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Activation of lysine-specific demethylase 1 inhibitor peptide by redox-controlled cleavage of a traceless linker.

Abstract：

: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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Amano Y,Umezawa N,Sato S,Watanabe H,Umehara T,Higuchi T

doi

10.1016/j.bmc.2016.12.033

subject

Has Abstract

pub_date

2017-02-01 00:00:00

pages

1227-1234

issue

3

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)31208-1

journal_volume

25

pub_type

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