Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan.
School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.
Antimicrob Agents Chemother. 2023 Mar 16;67(3):e0142822. doi: 10.1128/aac.01428-22. Epub 2023 Feb 22.
Ascofuranone (AF), a meroterpenoid isolated from various filamentous fungi, including , 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]; IC = 0.037 to 0.135 μM) and also complex I to III (NADH:cytochrome reductase; IC = 0.008 to 0.401 μM), 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. 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.
阿索呋喃酮（AF）是一种从各种丝状真菌中分离出来的倍半萜类化合物，包括 ，已被报道为针对寄生虫和癌症的药物开发的潜在先导候选物。在这项研究中，我们证明 AF 及其衍生物是有效的驱虫剂，特别是针对泡状棘球蚴，这是泡状棘球蚴病的病原体。我们测量了 AF 及其衍生物对泡状棘球蚴幼虫线粒体需氧和厌氧呼吸系统的抑制活性。几种衍生物抑制了复合物 II（琥珀酸：醌还原酶 [SQR]；IC = 0.037 至 0.135 μM）和复合物 I 至 III（NADH：细胞色素还原酶；IC = 0.008 至 0.401 μM），但不抑制复合物 I（NADH：醌还原酶），表明线粒体复合物 II 和 III 是靶标。特别是，厌氧途径中复合物 II 的抑制作用很明显，因为泡状棘球蚴除了 NADH 氧化酶（氧气呼吸）外，还使用 NADH：延胡索酸还原酶（延胡索酸呼吸），导致氧化磷酸化完全停止 ATP 合成。泡状棘球蚴复合物 II 的构效关系研究表明，AF 的功能基团对抑制是必不可少的。AF 衍生物与复合物 II 的结合模式预测表明，AF 衍生物与醌结合位点内的氨基酸残基之间存在潜在的疏水和氢键相互作用。培养实验表明，AF 衍生物在需氧和厌氧条件下逐渐降低原头蚴的活力。这些发现证实 AF 及其衍生物是泡状棘球蚴中延胡索酸和氧气呼吸的首次双重抑制剂，是抗包虫病药物开发的潜在先导化合物。
