Protein modification with poly(ethylene glycol) (PEG) can prolong circulatory lifetime and lower protein antigenicity in an animal. These benefits may arise from the proposed mechanism of PEG action, molecular shielding of the protein surface, and lowered interaction with other macromolecules. Proteins that depend on macromolecule association for their function would not seem good targets for PEG modification as the benefits may be mitigated by loss of function. Indeed, high loss of function applied to PEG-modified factor VIIa and to active site-blocked blood clotting factors Xa or IXa was studied. A surprising finding was that PEG-modified, active site-blocked factor VIIa (PEG-VIIai, PEG-40 000) retained 40% of its function despite an 18-fold increase in circulatory lifetime. The discrepancy between functional loss and increased circulatory lifetime was consistent with a process that was limited by the diffusion step of assembly rather than the chemical binding step. The impact of PEG-40 000 on diffusion of VIIai is small (about 3-fold) relative to its potential impact on molecular shielding during the chemical binding step of association. These properties extended to a mutant of VIIai (P10Q/K32E, QE-VIIai) that has 25-fold higher function than wild-type factor VIIai. Overall, properties of PEG-modified proteins can suggest features of the kinetic mechanism and may provide enhanced proteins for anticoagulation therapy.

中文翻译：

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聚乙二醇大分子屏蔽对于扩散极限反应的不寻常好处：因子VIIai和组织因子。

用聚乙二醇（PEG）进行蛋白质修饰可延长动物的循环寿命并降低其蛋白质抗原性。这些好处可能来自拟议的PEG作用机理，蛋白质表面的分子屏蔽以及与其他大分子的相互作用降低。依赖大分子缔合的功能的蛋白质似乎不是PEG修饰的好靶标，因为功能丧失可能会减轻其好处。实际上，已经研究了应用于PEG修饰的因子VIIa和活性位点阻断的凝血因子Xa或IXa的高功能丧失。令人惊讶的发现是，尽管循环寿命增加了18倍，PEG修饰的活性位点封闭因子VIIa（PEG-VIIai，PEG-40 000）仍保留了其功能的40％。功能丧失与循环寿命延长之间的差异与由组装扩散步骤而不是化学结合步骤所限制的过程是一致的。相对于其在缔合的化学结合步骤中对分子屏蔽的潜在影响，PEG-40 000对VIIai扩散的影响很小（约3倍）。这些特性扩展到了VIIai突变体（P10Q / K32E，QE-VIIai），其功能比野生型因子VIIai高25倍。总体而言，PEG修饰的蛋白质的性质可以暗示其动力学机制的特征，并且可以为抗凝治疗提供增强的蛋白质。相对于其在缔合的化学结合步骤中对分子屏蔽的潜在影响，PEG-40 000对VIIai扩散的影响很小（约3倍）。这些特性扩展到了VIIai突变体（P10Q / K32E，QE-VIIai），其功能比野生型因子VIIai高25倍。总体而言，PEG修饰的蛋白质的性质可以暗示其动力学机制的特征，并且可以为抗凝治疗提供增强的蛋白质。相对于其在缔合的化学结合步骤中对分子屏蔽的潜在影响，PEG-40 000对VIIai扩散的影响很小（约3倍）。这些特性扩展到了VIIai突变体（P10Q / K32E，QE-VIIai），其功能比野生型因子VIIai高25倍。总体而言，PEG修饰的蛋白质的性质可以暗示其动力学机制的特征，并且可以为抗凝治疗提供增强的蛋白质。