<p>Synthesis and Identification of a Novel Peptide, Ac-SDK (Biotin) Proline, That Can Elicit Anti-Fibrosis Effects in Rats Suffering from Silicosis</p>

Abstract

Background: N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a short peptide with an anti-silicosis effect. However, the short biological half-life and low plasma concentration of Ac-SDKP hamper discovery of specific targets in organisms and reduce the anti-silicosis effect. A novel peptide, Ac-SDK (biotin) proline, termed "Ac-B", with anti-fibrotic properties was synthesized. Methods: Ac-B was detected quantitatively by high-performance liquid chromatography. Phagocytosis of Ac-B by the alveolar epithelial cell line A549 was investigated by confocal laser scanning microscopy and flow cytometry. To further elucidate the cellular-uptake mechanism of Ac-B, chemical inhibitors of specific uptake pathways were used. After stimulation with transforming growth factor-β1, the effects of Ac-B on expression of the myofibroblast marker vimentin and accumulation of collagen type I in A549 cells were analyzed by Western blotting. Sirius Red staining and immunohistochemical analyses of the effect of Ac-B on expression of α-smooth muscle actin (SMA) in a rat model of silicosis were undertaken. Results: Ac-B had good traceability during the uptake, entry, and distribution in cells. Ac-B treatment prevented an increase in α-SMA expression in vivo and in vitro and was superior to that of Ac-SDKP. Caveolae-mediated uptake of Ac-B by A549 cells led to achieving antiepithelial-mesenchymal transformation (EMT) effects. Conclusion: Ac-B had an anti-fibrotic effect and could be a promising agent for the fibrosis observed in silicosis in the future.

Phospholipid Encapsulation of an Anti-Fibrotic Endopeptide to Enhance Cellular Uptake and Myocardial Retention

“…However, the therapeutic use of Ac-SDKP remained challenging because of its rapid breakdown by angiotensin-converting enzymes, resulting in a short plasma half-life of only 4.5 min [ 25 ]. Two research groups independently attempted to stabilize this peptide by synthesizing its analogues, but their biological implications were limited [ 26 , 27 ]. Wang et al [ 26 ] developed a biotinylated Ac-SDKP and tested its antifibrotic effects in a murine model of pulmonary fibrosis.…”

“…Two research groups independently attempted to stabilize this peptide by synthesizing its analogues, but their biological implications were limited [ 26 , 27 ]. Wang et al [ 26 ] developed a biotinylated Ac-SDKP and tested its antifibrotic effects in a murine model of pulmonary fibrosis. However, its plasma stability and tissue availability were not investigated.…”