生物活跃的葡萄糖基化葡萄糖像-1模拟的工程
Chaitra Chandrashekar1, Feng Lin1, Yuji Nishiuchi2,3
1The Florey, University of Melbourne, Parkville, Victoria 3010, Australia.
Journal of medicinal chemistry
|March 11, 2024
概括
一种新型的葡萄糖类-1 (GLP-1) 的新型糖类相似物提供了一个潜在的解决方案,来解决半谷氨酸缺乏问题. 这种替代方案在激活GLP-1受体和降低葡萄糖水平方面表现出相似的有效性.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
背景情况:
- 葡萄糖类-1受体 (GLP-1R) 激动剂,如塞马格卢提德,对于管理2型糖尿病和肥胖至关重要.
- 目前的西马格卢提德制造复杂,导致溶解性问题和生产挑战.
- 全球对塞马格卢提德的需求导致了严重的药物短缺,需要替代治疗选择.
研究的目的:
- 开发一种具有改进生产特性的新型塞马格卢提德类似物.
- 为了研究一种新的甘氨酸-GLP-1模拟剂的疗效和功效,作为西马格卢提德的潜在替代品.
主要方法:
- 一种新型的糖-GLP-1类似物的化学合成,通过用水性寡糖化物取代塞马格卢提德的疏水性脂肪酸.
- 对产量的比较分析,GLP-1受体激活强度和体内生物活性 (减少葡萄糖) 与西马格卢提德的比较.
主要成果:
- 这种新型的糖-GLP-1类似物被合成,产量大约是赛马格卢提德的10倍.
- 糖类类似物在激活GLP-1受体方面表现出类似的强度.
- 在体内研究证实,糖类同类药物有效降低葡萄糖水平,类似于半黄.
结论:
- 开发的糖-GLP-1模拟物呈现出一个有前途的,高收益的替代品,semaglutide.
- 这种新型化合物保持了类似的生物活性和受体激活功率.
- 这些发现表明,解决目前正在进行的二型糖尿病和肥胖治疗的塞马格卢提德短缺的潜在解决方案.
相关概念视频
Glucagon-like Receptor Agonists
321
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
321
Insulin: Biosynthesis, Chemistry, and Preparation
375
The endoplasmic reticulum (ER) of pancreatic β-cells synthesizes preproinsulin, which consists of a signal peptide, A and B chains, and a C-peptide. Preproinsulin is then cleaved and folded into proinsulin, which translocates to the Golgi apparatus for sorting and packaging into secretory granules. In these granules, enzymatic clipping generates insulin and C-peptide.
Damage or functional impairment of β-cells inhibits insulin production, leading to diabetes. Diabetes treatment...
Damage or functional impairment of β-cells inhibits insulin production, leading to diabetes. Diabetes treatment...
375
Oral Hypoglycemic Agents: Glinides
154
Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively...
154
GPCRs Regulate Adenylyl Cylase Activity
5.5K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.5K
Hypoglycemia and Glucagon
260
Without prolonged fasting, healthy individuals maintain blood glucose levels above 3.5 mM due to a well-adapted neuroendocrine counterregulatory system that effectively prevents acute hypoglycemia, a potentially life-threatening condition. The primary clinical scenarios for hypoglycemia encompass diabetes treatment, inappropriate production of endogenous insulin or insulin-like substances by tumors, and the use of glucose-lowering agents in non-diabetic individuals. Notably, hypoglycemia in the...
260
Glucose Homeostasis: Pancreatic Islets and Insulin Secretion
1.3K
The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
Insulin and C-peptide are...
Insulin and C-peptide are...
1.3K


