Discovery of aryl aminothiazole γ-secretase modulators with novel effects on amyloid β-peptide production.
Discovery of aryl aminothiazole γ-secretase modulators with novel effects on amyloid β-peptide production.
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DOI：
10.1016/j.bmcl.2021.128446
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发表时间：
2021-12-15
影响因子：
2.7
通讯作者：
Wolfe, Michael S.
中科院分区：
文献类型：
--
作者：
Bhattarai, Sanjay;Liu, Lei;Wolfe, Michael S.
合成了一系列基于芳基氨基噻唑γ-分泌酶调节剂（GSM）原型的类似物，并测试了它们对γ-分泌酶对前体蛋白底物进行蛋白水解产生的37-42-残基淀粉样β肽（Aβ）谱的影响。与母体分子相比，末端芳基D环上的某些取代导致Aβ产生谱发生改变。微小的结构变化导致Aβ37和Aβ38产生呈浓度依赖性增加，而其前体Aβ40和Aβ42分别未平行减少。因此，新化合物显然也刺激羧肽酶修剪Aβ肽≥43个残基，为γ-分泌酶进行性蛋白水解的机制研究提供了新的化学工具。
A series of analogs based on a prototype aryl aminothiazole γ-secretase modulator (GSM) were synthesized and tested for their effects on the profile of 37-to-42-residue amyloid β-peptides (Aβ), generated through processive proteolysis of precursor protein substrate by γ-secretase. Certain substitutions on the terminal aryl D ring resulted in an altered profile of Aβ production compared to that seen with the parent molecule. Small structural changes led to concentration-dependent increases in Aβ37 and Aβ38 production without parallel decreases in their precursors Aβ40 and Aβ42, respectively. The new compounds therefore apparently also stimulate carboxypeptidase trimming of Aβ peptides ≥43 residues, providing novel chemical tools for mechanistic studies of processive proteolysis by γ-secretase.
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DOI：
10.1016/j.jbc.2021.100393
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Liu L;Lauro BM;Wolfe MS;Selkoe DJ
通讯作者：
Selkoe DJ
影响因子：
6.7
作者：
Bhuniya, Debnath;Mukkavilli, Rao;Martin, Denis
通讯作者：
Martin, Denis
影响因子：
2.7
作者：
Rynearson, Kevin D.;Buckle, Ronald N.;Wagner, Steven L.
通讯作者：
Wagner, Steven L.
影响因子：
2.9
作者：
Wolfe, Michael S.
通讯作者：
Wolfe, Michael S.
影响因子：
7.3
作者：
Bursavich, Matthew G.;Harrison, Bryce A.;Blain, Jean-Francois
通讯作者：
Blain, Jean-Francois