Engineering a pharmacologically superior form of granulocyte-colony-stimulating factor by fusion with gelatin-like-protein polymer
Engineering a pharmacologically superior form of granulocyte-colony-stimulating factor by fusion with gelatin-like-protein polymer
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通过与明胶样蛋白质聚合物融合，设计出药理优越的粒细胞集落刺激因子
DOI：
10.1016/j.ejpb.2009.12.002
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发表时间：
2010-03-01
影响因子：
4.9
通讯作者：
Zhou, Lin-Fu
中科院分区：
文献类型：
--
作者：
Huang, Yan-Shan;Wen, Xiao-Fang;Zhou, Lin-Fu
治疗性蛋白质的血浆半衰期是许多临床应用中的关键因素。因此，对延长长效肽和蛋白质药物的血浆半衰期的新策略有很高的需求。我们设计了一种人工明胶样蛋白（GLK），并将这种亲水性GLK聚合物与粒细胞集落刺激因子（G-CSF）融合，产生了嵌合GLK/G-CSF融合蛋白。G-CSF（rGLK/G-CSF）融合蛋白从毕赤酵母中纯化。体外研究表明，与未融合的G-CSF相比，rGLK/G-CSF具有增大的流体动力学半径、改善的热稳定性和保留的全部生物活性。rGLK/G-CSF融合蛋白显示出较迟的血浆清除，并且刺激循环白色血细胞比G-CSF我们的研究结果表明，与这种人工亲水性GLK聚合物的融合在构建具有延长的血浆半衰期的有效造血因子方面提供了许多优势。这种方法可以很容易地应用于其他治疗性蛋白质，并具有重要的临床应用（c）2009 Elsevier B.V版权所有
The plasma half-life of therapeutic proteins is a critical factor in many clinical applications Therefore, new strategies to prolong plasma half-life of long-acting peptides and protein drugs are in high demand Here, we designed an artificial gelatin-like protein (GLK) and fused this hydrophilic GLK polymer to granulocyte-colony-stimulating factor (G-CSF) to generate a chimeric GLK/G-CSF fusion protein The genetically engineered recombinant GLK/G-CSF (rGLK/G-CSF) fusion protein was purified from Pichia pastoris In vitro studies demonstrated that rGLK/G-CSF possessed an enlarged hydrodynamic radius, improved thermal stability and retained full bioactivity compared to unfused G-CSF Following a single subcutaneous administration to rats, the rGLK/G-CSF fusion protein displayed a slower plasma clearance late and stimulated greater and longer lasting increases in circulating white blood cells than G-CSF Our findings indicate that fusion with this artificial, hydrophilic, GLK polymer provides many advantages in the construction of a potent hematopoietic factor with extended plasma half-life This approach could be easily applied to other therapeutic proteins and have important clinical applications (c) 2009 Elsevier B.V All rights reserved