Search for ryanodine binding inhibitor produced by microorganisms

寻找微生物产生的兰尼定结合抑制剂

• 批准号: 17590091
• 负责人: SHIOMI Kazuro
• 金额: $ 2.11万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590091/
• 关键词: ryanodine; receptor; antibiotics; bioactive compounds; insecticides; screening; 生活活性物質

A plant alkaloid, ryanodine, is an agonist of ryanodine receptor (RyR) and exhibits insecticidal activity. RyR is a Ca^<2+> release channel of the sarcoplasmic reticulum. There are three subtypes, RyR1, RyR2, and RyR3, in mammalian RyR. However, insects have a single but distinct RyR. Therefore, insect RyR is a potential target for new insecticides.In the course of screening for ryanodine binding inhibitors from microbial metabolites, we isolated altenusin and dehydroaltenusin from PenicHlium sp. FKI-3795, CJ-13,982 from Nigrospora sp. FKI-3299, and tenellic acid C from Penicillium sp. FKI-3647. Their activities of ryanodine binding inhibition have not ever been reported.We have previously isolated a new 24-membered cyclic depsipeptide, named verticilide, from the culture broth of Verticillium sp. FKI-1033 as a ryanodine binding inhibitor. The planer structure was already studied, and we elucidated the absolute structure by the analysis of its hydrolysates. We have also accomplished its total synthesis and confirmed the structure. Verticilide exhibited [^3H]-labeled ryanodine binding inhibition against cockroach RyR at the IC_<50> value of 4.2 μM and against mouse leg muscle RyR at the IC_<50> value of 53.9 μM. Therefore, it showed about 13 times more potent inhibition to cockroach receptor. Verticilide showed some good insecticidal and acaricidal activities. We are studying the synthesis of verticilide analogs having much potent activity.

植物生物碱，兰尼碱，是兰尼碱受体(RyR)的激动剂，具有杀虫活性。RyR是哺乳动物肌浆网的Ca 2+ 释放通道，有RyR1、RyR2和RyR3三种亚型。然而，昆虫具有单一但独特的RyR，因此，昆虫RyR是新型杀虫剂的潜在目标。从微生物代谢物中筛选兰尼碱结合抑制剂，我们从青霉菌 FKI-3795 中分离出阿藤菌素和脱氢阿藤菌素，从黑孢菌 FKI-3299 中分离出 CJ-13,982，以及从青霉菌 FKI-3647 中分离出软藻碱结合活性。抑制作用尚未有报道。我们之前已经分离出一种新的24 元环状缩肽，命名为 Verticillium sp. FKI-1033 的培养液，作为兰尼碱结合抑制剂，其平面结构已被研究，并且我们还通过分析其水解产物阐明了其绝对结构。其全合成并证实了其结构，[^3H]标记的兰尼碱对蟑螂RyR的结合抑制作用为IC_<50>值。 4.2μM，对小鼠腿部肌肉RyR的IC_<50>值为53.9μM，因此，它对蟑螂受体的抑制作用强约13倍，显示出一些良好的杀虫和杀螨活性。我们正在研究杀虫剂类似物的合成。具有很强的活性。