57(P23) Ser/ThrプロテインホスファターゼPP1,2A阻害剤カンタリジンのPP2B選択的阻害剤への変換(ポスター発表の部)
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Protein serine/threonine phosphatases (PPs) play an important role in intracellular signal transduction. The immunosuppressant drugs, FK506 and cyclosporin A (CsA), are known to act through protein phosphatase 2B (PP2B, calcineurin). These immunosuppressants bind to intracellular receptor proteins known as immunophilins (immunosuppressant binding proteins), and these complexes selectively inhibit PP2B leading to the suppression of T-cell proliferation. Both FK506 and CsA must, however, form complexes with immunophilins to exert their inhibitory action on PP2B. Recently, immunophilins were clarified to regulate a calcium ion channel and some important cellular processes. Thus it is of interest to find a direct inhibitor of PP2B (not inhibit immunophilins) as a useful biological tool for studies of PP2B as well as a candidate therapeutic agent. Various natural toxins and/or tumor promoters such as okadaic acid, microcystin-LR, tautomycin and cantharidin (1) are known to be strong protein phosphatase 1 (PP1) and/or 2A (PP2A) inhibitors, while they are very weak inhibitors of PP2B. We planned to design a selective PP2B inhibitor based on the tertiary structure of PPs. The X-ray structure of the PP1-microcystin complex reveals an interaction between the two carboxylic acid groups of microcystin with the catalytic site of PP1 containing two metal ions. Since it is expected that the two carboxylic acids in cantharidin (hydrolyzed form) also interact with this catalytic site, which is highly conserved through these three phosphatases, we selected this simple natural product, cantharidin (1) as a starting point of this project. We postulated that it might be possible to change the subtype specificity of cantharidin by introducing a substituent which favorably interacts with a neighboring non-conserved region of PP2B, but which also has unfavorable interactions with that of PP1 and PP2A. First, we synthesized several cantharidin derivatives and measured their ability to inhibit PP1, PP2A and PP2B, and build a binding model of the norcantharidin-PP2B catalytic site based on the results. Next, computational docking study was carried out, and cantharidin derivatives having two substituents to C1/C5 or C1/C6 position were designed and synthesized (Scheme 2). Among these compounds, 1,5-dibenzoyloxymethyl substituted cantharidin 39 was found to inhibit PP2B without inhibiting PP1 and PP2A (Figure 3). To our knowledge, it is the first direct inhibitor of PP2B with complete subtype selectivity.
- 天然有機化合物討論会の論文
- 1999-09-01
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