糖醇和蛋白质结构对通过脱胺和异构化对化学降解的影响
Ingrid Ramm1, Carl Diehl2, Amanda Västberg3
1Department of Process and Life Science Engineering, Lund University, 221 00 Lund, Sweden.
International journal of pharmaceutics
|November 1, 2025
概括
糖醇通过保护特定残留物免受降解,增强诸如附体GA-Z之类的治疗性蛋白质的稳定性. 这种稳定是结构依赖的,改善了蛋白质的功能,降低了免疫性风险.
科学领域:
- 生物化学 生物化学
- 蛋白质科学 蛋白质科学
- 化学工程是化学工程的重要组成部分.
背景情况:
- 治疗性蛋白质至关重要,但容易发生化学降解,影响有效性和安全性.
- 了解蛋白质结构稳定性关系对于优化生物制药开发至关重要.
研究的目的:
- 为了研究affibody GA-Z化学稳定的结构基础.
- 阐明糖醇在GA-Z上的稳定机制,以防止脱胺和异构化.
主要方法:
- 使用液体染色学-质谱学量化的残留物降解.
- 通过AlphaFold2和2D-NMR.分析了糖醇诱导的形状变化.
- 使用差分扫描热度计和差分扫描度计评估热稳定性.
主要成果:
- 残留物稳定性受到当地的蛋白质结构的影响.
- 糖醇对稳定性有不同的影响:在非结构区域中破坏Asp的稳定性,但在有序区域中稳定残留物.
- 在有序区域中,较高的初始降解与更强的糖稳定相关.
结论:
- 糖醇通过稳定折叠状态并增加α-螺旋体含量来增强GA-Z的稳定性.
- 糖醇的稳定作用依赖于残留物和结构.
- 这项研究加深了对治疗性蛋白质蛋白质稳定策略的理解.
相关概念视频
Protein Denaturation
8.4K
The function of proteins depends on their native three-dimensional structure, which is dictated by the amino acid sequence of the specific protein. Folding of the polypeptide chain takes place under specific conditions that energetically favor the folded conformation. In contrast, protein denaturation occurs spontaneously under unfavorable conditions that disrupt the integrity of the folded conformation. Thus, the chemical and physical environment of a protein, such as significant changes in pH...
8.4K
Protein Glycosylation
9.3K
Glycosylation, the most common post-translational modification for proteins, serves diverse functions. Adding sugars to proteins makes the proteins more resistant to proteolytic digestion. Glycosylated proteins can act as markers and receptors to promote cell-cell adhesion. Additionally, they have many essential quality control functions in the cell, such as correct protein folding and facilitating transport of misfolded proteins to the cytosol, which can be degraded.
Glycosylation occurs in...
Glycosylation occurs in...
9.3K
Protein Modifications in the RER
6.8K
Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
6.8K
Amino Acid Catabolism
966
Microorganisms rely on proteins as an essential carbon and energy source, particularly in environments with limited polysaccharides or lipids. However, proteins are too large to cross the plasma membrane unaided, necessitating enzymatic degradation. Microbes secrete extracellular proteases and peptidases that hydrolyze proteins into peptides, which can then be transported across the membrane. Once inside the cell, intracellular proteases degrade these peptides into free amino acids, which...
966
Amides to Carboxylic Acids: Hydrolysis
4.3K
Amides can undergo either acid-catalyzed hydrolysis or base-promoted hydrolysis through a typical nucleophilic acyl substitution. Each hydrolysis requires severe conditions.
Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
4.3K
Protein Folding
126.0K
Overview
126.0K


