Chemical and Enzymatic Site Specific PEGylation of hGH: The Stability and in vivo Activity of PEG-N-Terminal-hGH and PEG-Gln141-hGH Conjugates
Chemical and Enzymatic Site Specific PEGylation of hGH: The Stability and in vivo Activity of PEG-N-Terminal-hGH and PEG-Gln141-hGH Conjugates
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DOI：
10.1002/mabi.201500282
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发表时间：
2016-01-01
影响因子：
4.6
通讯作者：
Pasut, Gianfranco
中科院分区：
文献类型：
--
作者：
Grigoletto, Antonella;Mero, Anna;Pasut, Gianfranco
治疗性蛋白质的使用通常因其短的体内半衰期而受损。PEG化已被用于增强蛋白质稳定性和延长药代动力学。本文概述了两种位点特异性单聚乙二醇化形式的人生长激素（hGH）-化学N端聚乙二醇化hGH（PEG-Nter-hGH）和通过转氨酶酶促Gln 141聚乙二醇化hGH（PEG-Gln 141-hGH）-的生物物理特性，并比较了其药效学。PEG-Nter-hGH的热稳定性相对于hGH和PEG-Gln 141-hGH的热稳定性增加。大鼠中的药效学研究表明，就体重增加、股骨长度和胫骨骨干宽度而言，单次注射缀合物相对于每周一次的每日hGH具有更好或相当的效力。
The use of therapeutic proteins is often impaired by their short in vivo half-lives. PEGylation has been exploited to enhance protein stability and to prolong the pharmacokinetic. The biophysical characterization of two site-specific mono-PEGylated forms of human growth hormone (hGH) - chemically N-terminal PEGylated hGH (PEG-Nter-hGH) and enzymatically Gln141 PEGylated hGH (PEG-Gln141-hGH) via transglutaminase - is outlined here and their pharmacodynamics are compared. The thermal stability of PEG-Nter-hGH was increased with respect to that of hGH and PEG-Gln141-hGH. Pharmacodynamic studies in rats showed that a single injection of the conjugates had a better or comparable potency with respect to a daily hGH on a week schedule in terms of weight gain, femoral length, and tibial diaphysis width.