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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >Impact of polymer geometry on the interactions of protein-PEG conjugates
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Impact of polymer geometry on the interactions of protein-PEG conjugates

机译：聚合物几何形状对蛋白 - PEG缀合物相互作用的影响

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The conjugation of high molecular weight polyethylene glycol (PEG) to an active pharmaceutical ingredient (API) is an attractive strategy for the modification of biophysical and biodistribution properties of the API. Indeed, several therapeutic proteins conjugated to PEG have been safely administered in the clinic. While there have been studies on the configuration of these conjugates in solution, investigations on the impact of PEG geometry on protein-PEG conjugate interactions is limited. In this study, we use dynamic light scattering (DLS), rheology, and small-angle neutron scattering (SANS) to investigate the biophysical solution and interaction behavior of a 50 kDa Fab protein attached to either a linear or tetrameric (branched) 40 kDa PEG molecule. The hydrodynamic radii, diffusivity, viscosity and pair distance distribution function (PDDF) were obtained for the protein-PEG conjugates in solution. An analysis revealed that interactions between unconjugated proteins were quite attractive, however linear PEG-protein conjugates exhibited net repulsive interactions, similar to that of the unconjugated polymer. Tetramer PEG-protein conjugates on the other hand, exhibited a net weak attractive interaction, indicating a more balanced distribution of repulsive and attractive interaction states. Further analysis of the SANS data using geometric models consistent with the PDDF elucidated the conjugates' equilibrium configuration in solution. Insights gained from measurements and analysis used here can also be useful in predicting how conjugate geometries affect viscosity and aggregation behavior, which are important in determining suitable protein-polymer drug formulations.
机译：高分子量聚乙二醇（PEG）与活性药物成分（API）的缀合是用于修饰API的生物物理和生物分布性质的有吸引力的策略。实际上，在临床中安全地施用了与PEG缀合的几种治疗蛋白质。虽然已经有关于这些缀合物的构溶液的构型研究，但对PEG几何体对蛋白质-PEG缀合物相互作用的影响有限。在这项研究中，我们使用动态光散射（DLS），流变学和小角度中子散射（SAN）来研究50kDA Fab蛋白的生物物理溶液和相互作用行为，其连接到线性或四聚体（支链）40kDa PEG分子。在溶液中的蛋白-PEG缀合物获得水动力半径，扩散性，粘度和对距离分布函数（PDDF）。分析表明，未缀合的蛋白质之间的相互作用非常有吸引力，但是线性PEG蛋白缀合物表现出净排斥相互作用，类似于未缀合的聚合物的净排斥相互作用。另一方面，四聚体PEG-蛋白缀合物呈现出净弱的有吸引力的相互作用，表明令人厌恶和吸引力的相互作用状态的更平衡分布。使用与PDDF一致的几何模型进一步分析SAN数据，阐明了解决方案中的共轭物的平衡构型。从这里使用的测量和分析中获得的洞察也可以用于预测缀合格几何形状如何影响粘度和聚集行为，这对于确定合适的蛋白质 - 聚合物药物制剂很重要。

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