期刊
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
卷 19, 期 -, 页码 81-88出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ijpddr.2022.06.003
关键词
Malaria; Plasmodium berghei; Transmission; Drug; Phosphatase
资金
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01AI150553, U19AI089672]
- National Science Foundation of China [81429004, 81760367]
This study assessed the activity of a panel of phosphatase inhibitors against the sexual development of Plasmodium berghei and found that two compounds showed significant transmission-blocking activity. This suggests that phosphatases are valid targets for the development of antimalarial drugs.
Background: With the emergence of resistance to front-line antimalarials, there is an urgent need to develop new medicines, including those targeting sexual development. This study aimed to assess the activity of a panel of phosphatase inhibitors against the sexual development of Plasmodium berghei and evaluate their potential as transmission-blocking agents. Methods: Twenty-five compounds were screened for transmission-blocking activity in vitro using the P. berghei ookinete culture assay. The inhibitory effects on male gametogenesis, gamete-ookinete, and zygote-ookinete formation were evaluated. The transmission-blocking activity of two compounds was evaluated using an in vivo mosquito feeding assay. Their cytotoxic effects were assessed on the human cell line HepG2. Results: Twelve compounds inhibited P. berghei ookinete formation with an IC50 < 10 mu M. Two compounds, BVT948 and alexidine dihydrochloride, significantly inhibited different developmental stages from gametogenesis through ookinete maturation. They also showed a substantial in vivo transmission-blocking activity by the mosquito feeding assay. Conclusions: Some phosphatase inhibitors effectively inhibited Plasmodium sexual development and exhibited evident transmission-blocking activity, suggesting that phosphatases are valid targets for antimalarial development.
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