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IJP:生长激素拮抗剂N-末端PEG药效学研究获进展

2013-10-23 中科院过程工程所 中科院过程工程所

生长激素拮抗剂(GHA)是生长激素的类似物,可通过阻止生长激素与其受体的结合,降低血浆胰岛素样生长因子1(IGF-I)的水平,从而达到治疗肢端肥大症等疾病的目的。然而,GHA在体内的血浆半衰期只有15~20分钟,限制了GHA的临床应用。聚乙二醇(PEG)修饰可以延长GHA的血浆半衰期。然而,由于PEG链产生的空间屏蔽作用,降低了GHA的生物学活性。 针对上述科学问题,中科院过程工程研究所胡涛


生长激素拮抗剂(GHA)是生长激素的类似物,可通过阻止生长激素与其受体的结合,降低血浆胰岛素样生长因子1(IGF-I)的水平,从而达到治疗肢端肥大症等疾病的目的。然而,GHA在体内的血浆半衰期只有15~20分钟,限制了GHA的临床应用。聚乙二醇(PEG)修饰可以延长GHA的血浆半衰期。然而,由于PEG链产生的空间屏蔽作用,降低了GHA的生物学活性。

针对上述科学问题,中科院过程工程研究所胡涛研究员率领的科研团队探讨了不同链长的PEG分子对GHA生物活性的影响。采用了分子量为20kDa和40kDa的PEG定点单修饰GHA的N-末端,得到均一的定点修饰产物,并探讨了修饰产物的药代动力学与药效动力学间的平衡点。研究结果表明,PEG修饰能显著增加GHA的流体力学体积,从而增加了药物的血浆半衰期。其中,高分子量的PEG修饰产物表现出较高的药代动力学特征。但是,40kDa的PEG屏蔽了GHA分子上的受体结合位点,使得GHA的生物活性几乎完全丧失;而20kDa的PEG修饰产物表现出较高的药效,在延长GHA血浆半衰期的同时,能最大程度地保留GHA的生物活性。该研究发展了GHA的N-末端定点修饰方法,找到了药代动力学与药效动力学间的平衡点,对开发长效蛋白质药物具有指导意义。相关研究结果发表在International Journal of Pharmaceutics (2013, 453: 533-540) 上。

以上研究得到中国科学院“百人计划”择优支持和国家自然科学基金青年基金(20906095)的资助。

原文出处

Wu L, Ho SV, Wang W, Gao J, Zhang G, Su Z, Hu T.N-terminal mono-PEGylation of growth hormone antagonist: correlation of PEG size and pharmacodynamic behavior.Int J Pharm. 2013 Sep 10

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    2013-11-27 feather89
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    2014-01-01 lsndxfj
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    2013-10-25 wleon8899

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