Novel synthetic compounds with endoperoxide structure damage juvenile stage of Schistosoma mansoni by targeting lysosome-like organelles

Masafumi Yamabe, Takashi Kumagai, Rieko Shimogawara, Emmanuel Awusah Blay, Akina Hino, Koichiro Ichimura, Akira Sato, Hye-Sook Kim, Nobuo Ohta

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The new synthetic compound 1,2,6,7-tetraoxaspiro[7.11]nonadecan (N-89), a novel anti-malaria drug candidate, is also a promising drug candidate against schistosomiasis with killing effects against juvenile stage of S. mansoni. In order to investigate how N-89 kills schistosomes, we used a derivative of N-89, 6-(1,2,6,7-tetraoxaspiro[7.11] nonadec-4-yl)hexan-1-ol (N-251), which enables us to conjugate with fluorescent reagents. Firstly, N-251 showed strong killing effects to larvae of S. mansoni in vitro. Ultrastructural analysis showed the disruptions of the lysosome-like organelles or the acetabular glands, followed by cytoplasmic lysis inside the worm body in N-251-treated group under electron microscopy. For rhodamine-conjugated N-251 and organelle markers, we observed that N-251 accumulated in acidic organelle. In addition, LysoTracker signals in these acidic organelles disappeared in N-251-treated group over time. Finally, we observed that the activity of cathepsin B, a lysosome-specific enzyme, was also decreased together with alternation of acidic organelle marker signal by N-251-treated group. These results suggested that our synthesized compounds induced the dysfunction or the disruption of acidic lysosome-like organelles and finally led to worm death.

Original languageEnglish
Pages (from-to)917-924
Number of pages8
JournalParasitology International
Volume66
Issue number1
DOIs
Publication statusPublished - Feb 1 2017

Keywords

  • Acidic organelle
  • Cathepsin B
  • Lysosome
  • N-251
  • Schistosoma mansoni
  • Transmission electron microscopy

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

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