重工程化基质细胞衍生因子-1α与可转化血管生成多肽设计的未来。
Re-engineered stromal cell-derived factor-1α and the future of translatable angiogenic polypeptide design.
机构信息
Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
出版信息
Trends Cardiovasc Med. 2012 Aug;22(6):139-44. doi: 10.1016/j.tcm.2012.07.010. Epub 2012 Aug 16.
Abstract
Smaller engineered analogs of angiogenic cytokines may provide translational advantages, including enhanced stability and function, ease of synthesis, lower cost, and, most important, the potential for modulated delivery via engineered biomaterials. In order to create such a peptide, computational molecular modeling and design was employed to engineer a minimized, highly efficient polypeptide analog of the stromal cell-derived factor-1α (SDF) molecule. After removal of the large, central β-sheet region, a designed diproline linker connected the native N-terminus (responsible for receptor activation and binding) and C-terminus (responsible for extracellular stabilization). This yielded energetic and conformational advantages resulting in a small, low-molecular-weight engineered SDF polypeptide analog (ESA) that was shown to have angiogenic activity comparable to or better than that of recombinant human SDF both in vitro and in a murine model of ischemic heart failure.
摘要
较小的血管生成细胞因子工程模拟物可能具有转化优势，包括增强的稳定性和功能、易于合成、成本更低，最重要的是，通过工程生物材料进行调制递送的潜力。为了创建这样的肽，使用计算分子建模和设计来工程化基质细胞衍生因子-1α（SDF）分子的最小化、高效的多肽模拟物。在去除大的中心β-折叠区域后，设计的二脯氨酸接头连接了天然的 N 端（负责受体激活和结合）和 C 端（负责细胞外稳定）。这产生了能量和构象优势，导致产生了一种小的、低分子量的工程 SDF 多肽模拟物（ESA），该模拟物在体外和缺血性心力衰竭的小鼠模型中均显示出与重组人 SDF 相当或更好的血管生成活性。
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