GLP-1 类似物 comes up often in conversation and rarely with the context attached. Here we lay out the basics in order, then work through the practical considerations.
Last reviewed on 2025-09-22. Where a claim depends on a specific study, the study is described rather than over-claimed.
序列层面的改动同时解决了两个问题，即酶解稳定性与肾脏清除速度。天然 GLP-1 在循环中的半衰期仅约两分钟，主要被二肽基肽酶-4 迅速灭活。酰化侧链与白蛋白的可逆结合形成循环储库，使分子缓慢释放并持续激活受体。这种设计思路后来被广泛用于同类长效肽的开发，属于该类药物化学改造的典型范式。
Semaglutide 是一种经结构修饰的胰高血糖素样肽-1 类似物，其主链与内源性 GLP-1(7-36) 约有百分之九十四的序列一致性。第 8 位丙氨酸被 α-氨基异丁酸取代，使二肽基肽酶-4 无法识别原有切割位点。第 34 位赖氨酸换为精氨酸，进一步降低酶解速率。第 26 位赖氨酸经间隔基连接一条含十八个碳的二酸脂肪链，该侧链赋予分子与血浆白蛋白结合的能力。
Semaglutide is a synthetic peptide analogue of glucagon-like peptide-1, a gut hormone released by intestinal L cells after food intake. The natural hormone acts on pancreatic and central receptors but is degraded within minutes by dipeptidyl peptidase-4 and other peptidases. Semaglutide belongs to the class of long-acting GLP-1 receptor agonists, a group distinguished by structural changes that slow breakdown and extend circulation time. Its development followed earlier short-acting analogues and reflects a general strategy in peptide drug design: preserve receptor activity while blocking proteolytic clearance.
Three structural changes define the molecule. At position 8 an alpha-aminoisobutyric acid residue replaces alanine, which blocks dipeptidyl peptidase-4 cleavage. At position 34 arginine replaces lysine, and at position 26 a lysine carries a C18 fatty diacid attached through a short linker. The fatty chain binds serum albumin, and this albumin association reduces renal filtration and enzymatic attack. The unchanged backbone retains the receptor contacts that produce signalling. The free base has the formula C187H291N45O59 and a molecular weight near 4114 daltons.
Receptor activation follows the canonical Gs pathway: binding increases intracellular cyclic AMP, which promotes protein kinase A activity. In pancreatic beta cells this amplifies glucose-dependent insulin release, so secretion rises when blood glucose is high and changes little when it is low. The same signalling suppresses glucagon release from alpha cells and slows gastric emptying. Receptors in the hypothalamus and brainstem are thought to contribute to reduced appetite and lower energy intake. Which of these effects dominates clinical outcomes remains an area of active study.
| Property | Value | Notes |
|---|---|---|
| 分子式 | C187H291N45O59 | 按主链与 C18 二酸侧链计算 |
| 分子量 | 约 4113.6 道尔顿 | 游离碱形式，随反离子略有差异 |
| 外观 | 白色至类白色冻干粉末 | 具吸湿性，需干燥保存 |
| 溶解性 | 微溶于水，易溶于碱性缓冲液 | 溶解性随 pH 升高而改善 |
| 等电点 | 约 5.4 | 影响缓冲液选择与聚集倾向 |
Storage at minus 20 degrees Celsius or lower in a desiccated container preserves the peptide for extended periods, while working solutions are commonly held at two to eight degrees Celsius for short intervals. Light exposure and repeated freeze-thaw cycles accelerate degradation, so dividing material into single-use aliquots is generally recommended. Adsorption to glass and plastic surfaces can lower the measured concentration of dilute solutions, particularly below one milligram per millilitre. The degradation routes most often reported for GLP-1 analogues are deamidation, methionine oxidation, and backbone hydrolysis. Relative rates under specific conditions are frequently described only for individual formulations.
Reverse-phase high-performance liquid chromatography with ultraviolet detection near 214 or 280 nanometres is widely used to assess purity and to resolve related impurities. Liquid chromatography coupled to mass spectrometry confirms identity through the protonated molecular ion and fragment ions formed in tandem experiments. Capillary electrophoresis and peptide mapping after enzymatic digestion supply complementary information on charge variants and modification sites. Circular dichroism and nuclear magnetic resonance can report on secondary structure in solution. Absolute quantification usually depends on an external standard, and reported purity depends on the detection wavelength and integration parameters chosen.
