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Killing Two Birds with One Stone: Discovery of Dual Inhibitors of Oxygen and Fumarate Respiration in Zoonotic Parasite, Echinococcus multilocularis
http://hdl.handle.net/10069/00042067
http://hdl.handle.net/10069/00042067b4ce9dd7-0e7c-448e-805a-8fdd1d7848d8
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
AAC67_e01428-22.pdf (1.8 MB)
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| Item type | 学術雑誌論文 / Journal Article(1) | |||||
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| 公開日 | 2023-02-24 | |||||
| タイトル | ||||||
| タイトル | Killing Two Birds with One Stone: Discovery of Dual Inhibitors of Oxygen and Fumarate Respiration in Zoonotic Parasite, Echinococcus multilocularis | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Echinococcus multilocularis | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | ascofuranone | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | structure-activity relationship | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | mitochondrial complex II | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | fumarate respiration | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | drug development | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | dual inhibitors | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| 著者 |
Enkai, Shigehiro
× Enkai, Shigehiro× Kouguchi, Hirokazu× Inaoka, Daniel Ken× Shiba, Tomoo× Hidaka, Masahito× Matsuyama, Hiroyuki× Sakura, Takaya× Yagi, Kinpei× Kita, Kiyoshi |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Ascofuranone (AF), a meroterpenoid isolated from various filamentous fungi, including Acremonium egyptiacum, has been reported as a potential lead candidate for drug development against parasites and cancer. In this study, we demonstrated that AF and its derivatives are potent anthelminthic agents, particularly against Echinococcus multilocularis, which is the causative agent of alveolar echinococcosis. We measured the inhibitory activities of AF and its derivatives on the mitochondrial aerobic and anaerobic respiratory systems of E. multilocularis larvae. Several derivatives inhibited complex II (succinate:quinone reductase [SQR]; IC50 = 0.037 to 0.135 mM) and also complex I to III (NADH:cytochrome c reductase; IC50 = 0.008 to 0.401 mM), but not complex I (NADH:quinone reductase), indicating that mitochondrial complexes II and III are the targets. In particular, complex II inhibition in the anaerobic pathway was notable because E. multilocularis employs NADH:fumarate reductase (fumarate respiration), in addition to NADH oxidase (oxygen respiration), resulting in complete shutdown of ATP synthesis by oxidative phosphorylation. A structure-activity relationship study of E. multilocularis complex II revealed that the functional groups of AF are essential for inhibition. Binding mode prediction of AF derivatives to complex II indicated potential hydrophobic and hydrogen bond interactions between AF derivatives and amino acid residues within the quinone binding site. Ex vivo culture assays revealed that AF derivatives progressively reduced the viability of protoscoleces under both aerobic and anaerobic conditions. These findings confirm that AF and its derivatives are the first dual inhibitors of fumarate and oxygen respiration in E. multilocularis and are potential lead compounds in the development of anti-echinococcal drugs. | |||||
| 書誌情報 |
Antimicrobial Agents and Chemotherapy p. e01428-22, 発行日 2023-02-22 |
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| 出版者 | ||||||
| 出版者 | American Society for Microbiology | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 0066-4804 | |||||
| DOI | ||||||
| 関連タイプ | isIdenticalTo | |||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1128/aac.01428-22 | |||||
| 権利 | ||||||
| 権利情報 | © 2023 Enkai et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license. | |||||
| 著者版フラグ | ||||||
| 出版タイプ | VoR | |||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
| 引用 | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Antimicrobial Agents and Chemotherapy, art. no. e01428-22; 2023 | |||||
