Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors
Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors
复制标题
评估作为肽模拟 BACE1 抑制剂的卓越 BACE1 裂解序列中的过渡态模拟物
DOI：
10.1016/j.bmc.2015.07.023
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发表时间：
2015
影响因子：
3.5
通讯作者：
Akaji K
中科院分区：
文献类型：
--
作者：
Hattori Y;Kobayashi K;Deguchi A;Nohara Y;Akiyama T;Teruya K;Sanjoh A;Nakagawa A;Yamashita E;Akaji K
一个上级底物序列的BACE 1含有过渡态模拟物在易切割的网站进行了评估，作为一种蛋白酶抑制剂。选择羟甲基羰基（HMC）和羟乙基胺（HEA）等排体作为过渡态模拟物，并掺入覆盖P4至P1'位点的上级序列的易切割位点（Glu-Ile-Thi-Thi*Nva;* 表示切割位点）。分别合成了具有不同羟基绝对构型的电子等排体，并评价了构型的影响。各电子等排体的羟基构型对抑制活性有显著影响;易切断位点取代基的反构型对HMC型抑制剂有较强的抑制活性，而HEA型抑制剂的反构型则无抑制活性。基于重组BACE 1与每种抑制剂复合的X射线晶体学分析的结构评价提供了对蛋白质-配体相互作用的见解，特别是在主要位点。
A superior substrate sequence for BACE1 containing transition-state mimics at the scissile site was evaluated as a protease inhibitor. Hydroxymethylcarbonyl (HMC) and hydroxyethylamine (HEA) isosteres were selected as the transition state mimics, and incorporated into the scissile site of the superior sequence covering the P4to P1’ sites (Glu-Ile-Thi-Thi*Nva;*denotes the cleavage site). Isosteres having different absolute configurations of the hydroxyl group were synthesized separately, and the effect of the configuration was evaluated. Configuration of the hydroxyl group of each isostere showed a marked effect on the inhibitory activity;anti-configuration to the scissile site substituent had potent inhibitory activity in an HMC-type inhibitor, whereasanti-configuration of HEA-type inhibitors showed no inhibitory activity. Structural evaluations based on X-ray crystallographic analyses of recombinant BACE1 in complex with each inhibitor provided insights into the protein–ligand interactions, especially at the prime sites.