Development of pegylated interferons for the treatment of chronic hepatitis C
Development of pegylated interferons for the treatment of chronic hepatitis C
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DOI：
10.2165/00063030-200115070-00001
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发表时间：
2001-01-01
期刊：
影响因子：
6.8
通讯作者：
Harris, JM
中科院分区：
文献类型：
--
作者：
Kozlowski, A;Charles, SA;Harris, JM
聚乙二醇（PEG） [PEG]与治疗性蛋白质的化学附着有几个好处，包括提高血浆半衰期，降低毒性，提高药物稳定性和溶解度。在某些情况下，一种蛋白质的聚乙二醇化可以通过降低免疫系统检测和对该化合物发动攻击的能力来提高其治疗效果。通过首先激活PEG片段，使其与蛋白质发生反应并偶联，形成PEG-蛋白偶联物。PEG片段的分子量和构象变化很大，早期片段（单功能PEG； mpeg）在分子量为12kD或更小时呈线性，而后期片段的分子量增加。PEG2是PEG技术的最新创新，涉及30kD（或更少）的mPEG与赖氨酸的偶联，赖氨酸进一步反应形成分支结构，其行为类似于分子量大得多的线性mPEG。这些化合物的pH值和温度稳定，这一因素以及大分子量可能解释了利用这些试剂的药物的有限分布体积。三种peg蛋白缀合物目前在美国被批准用于临床应用，还有更多正在临床开发中。聚乙二醇酶用于治疗严重的联合免疫缺陷疾病，聚乙二醇酶用于治疗各种白血病，聚乙二醇干扰素- α用于治疗慢性丙型肝炎病毒感染。正如2个聚乙二醇化干扰素α的例子所示，所有聚乙二醇化的蛋白并不相同。PEG试剂和偶联化学的选择对PEG-蛋白偶联物的性质至关重要，部分的分子量影响其从体内清除的速率和途径，偶联化学影响PEG与治疗蛋白的共价附着强度。
The chemical attachment of poly(ethylene glycol) [PEG] to therapeutic proteins produces several benefits, including enhanced plasma half-life, lower toxicity, and increased drug stability and solubility. In certain instances, pegylation of a protein can increase its therapeutic efficacy by reducing the ability of the immune system to detect and mount an attack on the compound.A PEG-protein conjugate is formed by first activating the PEG moiety so that it will react with, and couple to, the protein. PEG moieties vary considerably in molecular weight and conformation, with the early moieties (monofunctional PEGs; mPEGs) being linear with molecular weights of 12kD or less, and later moieties being of increased molecular weights. PEG2, a recent innovation in PEG technology, involves the coupling of a 30kD (or less) mPEG to lysine that is further reacted to form a branched structure that behaves like a linear mPEG of much larger molecular weight. These compounds are pH and temperature stable, and this factor along with the large molecular weight may account for the restricted volume of distribution seen with drugs utilising these reagents.Three PEG-protein conjugates are currently approved for clinical use in the US, with more under clinical development. Pegademase is used in the treatment of severe combined immunodeficiency disease, pegaspargase for the treatment of various leukaemias, and pegylated interferon-alpha for chronic hepatitis C virus infections. As illustrated in the case of the 2 pegylated interferon-alphas, all pegylated proteins are not equal. The choice of PEG reagent and coupling chemistry is critical to the properties of the PEG-protein conjugate, with the molecular weight of the moiety affecting its rate and route of clearance from the body, and coupling chemistry affecting the strength of the covalent attachment of PEG to therapeutic protein.