Lyophilised material appears as a white to off-white cake or powder that is hygroscopic, and containers are usually equilibrated to room temperature before opening to limit condensation. Dissolution is performed in water, phosphate-buffered saline, or a mildly alkaline buffer, since solubility rises above neutral pH. Gentle inversion or low-speed mixing is preferred, because vigorous vortexing can promote surface denaturation and aggregation. Complete dissolution may require several minutes, and brief sonication is sometimes applied. Passing the solution through a 0.22 micrometre membrane removes particulates but does not by itself sterilise the liquid.
Semaglutide is a synthetic peptide that acts as an agonist at the glucagon-like peptide-1 receptor. It is a structural analogue of human GLP-1(7-37), modified to resist enzymatic degradation by dipeptidyl peptidase-4. The peptide backbone contains alpha-aminoisobutyric acid at position 8, a substitution that stabilises the helix and slows cleavage. A fatty diacid side chain attached through a linker at lysine 34 promotes binding to serum albumin, which extends the circulating half-life. These two modifications together allow less frequent administration than native GLP-1 requires.
Activation of the GLP-1 receptor couples to Gs signalling and raises intracellular cyclic AMP in pancreatic beta cells. The resulting insulin release depends on prevailing glucose concentrations, so the effect is greater when glucose is elevated. Receptor engagement also suppresses glucagon secretion and slows gastric emptying, which flattens post-meal glucose excursions. In the central nervous system, signalling in hypothalamic and brainstem regions is associated with reduced appetite and lower energy intake. Studies continue to examine effects on cardiac, renal and hepatic endpoints; whether those benefits are independent of weight change remains an open question.
Clinical development of this compound followed earlier short-acting GLP-1 analogues that required frequent injection. Once-weekly subcutaneous formulations entered use after 2017, and an oral formulation using a permeation enhancer later became available. The oral version pairs the peptide with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, a carrier that improves uptake across the gastric epithelium. Interest has expanded from glycaemic control into weight management and metabolic liver disease. Regulatory status and approved indications differ between countries, and the product remains subject to ongoing safety monitoring.
Faced with the threat of growing German Nazism, Italian fascism, Japanese militarism, and a world war, the Western Allies and the Soviet Union formed an alliance of necessity during World War II. After the Axis powers were defeated, the two most powerful states in the world became the Soviet Union and the United States. Both federations were called the world's superpowers. The underlying geopolitical and ideological differences between the recent allies led to the confrontation known as the Cold War, which lasted from about 1947 to 1991. It began with the second Red Scare and it ended with the fall of the Soviet Union. At the dawn of the new era, the historian John Lewis Gaddis wrote: The new world of the post–Cold War era is likely to have few, if any, of these [Cold War] characteristics: that is an indication of how much things have already changed since the Cold War ended. We are at one of those rare points of 'punctuation' in history at which old patterns of stability have broken up and new ones have not yet emerged to take their place. Historians will certainly regard the years 1989–1991 as a turning point comparable in importance to the years 1789–1794, or 1917–1918, or 1945–1947; precisely what has 'turned,' however, is much less certain. We know that a series of geopolitical earthquakes have taken place, but it is not yet clear how these upheavals have rearranged the landscape that lies before us.
The original protein and sequence are highly conserved in evolution, and are found in humans, chimpanzees, rhesus monkeys, and bush babies. Addison's disease (typically an autoimmune destruction of the adrenal glands) may also be seen in individuals with vitiligo.
== External links == "Tacrolimus Injection". MedlinePlus. "Tacrolimus Topical". MedlinePlus. Tacrolimus at the U.S. National Library of Medicine Medical Subject Headings (MeSH) "FDA Approves New Use of Transplant Drug Based on Real-World Evidence". U.S. Food and Drug Administration (FDA). 30 September 2021. Archived from the original on 16 July 2021.
Sources: en.wikipedia.org
=== GLP-1 agonists === Another popular medication that is used in T2D management are glucagon like peptide 1 (GLP-1) agonists. This class of medication works by mimicking a hormone called glucagon-like peptide which has many effects in the body. One effect of the hormone is that it helps time the release of insulin when patients eat and the blood glucose rises. In addition, it can significantly increase the amount of insulin release. Lastly, the medication also slows down the movement of food through the digestive tract and can increase feeling of fullness while eating, decreasing appetite and weight. These drugs are very effective at controlling T2D and reducing risk of heart attacks, strokes, and other complications due to diabetes. In addition, patients usually lose weight and have improved blood pressure and cholesterol. Common names of these medications include semaglutide (Ozempic and Wegovy), liraglutide (Victoza, Saxenda), and dulaglutide (Trulicity). These medications must be injected and are usually injected in the upper arm, thighs or stomach areas. They are usually given once a week but some of the medication can be as frequent as twice daily. The dose is usually started low and tapered gradually. Some of the common side effects of the medication is nausea, vomiting, and diarrhea. Patients with a family history of medullary thyroid cancer or Multiple Endocrine Neoplasia type 2 should not be prescribed the drug as it may increase the risk of developing cancer.
