人类神经生长因子通过表达KAHA结合的化学合成和Chaperone介导折叠
Nicolas Y Nötel1, Angus E McMillan1, Vijaya R Pattabiraman1
1Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland.
ACS central science
|September 2, 2025
概括
科学家通过化学合成神经生长因子 (NGF) 来治疗中枢神经系统疾病, 这种新方法可以设计出具有更好的治疗特性和更少副作用的NGF变体.
科学领域:
- 蛋白质化学
- 神经科学
- 生物技术
背景情况:
- 神经生长因子 (NGF) 对中枢神经系统疾病具有治疗潜力.
- 由于广泛的受体相互作用,其临床使用受到副作用的限制,如过敏症.
- 由于NGF的疏水性和依赖附带来折叠,因此NGF的化学合成具有挑战性.
研究的目的:
- 开发生物活性神经生长因子 (NGF) 的化学合成策略.
- 建立一个创建可能增强治疗特征和减少副作用的NGF变体的平台.
- 克服需要辅助折叠的复杂蛋白质的传统重组生产的局限性.
主要方法:
- 用于蛋白质组装的α-酸-胺 (KAHA) 结合.
- 采用重组生产N终端护卫,修改为C终端α-酸.
- 包含一种新型可溶性标签 (SOLACE) 和形成的KAHA结合,用于从合成和重组碎片组装proNGF.
- 通过伴奏实现了受控的折叠和二硫化键形成,随后进行裂变以产生活性NGF二聚体.
主要成果:
- 通过一种新的化学方法成功合成了生物活性神经生长因子 (NGF) 双质体.
- 在轴突生长试验中,合成NGF与重组NGF具有可比的生物活性.
- 该方法促进了对NGF结构和功能至关重要的受控折叠和二硫化键形成.
结论:
- 提供了NGF可行的化学合成途径,克服了以前的生产障碍.
- 建立了一个用于半合成神经和类似复杂蛋白质的多功能平台.
- 开辟了NGF变体的设计途径,用于针对神经疾病的定制治疗应用.
相关概念视频
Protein Folding
8.6K
Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
8.6K
Molecular Chaperones and Protein Folding
18.4K
The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
The...
18.4K
Bacterial Protein Maturation
81
Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...
81
Amyloid Fibrils
9.8K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
9.8K
Protein Folding Quality Check in the RER
3.8K
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
3.8K
Protein Organization
143.0K
Overview
143.0K


