deamidation raises a handful of sensible questions. This page answers them in order, starting with the fundamentals and moving to applications.
Reviewed 2026-04-21. Anything still debated is marked as such rather than presented as settled.
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 analog of glucagon-like peptide-1 (GLP-1), a hormone released from intestinal L-cells after food intake. The compound belongs to the incretin mimetic class and acts at GLP-1 receptors distributed across pancreatic, gastrointestinal, cardiovascular, and central nervous system tissues. Compared with native GLP-1, the molecule carries structural changes that extend its activity from minutes to roughly one week. It is studied for glycemic control in type 2 diabetes and for weight management, and its effects on cardiovascular and other outcomes remain active research areas.
Receptor binding triggers G protein signaling that raises intracellular cyclic AMP in pancreatic beta cells. Insulin release follows in a glucose-dependent manner, so secretion increases when blood glucose is elevated and diminishes when it is not. The same signaling suppresses glucagon release from alpha cells and slows gastric emptying, which blunts the post-meal glucose rise. In the brain, receptor activation in regions such as the arcuate nucleus is associated with reduced appetite and lower energy intake. How much each of these effects contributes to overall weight change is not fully settled.
Two structural features account for the prolonged half-life of semaglutide. A modified amino acid at position 8 resists cleavage by dipeptidyl peptidase-4, the enzyme that rapidly degrades native GLP-1. A fatty diacid side chain binds serum albumin, which limits renal clearance and protects the peptide from enzymatic breakdown. These modifications yield a plasma half-life of approximately one week in humans, allowing once-weekly administration. The relationship between plasma concentration and clinical effect varies between individuals, and sources of that variability are still being characterized.
| 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 |
The primary target is the GLP-1 receptor, a class B G protein-coupled receptor expressed on pancreatic beta cells, in the gut, and in several brain regions. Receptor activation raises intracellular cyclic AMP, which potentiates glucose-dependent insulin secretion and lowers glucagon release when blood glucose is elevated. Signalling in the hypothalamus and brainstem is associated with reduced appetite and slower gastric emptying. Because the insulinotropic effect depends on prevailing glucose levels, the hypoglycaemic risk of the peptide alone is described as low in most study settings. The relative contribution of peripheral and central actions remains an active research question.
Large randomised trials in adults with type 2 diabetes and in adults with obesity have reported reductions in body weight and improvements in several cardiovascular risk markers. One outcome trial found a lower incidence of major adverse cardiovascular events in participants with diabetes and established cardiovascular disease. Gastrointestinal effects such as nausea and vomiting are the most frequently reported adverse events and often diminish over time. Changes in lean body mass during weight loss are an area of ongoing investigation. Effects in adolescents and in pregnancy are less well characterised, and current labelling advises against use during pregnancy.
Semaglutide is a synthetic peptide analogue of glucagon-like peptide-1, a gut hormone released after nutrient intake. The molecule contains 31 amino acid residues and differs from the native sequence at several positions. A non-natural residue at position eight resists the enzyme that normally truncates the hormone, while a lysine-linked fatty diacid side chain promotes binding to serum albumin. These two modifications extend the circulating half-life from minutes to roughly one week. The peptide is produced by solid-phase synthesis followed by selective acylation, and its identity and purity are confirmed by spectrometric and chromatographic techniques.
Lyophilized semaglutide powder is typically held at minus twenty degrees Celsius for long-term storage. At that temperature, solid-state degradation reactions proceed slowly and the peptide remains intact for extended periods. Repeated freeze-thaw cycles are best avoided because they promote aggregation and can shift the proportion of monomeric peptide present. Working aliquots are often prepared so that each portion is thawed only once, and desiccant is placed inside the vial to limit moisture uptake.
Identity and purity are usually assessed by reverse-phase high-performance liquid chromatography coupled to mass spectrometry. Retention time and observed mass are compared against a reference standard run under identical conditions. Impurity profiles reveal deamidation products, oxidized methionine variants, and truncated fragments that arise during synthesis or storage. Peptide mapping through enzymatic digestion confirms the primary sequence, while amino acid analysis offers an independent check on overall composition.
Stability studies examine how temperature, pH, and moisture influence degradation rates over time. In aqueous solution, hydrolysis and deamidation accelerate as pH moves away from mildly acidic conditions. Light exposure and residual metal ions can also trigger oxidation of susceptible residues. Accelerated aging at elevated temperature is used to estimate shelf life, though extrapolation to room temperature carries uncertainty because individual degradation pathways do not always scale predictably.
== Historical uses == Following its discovery by Marie and Pierre Curie in 1898, radium (principally 226Ra) has had a number of uses. In the early 20th century, when the hazards of radiation were not well-known, radium was commonly used in consumer items such as toothpaste and hair creams. Radium was also formerly used as a radiation source for cancer treatment, but has since been replaced in this role by safer and more easily available alternatives. Until the 1960s, radium was used in luminous paint for watch dials and aircraft instruments.
=== Pharmacodynamics === In vitro, cannabidiol has low affinity for, and acts as a negative allosteric modulator of the CB1 cannabinoid receptor Cannabidiol may be an antagonist of GPR55, a G protein-coupled receptor and putative non-homologous CB3 cannabinoid receptor shown by in vitro studies to be widely distributed in the brain. Cannabidiol may interact with various neurotransmitters, such as serotonin, dopamine, and GABA. As of 2024, the cellular effects and mechanisms of cannabidiol in vivo are unknown, as research to date has been inconclusive and based on laboratory studies. The anticonvulsant effects provided by cannabidiol (Epidiolex) in people with certain forms of epilepsy do not appear to involve cannabinoid receptors. A possible mechanism for the effects of cannabidiol on seizures is by affecting the neuronal movement of calcium in brain structures involved in the excessive electrical activity of seizures.
