Therapeutic proteins are potent, fast-acting drugs that are highly effective in treating various conditions. Medicinal protein usage has increased in the past 10 years, and it will evolve further as we better understand disease molecular pathways. However, it is associated with high processing costs, limited stability, difficulty in being administered as an oral medication, and the inability of large proteins to penetrate tissue and reach their target locations. Many methods have been developed to overcome the problems with the stability and chaperone activity of therapeutic proteins, viz., the addition of external agents (changing the properties of the surrounding solvent by using stabilizing excipients, e.g., amino acids, sugars, polyols) and internal agents (chemical modifications that influence its structural properties, e.g., mutations, glycosylation). However, these methods must completely clear protein instability and chaperone issues. There is still much work to be done on finetuning chaperone proteins to increase their biological efficacy and stability. Methylglyoxal (MGO), a potent dicarbonyl compound, reacts with proteins and forms covalent cross-links. Much research on MGO scavengers has been conducted since they are known to alter protein structure, which may result in alterations in biological activity and stability. MGO is naturally produced within our body, however, its impact on chaperones and protein stability needs to be better understood and seems to vary based on concentration. This review highlights the efforts of several research groups on the effect of MGO on various proteins. It also addresses the impact of MGO on a client protein, α-crystallin, to understand the potential solutions to the protein’s chaperone and stability problems.

Graphical Abstract

中文翻译：

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甲基乙二醛诱导的修饰以稳定治疗性蛋白质：综述

治疗性蛋白质是强效、速效药物，在治疗各种病症方面非常有效。药用蛋白质的使用在过去 10 年中有所增加，并且随着我们更好地了解疾病分子途径，它将进一步发展。然而，它与高加工成本、有限的稳定性、难以作为口服药物给药以及大蛋白质无法穿透组织并到达其目标位置有关。已经开发了许多方法来克服治疗性蛋白质的稳定性和伴侣活性问题，即添加外部试剂（通过使用稳定赋形剂，例如氨基酸、糖、多元醇来改变周围溶剂的性质）和内部因素（影响其结构特性的化学修饰，例如突变、糖基化）。然而，这些方法必须完全解决蛋白质不稳定和伴侣问题。在微调伴侣蛋白以提高其生物功效和稳定性方面仍有许多工作要做。甲基乙二醛 (MGO) 是一种有效的二羰基化合物，可与蛋白质发生反应并形成共价交联。人们对 MGO 清除剂进行了大量研究，因为已知它们会改变蛋白质结构，从而可能导致生物活性和稳定性的改变。MGO 在我们体内自然产生，然而，它对伴侣和蛋白质稳定性的影响需要更好地了解，并且似乎会根据浓度而变化。这篇综述重点介绍了几个研究小组在 MGO 对各种蛋白质的影响方面所做的努力。它还解决了 MGO 对客户蛋白 α-晶状体蛋白的影响，以了解该蛋白的伴侣和稳定性问题的潜在解决方案。

图形概要