| Co-Investigator(Kenkyū-buntansha) |
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)
TAKAHASHI Yoko Kitasato University, Kitasato Institute for Life Sciences, Professor, 北里生命科学研究所, 教授 (80197186)
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| Research Abstract |
NADH-fumarate reductase (complex I+II) is a key enzyme of anaerobic energy metabolism in many adult helminths. In the course of the, screening of NADH-fumarate reductase inhibitors from adult roundworm, Ascaris suum, we have isolated harzianopyridone from Trichoderma sp. FTD-0795. We studied the target enzyme using atpenin A5, a more potent inhibitor of harzianopyridone analog, and found that it specifically inhibited complex II. Though atpenin A5 did not show selectivity between helminths and mammals, it showed 300 times more potent complex II inhibition than carboxin the most potent known inhibitor of complex II. Therefore, atpenin A5 may be a useful tool for biochemical study of complex II.
Our continuous screening achieved the finding of another five inhibitors, glisoprenin A, paecilaminol, verticipyrorie, decursin, and decursinol angelate. Among them, paecilaminol and verticipyrone are new compounds, and verticipyrone showed potent inhibition against A. suum NADH-fumarate reductase with IC_<50> value of 4.1 nM and weak inhibition to mammal bovine heart NADH oxidase (complex I+III+IV) with IC_<50> value of 56.0 nM. We are evaluating anthelmintic activities of these compounds now.
We found selective helminth complex I inhibitor, nafuredin, previously. Alkaline treatment of nafuredin yielded a new compound nafuredin-γ that showed almost the same complex I inhibition and anthelmintic activity as nafuredin. We have already finished the total synthesis of nafuredin-γ, and we will prepare more potent analogs of nafuredin-γ.
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