SOLID-PHASE AGGREGATION OF PROTEINS UNDER PHARMACEUTICALLY RELEVANT CONDITIONS
SOLID-PHASE AGGREGATION OF PROTEINS UNDER PHARMACEUTICALLY RELEVANT CONDITIONS
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DOI：
10.1002/jps.2600831205
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发表时间：
1994-12-01
影响因子：
3.8
通讯作者：
KLIBANOV, AM
中科院分区：
文献类型：
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作者：
COSTANTINO, HR;LANGER, R;KLIBANOV, AM
为了成功地将蛋白质用作药物，必须从机制上理解与其配方和递送相关的稳定性问题。各种有害的过程可能发生在蛋白质配方，从而降低其治疗价值。这篇综述集中在这个问题的一个方面，即固体蛋白质在药学相关条件下的聚集（升高的温度和水活性）。提出了进行这种研究的策略，重点是对集合体形成的机制分析。共价和非共价聚集途径都已被阐明。含有二硫键和自由硫醇残基的蛋白质可以通过硫醇-二硫交换聚集。对于含有二硫化物但不含游离硫醇残基的蛋白质，当完整的二硫化物经过β -消除时，分子间仍可能发生二硫化物键合，产生游离硫醇，可以催化二硫化物乱序。最后，不含半胱氨酸/胱氨酸残基的蛋白质可能通过其他共价途径或非共价途径聚集。在这些路径的基础上，提出并验证了一些合理的稳定策略。最终，这些知识的应用将导致更稳定和有效的药物蛋白质配方。
In order to successfully employ proteins as pharmaceuticals, it is essential to understand mechanistically the stability issues relevant to their formulation and delivery. Various deleterious processes may occur in protein formulations, thereby diminishing their therapeutic value. This review focuses upon one aspect of this problem, namely aggregation of solid proteins under pharmaceutically relevant conditions (elevated temperature and water activity). Strategies to pursue such studies are presented with an emphasis on a mechanistic analysis of aggregate formation. Both covalent and noncovalent aggregation pathways have been elucidated. Proteins that contain disulfide bonds as well as free thiol residues may aggregate via thiol-disulfide interchange. For proteins which contain disulfides but not free thiol residues, intermolecular disulfide bonding may still occur when intact disulfides undergo beta-elimination, yielding free thiols which can catalyze disulfide scrambling. Finally, proteins containing no cysteine/cystine residues may aggregate by other covalent pathways or by noncovalent routes. On the basis of these, pathways, some rational stabilization strategies have been proposed and verified. Ultimately, application of this knowledge should lead to more stable and effective pharmaceutical protein formulations.