Preparation, Characterization and Pharmacokinetic Study of N-Terminal PEGylated D-Form Antimicrobial Peptide OM19r-8
Preparation, Characterization and Pharmacokinetic Study of N-Terminal PEGylated D-Form Antimicrobial Peptide OM19r-8
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DOI：
10.1016/j.xphs.2020.10.048
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发表时间：
2021-02-15
影响因子：
3.8
通讯作者：
Ma, Hong-Xia
中科院分区：
文献类型：
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作者：
Cui, Qi;Xu, Qi-jun;Ma, Hong-Xia
最近，设计了新型阳离子抗菌肽OM19R，对一些革兰氏阴性菌（如大肠杆菌、沙门氏菌和志贺氏菌）具有较低的最低抑菌浓度（MIC）值。然而，这种杂合肽与大多数抗菌肽一样，酶稳定性低，半衰期短，这反过来又增加了药物的成本。在本研究中，获得了含有一些D-Arg氨基酸的抗菌肽（OM19r-8）。新的制剂是通过用D-精氨酸替代L-精氨酸并添加PEG链来进行的。首先通过设计D-Arg获得8个OM19r系列抗菌肽。然后，通过反相高效液相色谱(RT-HPLC)分离和纯化聚乙二醇修饰产物mPEG(5)-butyrALD-OM19r-8(mPEG(5)-OM19r-8)。酶稳定性测试表明，抗菌肽OM19r-8对蛋白酶降解的抵抗能力提高了4-32倍。此外，Time-kill研究表明mPEG(5)-OM19r-8和OM19r-8对大肠杆菌的杀菌动力学曲线具有相似的趋势，从而表明PEG修饰对原始肽的活性具有可接受的影响。此外，mPEG(5)-OM19r-8的半衰期(28.09+/-2.81min)消除，药物浓度-时间曲线下面积(2686.48+/-651.36min*ug/ml)显着延长。当前的研究展示了一个通过利用 L 到 D 氨基酸替换并包含 PEG 链来优化 AMP 的示例。这些结果为mPEG(5)-OM19r-8的临床应用提供了有用的数据。 (C) 2020 美国药剂师协会 (R)。由爱思唯尔公司出版。保留所有权利。
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 mPEG(5)-butyrALD-OM19r-8 (mPEG(5)-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 mPEG(5)-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 mPEG(5)-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 mPEG(5)-OM19r-8. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.