title: 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: Department of Environmental Parasitology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors: Masafumi
authors: M
authors: Yamabe
authors: Department of Environmental Parasitology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors: Takashi
authors: T
authors: Kumagai
authors: Department of Environmental Parasitology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors: Rieko
authors: R
authors: Shimogawara
authors: Department of Environmental Parasitology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors: Emmanuel Awusah
authors: EA
authors: Blay
authors: Department of Environmental Parasitology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors: Akina
authors: A
authors: Hino
authors: Department of Anatomy and Life Structure, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Koichiro
authors: K
authors: Ichimura
authors: Division of International Infectious Diseases Control, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors: Akira
authors: A
authors: Sato
authors: Division of International Infectious Diseases Control, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors: Hye-Sook
authors: HS
authors: Kim
authors: Department of Environmental Parasitology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. Electronic address: matata.vip@tmd.ac.jp.
authors: Nobuo
authors: N
authors: Ohta
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D055808:Drug Discovery; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D007814:Larva / Q000187:drug effects; D008018:Life Cycle Stages / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D015388:Organelles / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D012235:Rhodamines / Q000737:chemistry; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000254:growth & development* / Q000648:ultrastructure; D012556:Schistosomicides / Q000494:pharmacology*; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology*; D045568:Tetraoxanes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C430901:1,2,6,7-tetraoxaspiro(7.11)nonadecane; C571809:6-(1,2,6,7-tetraoxaspiro(7.11)nonadec-4-yl)hexan-1-ol; D006574:Heterocyclic Compounds, 2-Ring; D012235:Rhodamines; D012556:Schistosomicides; D013141:Spiro Compounds; D045568:Tetraoxanes; D002401:Cathepsin B
keywords: Acidic organelle; Cathepsin B; Lysosome; N-251; Schistosoma mansoni; Transmission electron microscopy