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However, its extremely short half\u2010life in vivo greatly compromises its potential applications. Here, we report an Ac\u2010SDKP analog peptide with <jats:sc>d<\/jats:sc>\u2010amino acid replacement (Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P). The stability of Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P and its prevention of liver fibrosis were investigated in vitro and in vivo. The stabilities of Ac\u2010SDKP and Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P exposed to angiotensin\u20101\u2010converting enzyme (ACE) and their half\u2010lives in rats and human sera were determined by high\u2010performance liquid chromatography. The inhibitory effects of Ac\u2010SDKP and Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P on the proliferation and activation of hepatic stellate cells (HSC\u2010T6) were evaluated using the Cell Counting Kit\u20108, Western blotting, reverse transcription quantitative polymerase chain reaction, and immunofluorescence assays. Finally, the protective effects of Ac\u2010SDKP and Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P on carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)\u2010induced liver fibrosis in rats were compared. <jats:sc>d<\/jats:sc>\u2010Amino acid replacement significantly enhanced the stability of the peptide to ACE and prolonged the half\u2010life of Ac\u2010SDKP in rats and human sera. The Ac\u2010SDKP\u2010mediated inhibition of HSC\u2010T6 cell proliferation was well preserved, and Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P exerted inhibitory effects comparable to Ac\u2010SDKP on \u03b1\u2010smooth muscle actin (\u03b1\u2010SMA), collagen I and III expression, and phosphorylated\u2010Smad\u20102 expression. After intraperitoneal (i.p.) administration, Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P exhibited significantly greater protection than Ac\u2010SDKP against CCl<jats:sub>4<\/jats:sub>\u2010induced liver fibrosis in rats. The serum alanine aminotransferase, aspartate aminotransferase, albumin, and total protein levels of the Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P\u2010treated rats were significantly lower than those of the Ac\u2010SDKP\u2010treated rats. \u03b1\u2010SMA, CD45, and collagen I and III expression, as well as Smad\u20102 phosphorylation were significantly attenuated in the livers of the Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P\u2010treated rats compared to those of the Ac\u2010SDKP\u2010treated rats. Furthermore, we showed that the Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P concentration in the rat liver increased to a physiological level of 60\u2009min after i.p. administration, although i.p. administration of Ac\u2010SDKP failed to enhance the peptide concentration in the rat liver. Our findings indicate that <jats:sc>d<\/jats:sc>\u2010amino acid replacement is a simple and effective method to enhance the stability of Ac\u2010SDKP. Ac\u2010SD<jats:sub>D<\/jats:sub>K<jats:sub>D<\/jats:sub>P represents potential application of Ac\u2010SDKP in fibrosis treatment and provides a new potential treatment strategy for liver fibrosis. \u00a9 2019 IUBMB Life, 71(9):1302\u20131312, 2019<\/jats:p>","DOI":"10.1002\/iub.2037","type":"journal-article","created":{"date-parts":[[2019,3,22]],"date-time":"2019-03-22T04:54:26Z","timestamp":1553230466000},"page":"1302-1312","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>d<\/scp>\u2010amino acid modification protects <i>N<\/i>\u2010Acetyl\u2010seryl\u2010aspartyl\u2010lysyl\u2010proline from physiological hydroxylation and increases its antifibrotic effects on hepatic fibrosis"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0986-7984","authenticated-orcid":false,"given":"Xutao","family":"Zhang","sequence":"first","affiliation":[{"name":"Biotechnology Center, School of Pharmacy The Fourth Military Medical University  Xian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiming","family":"Zhou","sequence":"additional","affiliation":[{"name":"Biotechnology Center, School of Pharmacy The Fourth Military Medical University  Xian China"},{"name":"Department of Cardiology 988 Central Hospital of People's Liberation Army  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Biotechnology Center, School of Pharmacy The Fourth Military Medical University  Xian China"},{"name":"The Brigade of Undergraduates The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"He","sequence":"additional","affiliation":[{"name":"Biotechnology Center, School of Pharmacy The Fourth Military Medical University  Xian 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