The novel peptide DR4penA attenuates the bleomycin- and paraquat-induced pulmonary fibrosis by suppressing the TGF-β/Smad signaling pathway

Pulmonary fibrosis (PF), which is caused by continuous alveolar epithelial cell injury and abnormal repair, is referred to as a difficult disease of the lung system by the World Health Organization due to its rapid progression, poor prognosis, and high mortality rate. However, there is still a lack of ideal therapeutic strategies. The peptide DR8 (DHNNPQIR-NH2), which is derived from rapeseed, exerted antifibrotic activity in the lung, liver, and kidney in our previous studies. By studying the structure-activity relationship and rational design, we introduced an unnatural hydrophobic amino acid (alpha-(4-pentenyl)-Ala) into DR8 and screened the novel peptide DR4penA (DHN alpha-(4-pentenyl)-APQIR-NH2), which had higher anti-PF activity, higher antioxidant activity and a longer half-life than DR8. Notably, DR4penA attenuated bleomycin- and paraquat-induced PF, and the anti-PF activity of DR4penA was equivalent to that of pirfenidone. Additionally, DR4penA suppressed the TGF-beta/Smad pathway in TGF-beta 1-induced A549 cells and paraquat-induced rats. This study demonstrates that the novel peptide DR4penA is a potential candidate compound for PF therapy, and its antifibrotic activity in different preclinical models of PF provides a theoretical basis for further study.

Automated summary

In this study, a novel peptide DR4penA was designed based on the structure-activity relationship and rational design. DR4penA showed higher anti-PF activity, antioxidant activity, and a longer half-life compared to the original peptide DR8. It was found that DR4penA attenuated bleomycin- and paraquat-induced PF, and its anti-PF activity was equivalent to that of pirfenidone. Furthermore, DR4penA suppressed the TGF-beta/Smad pathway in TGF-beta 1-induced A549 cells and paraquat-induced rats. This study suggests that DR4penA is a potential candidate for PF therapy.