Study of pH-Dependent Kinetics of Filgrastim Pegylation with Succinimide Derivatives of Poly(Ethylene Glycol) and Comparison of the Properties of Pegylated Forms Obtained Under Various Conditions

IF 0.8 4区医学 Q4 CHEMISTRY, MEDICINAL

Pharmaceutical Chemistry Journal Pub Date : 2024-06-26 DOI:10.1007/s11094-024-03147-5

D. V. Lonshakov, S. V. Sheremet’ev, E. M. Khursevich, I. V. Bobrysheva, O. A. Grebennikova, S. A. Korovkin

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Abstract

Filgrastim was pegylated by acylation with a linear 20-kDa pegylating agent (PEG agent) to search for conjugates characterized by biological activity comparable to or exceeding that of commercial drugs. The pegylation kinetics were studied at different pH values taking into account the contribution of the hydrolysis kinetics of the PEG agent. The optimal time for pegylation to a required protein conversion and the method of adding the PEG agent to the reaction mixture (once or fractionally) at a given pH value and ratio between the PEG agent and protein were calculated using a proposed equation based on previously obtained pegylation and hydrolysis rate constants. Various mixtures of pegylated positional isomers were obtained. Their contents in the mixtures depended on the pH value because of the different pK_a values of the amino-acid residues involved in the reaction. The estimated specific biological activity of the obtained monopegylated forms of Filgrastim appeared comparable with that of the product Neulastim.

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聚乙二醇琥珀酰亚胺衍生物与 Filgrastim Pegylation 的 pH 值相关动力学研究以及在不同条件下获得的 Pegylated 形式的特性比较

Filgrastim 通过与一种 20 kDa 的线性珠光体化剂（PEG 剂）酰化进行珠光体化，以寻找生物活性与商业药物相当或超过商业药物的共轭物。考虑到 PEG 制剂水解动力学的影响，研究了不同 pH 值下的聚乙二醇化动力学。根据之前获得的聚乙二醇化和水解速率常数，利用一个拟议方程计算出了在给定的 pH 值和聚乙二醇剂与蛋白质的比例下，聚乙二醇化达到所需蛋白质转化率的最佳时间，以及向反应混合物中添加聚乙二醇剂的方法（一次或分次）。结果得到了各种位置异构体的混合物。由于参与反应的氨基酸残基的 pKa 值不同，它们在混合物中的含量取决于 pH 值。所获得的 Filgrastim 单egylated 形式的估计特异性生物活性与产品 Neulastim 相当。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmaceutical Chemistry Journal CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

1.30

自引率

22.20%

发文量

226

审稿时长

3-8 weeks

期刊介绍： Pharmaceutical Chemistry Journal is a monthly publication devoted to scientific and technical research on the creation of new drugs and the improvement of manufacturing technology of drugs and intermediates. International contributors cover the entire spectrum of new drug research, including: methods of synthesis; results of pharmacological, toxicological, and biochemical studies; investigation of structure - activity relationships in prediction of new compounds; methods and technical facilities used; and problems associated with the development of ecologically safe and economically feasible methods of industrial production. In addition, analytical reviews of the international literature in the field provide coverage of the most recent developments around the world. Pharmaceutical Chemistry Journal is a translation of the Russian journal Khimiko-Farmatsevticheskii Zhurnal. The Russian Volume Year is published in English from April. All articles are peer-reviewed.