An NSAID-like compound, FT-9, preferentially inhibits gamma-secretase cleavage of the amyloid precursor protein compared to its effect on amyloid precursor-like protein 1.
An NSAID-like compound, FT-9, preferentially inhibits gamma-secretase cleavage of the amyloid precursor protein compared to its effect on amyloid precursor-like protein 1.
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DOI：
10.1021/bi901237k
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发表时间：
2009-11-24
期刊：
影响因子：
2.9
通讯作者：
Walsh DM
中科院分区：
文献类型：
--
作者：
Sala Frigerio C;Kukar TL;Fauq A;Engel PC;Golde TE;Walsh DM
抑制淀粉样前体蛋白（APP）的γ-分泌酶裂解是开发治疗阿尔茨海默病的治疗剂的主要目标;然而，完全抑制这种活性也会损害许多其他蛋白质的加工，包括APP同系物、淀粉样蛋白受体样蛋白（APLP）1和2。为了防止不希望的副作用，治疗上有用的γ-分泌酶抑制剂应该特异性靶向APP加工，同时避免切割其他γ-底物。因此，由于APLP 1和APLP 2与APP比任何其他已知的γ-分泌酶底物更相似，并且本身具有重要的生理作用，因此我们推断，比较γ-分泌酶抑制剂对APLP加工的影响应提供推定抑制剂选择性的灵敏指标。为了解决这个问题，我们优化了微粒体和细胞培养试验，以监测APP和APLPs的γ-分泌酶蛋白水解。APLP 1产生γ-分泌酶产生的胞内结构域（ICD）的速度比APLP 2或APP更快，表明APLP 1是更好的γ-底物，底物识别不限于ε-位点周围的高度保守氨基酸序列。正如预期，充分表征的γ-分泌酶调节剂非诺贝特不抑制ICD释放，而相关化合物FT-9抑制微粒体和全细胞中的γ-分泌酶。重要的是，FT-9显示出优先效应，抑制APP的切割比APLP 1的切割有效得多。这些研究结果表明，选择性抑制剂可以开发和筛选的化合物对APP和APLPs应有助于这一进程。
Inhibition of γ-secretase cleavage of the amyloid precursor protein (APP) is a prime target for the development of therapeutics for treating Alzheimer’s disease; however, complete inhibition of this activity would also impair the processing of many other proteins, including the APP homologues, amyloid precursor-like protein (APLP) 1 and 2. To prevent unwanted side effects, therapeutically useful γ-secretase inhibitors should specifically target APP processing while sparing cleavage of other γ-substrates. Thus, since APLP1 and APLP2 are more similar to APP than any of the other known γ-secretase substrates and have important physiological roles in their own right, we reasoned that comparison of the effect of γ-secretase inhibitors on APLP processing should provide a sensitive indicator of the selectivity of putative inhibitors. To address this issue, we have optimized microsome and cell culture assays to monitor the γ-secretase proteolysis of APP and APLPs. Production of the γ-secretase-generated intracellular domain (ICD) occurs more rapidly from APLP1 than from either APLP2 or APP, suggesting that APLP1 is a better γ-substrate and that substrate recognition is not restricted to the highly conserved amino acid sequences surrounding the ε-site. As expected, the well-characterized γ-secretase modulator, fenofibrate, did not inhibit ICD release, whereas a related compound, FT-9, inhibited γ-secretase both in microsomes and in whole cells. Importantly, FT-9 displayed a preferential effect, inhibiting cleavage of APP much more effectively than cleavage of APLP1. These findings suggest that selective inhibitors can be developed and that screening of compounds against APP and APLPs should assist in this process.
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影响因子：
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