Targeting Smad-Dependent TGF-β Signaling with Peptide Aptamers

Abstract

Peptide aptamers, variable constrained protein motifs displayed on a rigid protein scaffold, have been used to disrupt a number of different protein-protein interactions in cells, resulting in specific changes in cell proliferation or signaling. TGF-beta signal transduction relies on the assembly of protein complexes around the Smad heterotrimer to activate or repress specific gene expression responses. In order to understand which Smad protein interactions are important for specific responses to TGF-beta, and to identify protein binding sites on Smads that might be selective therapeutic targets, we are developing a library of Smad-binding peptide aptamers, initially based on displaying known, Smad binding motifs on the Thioredoxin A (Trx) scaffold. We review here the use of peptide aptamers, the known Smad binding motifs, and our initial studies that demonstrate that peptide aptamers have selective effects on TGF-beta induced transcription.