<br>外毒素 A 的免疫毒素活性对结构域修饰敏感。,International Journal of Biological Macromolecules

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外毒素 A 的免疫毒素活性对结构域修饰敏感。
International Journal of Biological Macromolecules ( IF 7.7 ) Pub Date : 2019-05-23 , DOI: 10.1016/j.ijbiomac.2019.05.137
Zeinab Amiri Tehranizadeh ₁ , Mojtaba Sankian ₂ , Bibi Sedigheh Fazly Bazzaz ₃ , Jamshidkhan Chamani ₄ , Soghra Mehri ₅ , Ali Baratian ₆ , Mohammad Reza Saberi ₇

Affiliation

免疫毒素是一类重组蛋白，由抗体和部分细菌或草药毒素组成。含有铜绿假单胞菌外毒素 A (PEA) 的免疫毒素已被发现在临床试验中非常适用。许多障碍（例如溶解度和吸收性）降低了它们在实体瘤中的可用性。当前的研究旨在通过结构方法添加和删除功能和非功能域来克服上述障碍。在实验部分，我们利用分子动力学模拟来预测针对人类 HER2 受体的候选免疫毒素的功能，并通过体外实验证实了我们的发现。我们发现，当 PEA 结构域 II 不发生变化时，向免疫毒素中添加增溶结构域不会降低其靶向和抗肿瘤活性，同时会增加表达产量和稳定性。另一方面，当我们用弗林蛋白酶切割位点（FCS）的11个氨基酸替换结构域II时，免疫毒素的活性主要受到FCS邻近结构域和接头的影响。还评估了结构域 III 中七个有益点突变的组合，并再次确认免疫毒素的毒性将显着降低。获得的结果表明结构域的添加或去除不能描述免疫毒素的活性，应提前对此事进行结构评估。

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The immunotoxin activity of exotoxin A is sensitive to domain modifications.

Immunotoxins are a class of recombinant proteins which consist of an antibody and a part of a bacterial or herbal toxin. Immunotoxins containing Pseudomonas aeruginosa exotoxin A (PEA) have been found to be very applicable in clinical trials. Many obstacles such as solubility and absorbency reduce their usability in solid tumors. The current study aims to overcome the mentioned barriers by addition and removal of functional and non-functional domains with a structural approach. In the experimental section, we took advantage of molecular dynamics simulations to predict the functionality of candidate immunotoxins which target human HER2 receptors and confirmed our findings with in vitro experiments. We found out when no changes were made to domain II of PEA, addition of solubilizing domains to immunotoxins would not reduce their targeting and anti-tumor activity, while increasing the yield of expression and stability. On the other side, when we replaced domain II with eleven amino acids of furin cleavage site (FCS), the activity of the immunotoxin was mainly affected by the FCS neighboring domains and linkers. A combination of seven beneficial point mutations in domain III was also assessed and reconfirmed that the toxicity of the immunotoxin would be reduced dramatically. The obtained results indicate that the addition or removal of domains cannot depict the activity of immunotoxins and the matter should be assessed structurally in advance.

更新日期：2019-05-23

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