Search for ryanodine binding inhibitor produced by microorganisms

植物生物碱兰尼定是兰诺定受体(RyR)的激动剂，具有杀虫活性。RyR是肌浆网钙离子释放通道。哺乳动物的RyR有三种亚型：RyR1、RyR2和RyR3。然而，昆虫有一个单一但独特的RyR。因此，昆虫RyR是一种潜在的新型杀虫剂靶标。在从微生物代谢产物中筛选Ryanodine结合抑制剂的过程中，我们从青霉中分离到了Altenusin和脱氢Altenusin。从黑孢子菌FKI-3795、CJ-13,982分离得到。FKI-3299和从青霉菌(Penicillium sp.)FKI-3647。它们的兰尼定结合抑制活性尚未见报道。我们以前从黄萎病菌的发酵液中分离到一种新的24元环去脂肽，命名为Verticilide。FKI-1033作为兰尼定结合抑制剂。对其平面结构进行了研究，并通过对其水解物的分析确定了其绝对结构。我们还完成了它的全合成和结构确证。Verticilide对蟑螂RyR的IC50&gt；值为4.2μM，对小鼠腿肌RyR的IC50&gt；值为53.9μM。因此，它对蟑螂受体的抑制作用约为13倍。轮枝菌素具有较好的杀虫、杀螨活性。我们正在研究合成具有很强活性的轮状内酯类似物。

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.