多价值罗利丁类药物作为对高氏病的药理护理剂
Marc Borie-Guichot1, My Lan Tran1, Virginie Garcia2
1Université Paul Sabatier-Toulouse III CNRS SPCMIB, UMR5068, 118 Route de Narbonne, F-31062 Toulouse, France.
Bioorganic chemistry
|March 21, 2024
概括
研究人员使用点击化学开发了新的多价值罗利丁,用于潜在的高氏病治疗. 这些化合物显示出作为酶抑制剂和药理伴侣的前景,增加治疗性酶活性.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 生物化学 生物化学
背景情况:
- 氏病是一种 lysosomal 储存障碍,由缺乏β-glucocerebrosidase (GCase) 活性引起.
- 药理伴随剂通过稳定和增强突变GCase的活性来提供治疗策略.
- 开发新的,有效的药理伴随者对于高氏病治疗至关重要.
研究的目的:
- 合成具有潜在治疗应用的新型,多价值的免疫糖集群.
- 为了评估这些化合物作为β-葡萄糖脑化酶的抑制剂.
- 评估它们在高氏病模型中作为药理伴随者的有效性.
主要方法:
- 通过Crabbé-Mala 聚合而成的可点击的等离子体罗利丁的不对称合成.
- 无铜菌株促进的酸循环添加,用于将免疫糖移植到树突上.
- 在体外测定患者纤维细胞中的β-葡萄糖核糖酶抑制和酶活性.
- 分子对接研究以合理化结合相互作用.
主要成果:
- 成功合成了六价和十二价罗利丁集群.
- 已证明抑制β-葡萄糖核糖酶酶,这表明单环氧三醇组在蛋白质亲和力中发挥了作用.
- 在低微分子和亚微分子度下,Gaucher患者纤维细胞中的GCase活性显著增加.
- 识别这些集群作为强大的多价值抑制剂和有效的药理伴侣.
结论:
- 合成的多价值罗利丁集群是高氏病的有效药理伴侣.
- 这项研究提供了第一个多价值罗利丁的例子,它们在高氏病中充当护送者.
- 这些发现为开发针对性治疗溶酶体储存障碍的新途径开辟了道路.
相关概念视频
03:00Molecular Chaperones and Protein Folding
17.9K
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...
17.9K
01:22Lysosomal Hydrolases
3.8K
Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
3.8K
01:24Parkinson's Disease: Treatment
264
Neurodegenerative disorders, such as Parkinson's Disease (PD), involve the gradual and irreversible destruction of neurons in particular brain areas. These disorders exhibit standard features like proteinopathies, selective vulnerability of some neurons, and an interaction of intrinsic properties, genetics, and environmental influences in neural injury.
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
264
01:29Protein Folding Quality Check in the RER
3.7K
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...
3.7K
01:30Indirect-Acting Cholinergic Agonists: Pharmacological Actions
663
Indirect-acting cholinergic agonists, also known as anticholinesterases, exert their pharmacological effects by enhancing cholinergic transmission in various body parts, including the neuromuscular junction, autonomic cholinergic synapses, and the brain.
At the neuromuscular junction, these agents work by inhibiting the breakdown of acetylcholine, allowing it to remain bound to the receptor and bind to nearby receptors. This process leads to repetitive firing of the endplate, causing muscle...
At the neuromuscular junction, these agents work by inhibiting the breakdown of acetylcholine, allowing it to remain bound to the receptor and bind to nearby receptors. This process leads to repetitive firing of the endplate, causing muscle...
663