2006 Fiscal Year Final Research Report Summary
Search for ryanodine binding inhibitor produced by microorganisms
| Project/Area Number |
17590091
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Kitasato University |
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Principal Investigator |
SHIOMI Kazuro Kitasato University, Kitasato Institute for life Sciences, Professor, 北里生命科学研究所, 教授 (40235502)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Yoko Kitasato University, Kitasato Institute for Life Sciences, Professor, 北里生命科学研究所, 教授 (80197186)
MASUMA Rokuro Kitasato University, Kitasato Institute for Life Sciences, Assistant Professor, 北里生命科学研究所, 専任講師 (90219353)
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| Project Period (FY) |
2005 – 2006
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| Keywords | ryanodine / receptor / antibiotics / bioactive compounds / insecticides / screening |
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| Research Abstract |
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.
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