=== Cuban opposition === On 6 February, El País conducted interviews with various Cuban dissidents, including José Daniel Ferrer, Manuel Cuesta Morúa, and María Payá Acevedo. Their reactions were a mix of hope and warning against manipulations, including views that the Cuban government could cease talks when it stabilizes itself. On 22 May, Cuban opposition leader Ferrer claimed that there is no doubt that the communist regime will end by the end of 2026.
Sources: en.wikipedia.org
=== Menstrual disturbances === Spironolactone at higher doses can cause menstrual irregularities as a side effect in women, including metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding. They are common during spironolactone therapy, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses. For example, about 20% of women experienced menstrual irregularities with 50 to 100 mg/day spironolactone, whereas about 70% experienced menstrual irregularities at 200 mg/day. Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation. Spironolactone produces an irregular and anovulatory pattern of menstrual cycles. It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women, as well as with polymenorrhea (short menstrual cycles). The medication reportedly has no birth control effect. The weak progestogenic activity of spironolactone has been suggested to be responsible for these effects, although not established, and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women. An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels. Indeed, CYP17A1 genotype is associated with polymenorrhea.
If the mutation occurs in the region of the gene where transcriptional machinery binds to the protein, the mutation can affect the way in which transcription factors bind to the protein. The mechanisms of transcription bind to a protein through recognition of short nucleotide sequences. A mutation in this region may alter these sequences and, thus, change the way the transcription factors bind to the protein. Mutations in this region can affect the efficiency of gene transcription, which controls both the levels of mRNA and overall protein levels.
== Advantages == Avoiding the use of pressure to introduce the mobile phase into the column, results in a number of important advantages. Firstly, the pressure driven flow rate across a column depends directly on the square of the particle diameter and inversely on the length of the column. This restricts the length of the column and size of the particle, particle size is seldom less than 3 micrometer and the length of the column is restricted to 25 cm. Electrically driven flow rate is independent of length of column and size. A second advantage of using electroosmosis to pass the mobile phase into the column is the plug-like flow velocity profile of EOF, which reduces the solute dispersion in the column, increasing column efficiency.
=== Potential treatment for osteoporosis === Osteoporosis is a bone disease where bone mass is less than the average and can increase fractures. Some causes that lead to osteoporosis is how old you are, and decreasing amount of estrogen, which is why it mainly occurs in older women (however it can also impact men as well). During a recent study performed at Children's Medical Center Research Institute at UT Southwestern, Bone Growth Factor Osteolectin (Clec11a) has also shown regenerative properties. Ovaries were removed from mice to simulate osteoporosis of post menopausal women. Results were based on daily injections of Osteolectin to determine the effects. This research showed an increase in bone volume of mice with bone loss after their ovaries were removed. To be more specific, in order to help people with osteoporosis, medication is used along with treating bone fractures. Clec11a is a glycoprotein that bone marrow expresses which Elifesciences states.
Sources: en.wikipedia.org
Metabolites are the substrates, intermediates and products of metabolism. Within the context of metabolomics, a metabolite is usually defined as any molecule less than 1.5 kDa in size. However, there are exceptions to this depending on the sample and detection method. For example, macromolecules such as lipoproteins and albumin are reliably detected in NMR-based metabolomics studies of blood plasma. In plant-based metabolomics, it is common to refer to "primary" and "secondary" metabolites. A primary metabolite is directly involved in the normal growth, development, and reproduction. A secondary metabolite is not directly involved in those processes, but usually has important ecological function. Examples include antibiotics and pigments. By contrast, in human-based metabolomics, it is more common to describe metabolites as being either endogenous (produced by the host organism) or exogenous. Metabolites of foreign substances such as drugs are termed xenometabolites. The metabolome derives from a large network of metabolic reactions, where outputs from one enzymatic chemical reaction are inputs to other chemical reactions. Such systems have been described as hypercycles.
=== Muscle spasticity === Tizanidine is approved and used as a muscle relaxant to treat muscle spasticity. It has been found to be as effective as other muscle relaxants and is more tolerable than baclofen and diazepam. Due to its short elimination half-life and duration, tizanidine is generally taken once every 6 to 8 hours as needed, with a maximum of 3 doses per 24 hours.
The wide audience that TikTok videos are able to reach compared to other platforms allows just a small number of viral videos about a similar style of clothing to create a new microtrend. The high quantity of new microtrends produced by TikTok users has increased the popularity of fast fashion retailers such as Shein, who are able to rapidly reproduce and sell items that are trending on TikTok. Fashion trends and fads that have become popular through social media platforms have collectively become known as "internet aesthetics". Haul videos are popular amongst TikTok fashion creators. Shein successfully worked with influencers on TikTok and Instagram to grow its business by sending them free clothing and discount codes to share with their followers that earn them a commission on sales. Influencers are also paid to post haul videos for Shein with the free clothing. The popularity of haul videos on TikTok also results in users advertising Shein for free by making and posting their own Shein haul.
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 degraded within minutes by dipeptidyl peptidase-4 and cleared quickly. Semaglutide carries a position 8 substitution that blocks that cleavage and a fatty diacid chain that binds albumin. Together these changes extend its circulating half-life to about one week.