Phosphatase inhibitors BVT-948 and alexidine dihydrochloride inhibit sexual development of the malaria parasite Plasmodium berghei

  • Int J Parasitol Drugs Drug Resist. 2022 Aug;19:81-88. doi: 10.1016/j.ijpddr.2022.06.003.
Xitong Jia  1 ,  Fei Liu  2 ,  Jie Bai  2 ,  Yongzhe Zhang  3 ,  Liwang Cui  4 ,  Yaming Cao  5 ,  Enjie Luo  6
Affiliations
  • 1. Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, 110122, China.
  • 2. Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, 110122, China.
  • 3. Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, 110122, China; Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
  • 4. Department of Internal Medicine, Morsani College of Medicine, University of South Florida, 3720 Spectrum Boulevard, Suite 304, Tampa, FL, 33612-9415, USA.
  • 5. Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, 110122, China. Electronic address: [email protected].
  • 6. Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, 110122, China. Electronic address: [email protected].
PMID: 35792443 DOI: 10.1016/j.ijpddr.2022.06.003
Abstract

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 μM. Two compounds, BVT-948 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.

Keywords
Drug; Malaria; Phosphatase; Plasmodium berghei; Transmission.
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