== Function and Terminology == The “pre-” prefix of preproglucagon indicates that it is composed of proglucagon together with a signal peptide. The signal peptide is a 20 amino acid fragment that signals that the protein needs to be secreted out of the cell. Proglucagon has the “pro-“ prefix because it is a prohormone, which means it is an inactivate precursor that needs to be further modified in order to produce active hormone(s). In particular, proglucagon is cleaved (cut) into different active hormones depending on the organ. Omitting various inactive fragments, preproglucagon is cleaved into the following:
Like DALI and SSAP, CE has been used to construct an all-to-all fold classification database Archived 1998-12-03 at the Wayback Machine from the known protein structures in the PDB. The RCSB PDB has recently released an updated version of CE, Mammoth, and FATCAT as part of the RCSB PDB Protein Comparison Tool. It provides a new variation of CE that can detect circular permutations in protein structures.
== Precursors == The earliest use of chromatography is sometimes attributed to German chemist Friedlieb Ferdinand Runge, who in 1855 described the use of paper to analyze dyes. Runge dropped spots of different inorganic chemicals onto circles of filter paper already impregnated with another chemical, and reactions between the different chemicals created unique color patterns. According to historical analysis of L. S. Ettre, however, Runge's work had "nothing to do with chromatography" (and instead should be considered a precursor of chemical spot tests such as the Schiff test). In the 1860s, Christian Friedrich Schönbein and his student Friedrich Goppelsroeder published the first attempts to study the different rates at which different substances move through filter paper. Schönbein, who thought capillary action (rather than adsorption) was responsible for the movement, called the technique capillary analysis, and Goppelsroeder spent much of his career using capillary analysis to test the movement rates of a wide variety of substances. Unlike modern paper chromatography, capillary analysis used reservoirs of the substance being analyzed, creating overlapping zones of the solution components rather than separate points or bands. Work on capillary analysis continued, but without much technical development, well into the 20th century. The first significant advances over Goppelsroeder's methods came with the work of Raphael E.
Sources: en.wikipedia.org
31 October The Independent Schools Council, which represents around 1,400 private schools in the UK, votes to take legal action against government plans to end their tax exemption status from January 2025. GB News is fined £100,000 by Ofcom for breaking impartiality rules with a programme featuring the former Prime Minister Rishi Sunak.
== Chemistry == Chemical constituents of the roots (Radix Astragali) include polysaccharides and triterpenoids (such as astragalosides), as well as isoflavones (including kumatakenin, calycosin, and formononetin) and their glycosides and malonates. It contains the saponin cycloastragenol.
Milk thistle (Silybum marianum) extract (70–80% Silymarin) (225 mg) Bacopa (Bacopa monnieri) extract (45% bacosides) (150 mg) Ashwagandha (Withania somnifera) powder (150 mg) Green tea (Camellia sinensis) extract (98% polyphenols, 45% EGCG) (75 mg) Turmeric (Curcuma longa) extract (95% curcumin) (75 mg)
Sources: en.wikipedia.org
差别集中在三处：第 8 位残基被非天然氨基酸取代，第 34 位换成精氨酸，第 26 位增加一条脂肪酸侧链。前两处改动降低酶解速率，侧链则通过白蛋白结合延长循环时间。综合结果是半衰期从约两分钟延长到约一周。
胰岛素释放需要细胞内环腺苷酸与钙信号升高，同时依赖葡萄糖代谢产生的协同信号。血糖水平较低时协同信号不足，分泌增强有限。这一机制在降糖效果与低血糖风险之间提供了缓冲。
白蛋白结合是主要原因，它减少肾小球滤过并保护分子免受蛋白酶降解。序列修饰带来的酶解抵抗同样不可忽略，二者共同作用。脂肪链的疏水性还会影响组织分布，但其对总半衰期的贡献程度仍在研究之中。
Native GLP-1 is a short-lived peptide cleared within one to two minutes by dipeptidyl peptidase-4 and related enzymes. Semaglutide keeps the receptor-binding backbone but adds substitutions and a lipid chain. These changes block the main cleavage site and allow reversible albumin binding, extending the half-life to roughly 165 hours.