Development and Characterization of Monomeric N-End Rule Inhibitors through In Vitro Model Substrates
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- 作者：Shashi Sriram ; Jung Hoon Lee ; Binh Khanh Mai ; Yanxialei Jiang ; Yongho Kim ; Young Dong Yoo ; Rajkumar Banerjee ; Seung-Han Lee ; Min Jae Lee
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：March 28, 2013
- 年：2013
- 卷：56
- 期：6
- 页码：2540-2546
- 全文大小：387K
- 年卷期：v.56,no.6(March 28, 2013)
- ISSN：1520-4804
文摘
In the N-end rule pathway, a set of N-terminal amino acids, called N-degrons, are recognized and ubiquitinated by the UBR proteins. Here we examined various N-end rule inhibitors to identify essential structural components of the system. Our study using in vitro biochemical assay indicated that the l-conformation and protonated 伪-amino group of the first residue were critical for N-degrons to properly interact with the UBR proteins. The monomeric molecules with minimum interacting motifs showed endopeptidase resistance and better inhibitory activities than traditional dipeptide inhibitors. Collectively, our study identifies a pharmacophore of N-end rule inhibitors, which provides a structural platform to improve the efficiency and druggable properties of inhibitors. Considering that the N-end rule has been implicated in many pathophysiological processes in cells, inhibitors of this pathway, such as p-chloroamphetamine, are potentially of clinical interest in a novel aspect of action mechanisms.