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

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.

• Authors: Masafumi Yamabe, Takashi Kumagai, Rieko Shimogawara, Emmanuel Awusah Blay, Akina Hino, Koichiro Ichimura, Akira Sato, Hye-Sook Kim, Nobuo Ohta
• Journal: Parasitology international (Parasitol Int) Vol. 66 Issue 1 Pg. 917-924 (Feb 2017) ISSN: 1873-0329 [Electronic] Netherlands
• PMID: 27771462 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 1,2,6,7-tetraoxaspiro(7.11)nonadecane
• 6-(1,2,6,7-tetraoxaspiro(7.11)nonadec-4-yl)hexan-1-ol
• Heterocyclic Compounds, 2-Ring
• Rhodamines
• Schistosomicides
• Spiro Compounds
• Tetraoxanes
• Cathepsin B

Topics

• Animals
• Cathepsin B (metabolism)
• Drug Discovery
• Heterocyclic Compounds, 2-Ring (pharmacology)
• Larva (drug effects)
• Life Cycle Stages (drug effects)
• Lysosomes (drug effects, pathology, ultrastructure)
• Microscopy, Electron, Transmission
• Organelles (chemistry, drug effects, ultrastructure)
• Rhodamines (chemistry)
• Schistosoma mansoni (drug effects, growth & development, ultrastructure)
• Schistosomicides (pharmacology)
• Spiro Compounds (metabolism, pharmacology)
• Tetraoxanes (metabolism, pharmacology)