1. Preparation, Characterization and Pharmacokinetic Study of N-Terminal PEGylated D-Form Antimicrobial Peptide OM19r-8
- Author
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Hong-Xia Ma, Li-li Guan, Lei Liu, Qi-Jun Xu, Qi Cui, Xiu-Yun Jiang, Ling-Cong Kong, and Muhammad Inam
- Subjects
Pore Forming Cytotoxic Proteins ,Arginine ,medicine.medical_treatment ,Pharmaceutical Science ,Peptide ,02 engineering and technology ,Microbial Sensitivity Tests ,medicine.disease_cause ,030226 pharmacology & pharmacy ,Polyethylene Glycols ,03 medical and health sciences ,Minimum inhibitory concentration ,0302 clinical medicine ,PEG ratio ,Gram-Negative Bacteria ,medicine ,Escherichia coli ,chemistry.chemical_classification ,Protease ,Chromatography ,Chemistry ,021001 nanoscience & nanotechnology ,Antimicrobial ,Amino acid ,Anti-Bacterial Agents ,0210 nano-technology ,Peptides - Abstract
Recently, new cationic antibacterial peptide OM19R has been designed with low minimum inhibitory concentration (MIC) values against some gram-negative bacteria, such as Escherichia coli, Salmonella, and Shigella. However, this hybrid peptide, like most antibacterial peptides, has low enzyme stability and short half-life, which, in turn, increases the drug's cost. In this study, an antibacterial peptide (OM19r-8) was obtained containing some D-Arg amino acids. The new preparations were carried out through the replacement of l -Arginine by d -Arginine and the addition of PEG chains. Firstly, eight OM19r series of antibacterial peptides were obtained by designing D-Arg. Then, a polyethylene glycol-modified product mPEG5-butyrALD-OM19r-8 (mPEG5-OM19r-8) was isolated and purified by reverse-phase high-performance liquid chromatography (RT-HPLC). The enzyme stability test showed that the resistance of antibacterial peptide OM19r-8 to protease degradation increased by 4-32-fold. Moreover, the Time-kill studies showed that the germicidal kinetics curves of mPEG5-OM19r-8 and OM19r-8 to Escherichia coli had a similar trend, thus suggesting that PEG modification has an acceptable effect on the activity of the original peptide. Furthermore, the elimination of half-life (28.09 ± 2.81min) of mPEG5-OM19r-8, and the area under the drug concentration-time curve (2686.48 ± 651.36min∗ug/ml) was significantly prolonged. The current study demonstrates an example that optimizes the AMP by utilizing L-to-D amino acid replacement and including PEG chains. These results provide useful data for the clinical application of the mPEG5-OM19r-8.
- Published
- 2020