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Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling.

Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling.
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Kang JH, Jung MY, Yin X, Andrianifahanana M, Hernandez DM, Leof EB,


Kang JH, Jung MY, Yin X, Andrianifahanana M, Hernandez DM, Leof EB, (click to view)

Kang JH, Jung MY, Yin X, Andrianifahanana M, Hernandez DM, Leof EB,

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The Journal of clinical investigation 2017 05 22127(7) 2541-2554 doi 10.1172/JCI88696

Abstract

TGF-β is considered a master switch in the pathogenesis of organ fibrosis. The primary mediators of this activity are the SMAD proteins, particularly SMAD3. In the current study, we have developed a cell-penetrating peptide (CPP) conjugate of the HIV TAT protein that is fused to an aminoterminal sequence of sorting nexin 9 (SNX9), which was previously shown to bind phosphorylated SMAD3 (pSMAD3). We determined that specifically preventing the nuclear import of pSMAD3 using the TAT-SNX9 peptide inhibited profibrotic TGF-β activity in murine cells and human lung fibroblasts as well as in vivo with no demonstrable toxicity. TGF-β signaling mediated by pSMAD2, bone morphogenetic protein 4 (BMP4), EGF, or PDGF was unaffected by the TAT-SNX9 peptide. Furthermore, while the TAT-SNX9 peptide prevented TGF-β’s profibrotic activity in vitro as well as in 2 murine treatment models of pulmonary fibrosis, a 3-amino acid point mutant that was unable to bind pSMAD3 proved ineffective. These findings indicate that specifically targeting pSMAD3 can ameliorate both the direct and indirect fibroproliferative actions of TGF-β.

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