Investigating the antifibrotic potential of N-acetyl seryl-aspartyl-lysyl-proline sequence peptides.

Abstract

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a physiological antifibrotic peptide that is hydrolysed by angiotensin I-converting enzyme (ACE). The beneficial antifibrotic effects of ACE inhibitors have been attributed, in part, to its inhibition of Ac-SDKP cleavage. There is indirect evidence that the SDK fragment of Ac-SDKP is the main component required for its antiproliferative action. However, the exact component of the physiological peptide that is responsible for its antifibrotic effect has yet to be determined. Ac-SDKP-derived analogues that are resistant to ACE degradation may provide a new avenue for fibrosis therapy. We tested the antifibrotic potential of various Ac-SDKP peptide sequences and an analogue resistant to ACE degradation in lung fibroblasts. We investigated the contribution and molecular mechanism of action of the amino acid residues in the Ac-SDKP sequence to its antifibrotic effects, and the effects of Ac-SDKP peptides in the prevention of collagen deposition in cells. The Ac-DKP fragment moderately inhibited endothelin-1 (ET-1) mediated transforming growth factor-β (TGF- β) expression, and could be slowly cleaved by ACE, revealing a different sequence requirement for the antifibrotic action of Ac-SDKP. The Ac-SDψKP analogue (where the peptide bond between the aspartate and lysine is reduced) inhibited TGF-β/small mother against decapentaplegic (Smad)-3 signalling and collagen deposition. The Ac-SDKP peptide, in combination with ACEi, demonstrated a greater inhibition of hydroxyproline as compared to Ac-SDKP alone.

• Authors: Vinasha Ramasamy, Mpiko Ntsekhe, Edward Sturrock
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 48 Issue 11 Pg. 1558-1565 (11 2021) ISSN: 1440-1681 [Electronic] Australia
• PMID: 34347311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 John Wiley & Sons Australia, Ltd.

Chemical References

• Oligopeptides
• goralatide

Topics

• Oligopeptides