In Vitro Properties and Pharmacokinetics of Temporarily PEGylated Onc72 Prodrugs

卷:12

Article

关键词: SHORT PROLINE-RICH;    ANTIMICROBIAL PEPTIDES;    ANTIBACTERIAL ACTIVITY;    ESCHERICHIA-COLI;    ONCOCIN;    RELEASE;    BACTERIA;    API88;   

DOI  :  10.1002/adhm.202202368

来源: SCIE

【 摘 要 】

The favorable properties of antimicrobial peptides (AMPs) to rapidly kill pathogens are often limited by unfavorable pharmacokinetics due to fast degradation and renal clearance rates. Here, a prodrug strategy linking proline-rich AMP Onc72 to polyethylene glycol (PEGs) with average molecular weights of 5 and 20 kDa via a peptide linker containing a protease cleavage site is tested for the first time in vivo. Onc72 is released from these 5k- and 20k-prodrugs in mouse serum with half-life times (t(1/2)) of 8 and 14 h, 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-1 mice, the prodrugs elimination t(1/2) are 66 min and approximate to 5.5 h, respectively, compared to 43 min of free Onc72. The maximal Onc72 plasma levels are obtained approximate to 1 and approximate to 8 h postadministration, respectively. In conclusion, the prodrugs provide extended elimination t(1/2) and a constant release of Onc72 in mice, potentially limiting adverse effects and increasing efficacy.

【 授权许可】

Free