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The beneficial antifibrotic effects of ACE inhibitors have been attributed, in part, to its inhibition of Ac\u2010SDKP cleavage. There is indirect evidence that the SDK fragment of Ac\u2010SDKP 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\u2010SDKP\u2010derived analogues that are resistant to ACE degradation may provide a new avenue for fibrosis therapy. We tested the antifibrotic potential of various Ac\u2010SDKP 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\u2010SDKP sequence to its antifibrotic effects, and the effects of Ac\u2010SDKP peptides in the prevention of collagen deposition in cells. The Ac\u2010DKP fragment moderately inhibited endothelin\u20101 (ET\u20101) mediated transforming growth factor\u2010\u03b2 (TGF\u2010 \u03b2) expression, and could be slowly cleaved by ACE, revealing a different sequence requirement for the antifibrotic action of Ac\u2010SDKP. The Ac\u2010SD\u03c8KP analogue (where the peptide bond between the aspartate and lysine is reduced) inhibited TGF\u2010\u03b2\/small mother against decapentaplegic (Smad)\u20103 signalling and collagen deposition. The Ac\u2010SDKP peptide, in combination with ACEi, demonstrated a greater inhibition of hydroxyproline as compared to Ac\u2010SDKP alone.<\/jats:p>","DOI":"10.1111\/1440-1681.13565","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T16:05:52Z","timestamp":1628093152000},"page":"1558-1565","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Investigating the antifibrotic potential of N\u2010acetyl seryl\u2010aspartyl\u2010lysyl\u2010proline sequence peptides"],"prefix":"10.1111","volume":"48","author":[{"given":"Vinasha","family":"Ramasamy","sequence":"first","affiliation":[{"name":"Institute of Infectious Disease &amp; Molecular Medicine Department of Integrative Biomedical Sciences University of Cape Town Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mpiko","family":"Ntsekhe","sequence":"additional","affiliation":[{"name":"Division of 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