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Here, a prodrug strategy linking proline\u2010rich AMP Onc72 to polyethylene glycol (PEGs) with average molecular weights of 5 and 20\u00a0kDa via a peptide linker containing a protease cleavage site is tested for the first time in vivo. Onc72 is released from these 5k\u2010 and 20k\u2010prodrugs in mouse serum with half\u2010life times (<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>) of 8 and 14\u00a0h, respectively. Importantly, PEGylation protects Onc72 from proteolytic degradation providing a prolonged release of Onc72, balancing the degradation of free Onc72, and leading to relatively stable Onc72 concentrations and high antibacterial activities. The prodrugs are not hemolytic on human erythrocytes and show only slight cytotoxic effects on human cell lines indicating promising safety margins. When administered subcutaneously to female CD\u20101 mice, the prodrugs elimination <jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub> are 66\u00a0min and \u22485.5\u00a0h, respectively, compared to 43\u00a0min of free Onc72. The maximal Onc72 plasma levels are obtained \u22481 and \u22488\u00a0h postadministration, respectively. In conclusion, the prodrugs provide extended elimination <jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub> and a constant release of Onc72 in mice, potentially limiting adverse effects and increasing efficacy.<\/jats:p>","DOI":"10.1002\/adhm.202202368","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:23:46Z","timestamp":1673483026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In Vitro Properties and Pharmacokinetics of Temporarily PEGylated Onc72 Prodrugs"],"prefix":"10.1002","volume":"12","author":[{"given":"Gubran Khalil","family":"Mohammed","sequence":"first","affiliation":[{"name":"Institute of Bioanalytical Chemistry Faculty of Chemistry and Mineralogy Leipzig University  04103 Leipzig Germany"},{"name":"Center for Biotechnology and Biomedicine Leipzig University  04103 Leipzig 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