Probing pockets S2-S4′ of the γ-secretase active site with (hydroxyethyl)urea peptidomimeties
Probing pockets S2-S4′ of the γ-secretase active site with (hydroxyethyl)urea peptidomimeties
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DOI：
10.1016/j.bmcl.2004.01.077
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发表时间：
2004-04-19
影响因子：
2.7
通讯作者：
Wolfe, MS
中科院分区：
文献类型：
--
作者：
Esler, WP;Das, C;Wolfe, MS
（羟乙基）脲肽模拟物是γ-分泌酶的有效抑制剂，其可在几个合成步骤中获得。P2-P4'的系统改变揭示了相应的S2-S4'活性位点口袋容纳各种取代基，这与该蛋白酶切割各种单程膜蛋白的事实一致;然而，苯丙氨酸在P2 '处耐受性不好。跨越P2-P3'的化合物被鉴定为在细胞中和在无细胞条件下γ-分泌酶活性的低nM抑制剂。(C)2004年由Elsevier Ltd.出版。
(Hydroxyethyl)urea peptidomimetics are potent inhibitors of gamma-secretase that are accessible in a few synthetic steps. Systematic alteration of P2-P4' revealed that the corresponding S2-S4' active site pockets accommodate a variety of substituents, consistent with the fact that this protease cleaves a variety of single-pass membrane proteins; however, phenylalanine is not well tolerated at P2'. A compound spanning P2-P3' was identified as a low nM inhibitor of gamma-secretase activity both in cells and under cell-free conditions. (C) 2004 Published by Elsevier Ltd.