Activation of lysine-specific demethylase 1 inhibitor peptide by redox-controlled cleavage of a traceless linker
Activation of lysine-specific demethylase 1 inhibitor peptide by redox-controlled cleavage of a traceless linker
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DOI：
10.1016/j.bmc.2016.12.033
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发表时间：
2017-02-01
影响因子：
3.5
通讯作者：
Higuchi, Tsunehiko
中科院分区：
文献类型：
--
作者：
Amano, Yuichi;Umezawa, Naoki;Higuchi, Tsunehiko
我们之前曾采用线性肽的环化作为调节肽功能和性质的策略，但切割以再生线性肽会留下肽上连接体结构的部分，从而干扰其活性。在这里，我们重点关注通过“无痕”二硫键连接对线性肽进行环化，该连接在还原环境中被裂解并完全去除，从而重新生成没有任何连接体相关结构的原始线性肽。因此，连接体将充当氧化还原开关，在细胞内环境中被激活。我们将此策略应用于赖氨酸特异性脱甲基酶 1 (LSD1) 抑制剂肽 1。所得环肽 2 的 LSD1 抑制活性比肽 1 弱约 20 倍。添加还原剂后，接头被完全去除，重新生成线性肽 1，LSD1 抑制活性完全恢复。此外，环肽比线性肽更不易被蛋白水解作用。因此，这种开关设计不仅能够控制功能活动，而且还提高了稳定性。这种方法应该适用于广泛的肽，并且可能有助于肽药物的开发。 (C) 2016 Elsevier Ltd. 保留所有权利。
We have previously employed cyclization of a linear peptide as a strategy to modulate peptide function and properties, but cleavage to regenerate the linear peptide left parts of the linker structure on the peptide, interfering with its activity. Here, we focused on cyclization of a linear peptide via a "traceless" disulfide-based linkage that would be cleaved and completely removed in a reducing environment, regenerating the original linear peptide without any linker-related structure. Thus, the linker would serve as a redox switch that would be activated in the intracellular environment. We applied this strategy to a lysine-specific demethylase 1 (LSD1) inhibitor peptide 1. The resulting cyclic peptide 2 exhibited approximately 20 times weaker LSD1-inhibitory activity than peptide 1. Upon addition of reducing reagent, the linker was completely removed to regenerate the linear peptide 1, with full restoration of the LSD1-inhibitory activity. In addition, the cyclic peptide was far less susceptible to proteolysis than the linear counterpart. Thus, this switch design not only enables control of functional activity, but also improves stability. This approach should be applicable to a wide range of peptides, and may be useful in the development of peptide pharmaceuticals. (C) 2016 Elsevier Ltd. All rights reserved.