & Price, R. N. (2023). Am. J. Trop. Med. Hyg. 108, 76-80.]).
Date Issued
2025-01-01
Date Acceptance
2024-11-21
Citation
Acta Crystallographica Section F: Structural Biology and Crystallization Communications Online, 2025, 81 (1)
ISSN
1744-3091
Publisher
International Union of Crystallography
Journal / Book Title
Acta Crystallographica Section F: Structural Biology and Crystallization Communications Online
Volume
81
Issue
1
Copyright Statement
This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39655507
S2053230X24011348
Subjects
N-myristoyltransferases
Plasmodium vivax
drug repurposing
inhibitor complexes
malaria
Publication Status
Published
Coverage Spatial
United States
Article Number
F81
Date Publish Online
2025-01-01