Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA.
Angew Chem Int Ed Engl. 2017 Jan 24;56(5):1239-1243. doi: 10.1002/anie.201610753. Epub 2016 Dec 29.
PEGylation is an attractive approach to modifying oligonucleotides intended for therapeutic purposes. PEG conjugation reduces protein interactions with the oligonucleotide, and helps to overcome their intrinsic biopharmaceutical shortcomings, such as poor enzymatic stability, rapid body clearance, and unwanted immunostimulation. However, the effect of PEG architecture and the manner in which the PEG component interferes with the hybridization of the oligonucleotide remain poorly understood. In this study, we systematically compare the hybridization thermodynamics and protein accessibility of several DNA conjugates involving linear, Y-shaped, and brush-type PEG. It is found that PEGylated DNA experiences two opposing effects: local excluded volume effect and chemical interactions, the strengths of which are architecture-dependent. Notably, the brush architecture is able to offer significantly greater protein shielding capacity than its linear or Y-shaped counterparts, while maintaining nearly identical free energy for DNA hybridization compared with free DNA.
聚乙二醇化是一种有吸引力的方法，可以修饰用于治疗目的的寡核苷酸。PEG 缀合降低了蛋白质与寡核苷酸的相互作用，并有助于克服它们固有的生物制药缺陷，如酶稳定性差、快速清除和不必要的免疫刺激。然而，PEG 结构的影响以及 PEG 成分干扰寡核苷酸杂交的方式仍知之甚少。在这项研究中，我们系统地比较了几种涉及线性、Y 型和刷型 PEG 的 DNA 缀合物的杂交热力学和蛋白质可及性。结果发现，聚乙二醇化 DNA 经历了两种相反的效应：局部排除体积效应和化学相互作用，其强度取决于结构。值得注意的是，与线性或 Y 型相比，刷型结构能够提供更大的蛋白质屏蔽能力，同时与游离 DNA 相比，保持几乎相同的 DNA 杂交自由能。
