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

• Published in: Parasitology international Vol. 66; no. 1; pp. 917 - 924
• Main Authors: Yamabe, Masafumi, Kumagai, Takashi, Shimogawara, Rieko, Blay, Emmanuel Awusah, Hino, Akina, Ichimura, Koichiro, Sato, Akira, Kim, Hye-Sook, Ohta, Nobuo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2017
• Subjects: Acidic organelle; Animals; Cathepsin B; Cathepsin B - metabolism; Drug Discovery; Gastroenterology and Hepatology; Heterocyclic Compounds, 2-Ring - pharmacology; Infectious Disease; Larva - drug effects; Life Cycle Stages - drug effects; Lysosome; Lysosomes - drug effects; Lysosomes - pathology; Lysosomes - ultrastructure; Microscopy, Electron, Transmission; N-251; Organelles - chemistry; Organelles - drug effects; Organelles - ultrastructure; Rhodamines - chemistry; Schistosoma mansoni; Schistosoma mansoni - drug effects; Schistosoma mansoni - growth & development; Schistosoma mansoni - ultrastructure; Schistosomicides - pharmacology; Spiro Compounds - metabolism; Spiro Compounds - pharmacology; Tetraoxanes - metabolism; Tetraoxanes - pharmacology; Transmission electron microscopy; C athepsin B; Schistosoma mansoni; Transmission electron microscopy; A cidic organelle; L ysosome; N-251; Cathepsin B; Acidic organelle; Lysosome
• ISSN: 1383-5769; 1873-0329
• DOI: 10.1016/j.parint.2016.10.013

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.