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Last reviewed on 2025-11-15. 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。
该分子作为 GLP-1 受体的选择性激动剂发挥作用，受体属于 B 类 G 蛋白偶联受体家族，激活后经 Gs 通路提升细胞内环腺苷酸水平。在胰腺 β 细胞，信号促进葡萄糖依赖性的胰岛素释放，血糖偏低时该作用明显减弱。在胰岛 α 细胞，胰高血糖素分泌受到抑制。中枢神经系统与胃肠道同样存在受体表达，相应信号参与食欲调节以及胃排空速率的降低。
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.
| 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 semaglutide sequence is a 31-residue analogue of human GLP-1, altered at three positions relative to the parent hormone. Aminoisobutyric acid replaces alanine at position 8, arginine replaces lysine at position 34, and a lipophilic diacid is attached to lysine 26 through a short linker. These features are reported consistently in the structural literature. The position 8 substitution blocks recognition by dipeptidyl peptidase-4, while the attached chain drives strong, reversible association with a carrier protein in blood.
Receptor activation raises intracellular cyclic AMP through Gs coupling, which promotes glucose-dependent insulin release and suppresses glucagon secretion when blood glucose is elevated. Effects outside the pancreas include slower gastric emptying and altered appetite signalling in the hypothalamus and hindbrain. The relative contribution of each tissue to overall metabolic outcomes remains an area of active investigation. Central mechanisms in particular are inferred mainly from animal models and indirect human measures rather than direct observation.
Serum protein binding dominates the pharmacokinetic profile. The attached chain associates strongly with albumin, shielding the peptide from enzymatic attack and slowing filtration by the kidney. This interaction extends the circulation half-life to roughly one week in humans, which supports weekly administration intervals. An oral version pairs the peptide with an absorption enhancer that transiently alters gastric epithelium, permitting limited uptake; bioavailability by that route is substantially lower than by injection.
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.
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.
== Further reading == Wang, Juan; Li, Yuan Zhi; Chen, Ren Ren; Bao, Jin Yong; Yang, Gong Ming (January 2007). "Comparison of volatiles of banana powder dehydrated by vacuum belt drying, freeze-drying and air-drying". Food Chemistry. 104 (4): 1516. doi:10.1016/j.foodchem.2007.02.029. von Meysenbug, L.; Fine, Archie (May 1936). "Banana powder and the fecal flora of infants". The Journal of Pediatrics. 8 (5): 630. doi:10.1016/S0022-3476(36)80163-2.
If two neighboring carbon atoms are labeled, a doublet of doublets may degenerate into a triplet if the doublet splittings are equal. The drawbacks to using NMR techniques for metabolic flux analysis purposes is that it is different from other NMR applications because it is a rather specialized discipline. An NMR spectrometer may not be directly available for all research teams. The optimization of NMR measurement parameters and proper analysis of peak structures requires a skilled NMR specialist. Certain metabolites also may require specialized measurement procedures to obtain additional isotopomer data. In addition, specially adapted software tools are needed to determine the precise quantity of peak areas as well as identifying the decomposition of entangled singlet, doublet, and triplet peaks. As opposed to nuclear magnetic resonance, mass spectrometry (MS) is another method that is more applicable and sensitive to metabolic flux analysis experiments. MS instruments are available in different variants. Different from two-dimensional nuclear magnetic resonance (2D-NMR), the MS instruments work directly with hydrolysate. In gas chromatography-mass spectrometry (GC-MS), the MS is coupled to a gas chromatograph to separate the compounds of the hydrolysate. The compounds eluting from the GC column are then ionized and simultaneously fragmented. The benefit in using GC-MS is that not only are the mass isotopomers of the molecular ion measured but also the mass isotopomer spectrum of several fragments, which significantly increases the measured information.
== Career and research == Williams then spent another period back at Merton, having won a junior research fellowship, Then, “out of the blue, in 1954, Cyril Hinshelwood, then Oxford Professor of Chemistry, asked to see Bob.” He was told that three colleges—Christ Church, Pembroke and Wadham—needed a tutor in chemistry. “Each one will invite you to dine. Come back again in two weeks to give me your decision.” Williams joined Wadham College, Oxford in 1955 and remained there for the rest of his life. His doctoral students include Peter Day, Carole Perry and Michael Thor Pope. William's work in pure inorganic chemistry led to a two-volume textbook of inorganic chemistry, written with Courtenay Phillips, He became increasingly interested in enzyme catalysis, and in particular the role of metal ions, as for example the role of copper in proteins. He and Bert Vallee proposed of the concept of the entatic state whereby atoms and groups in enzyme active sites are maintained by binding to the apoenzyme in positions and states appropriate to catalyse reactions. In the first paper ever published in the Journal of Theoretical Biology Williams argued that spatial separation of the H+ and OH– ions produced in the conversion of ATP to ADP would be necessary for the catalysis. In the same year Peter Mitchell proposed a similar idea in the form of the chemiosmotic hypothesis. In a special issue of the Journal of Theoretical Biology in celebration of 50 years of its existence Williams described the correspondence between Mitchell and himself.
Sources: en.wikipedia.org
=== Refresh frequency limits for standard video === Color depth of 8 bpc (24 bit/px or 16.7 million colors) is assumed for all formats in these tables. This is the standard color depth used on most computer displays. Note that some operating systems refer to this as "32-bit" color depth—this is the same as 24-bit color depth. The 8 extra bits are for alpha channel information, which is only present in software. At the transmission stage, this information has already been incorporated into the primary color channels, so the actual video data transmitted across the cable only contains 24 bits per pixel.
== Signs and symptoms == People with hypothyroidism often have no or only mild symptoms. Numerous signs and symptoms are associated with hypothyroidism and can be related to the underlying cause, or a direct effect of not having enough thyroid hormones. Many symptoms of hypothyroidism are otherwise common and do not necessarily indicate thyroid problem. Hashimoto's thyroiditis may present with the mass effect of a goiter (enlarged thyroid gland). In middle-aged women, the symptoms may be mistaken for those of menopause.
=== Lunar distance === Lunar distance (LD), the distance from the centre of Earth to the centre of the Moon, is a unit of measure in astronomy. The lunar distance is approximately 384,400 km (238,900 mi), or 1.28 light-seconds; this is roughly 30 times Earth's diameter. A little less than 400 lunar distances make up an astronomical unit.
Cardiovascular Bradycardia Bundle branch blocks Complete heart block and arrhythmias Cardiomegaly Elevated diastolic blood pressure—early Hypotension—late Low cardiac output Non-specific ECG findings Pericardial effusion Polymorphic ventricular tachycardia (torsades de pointes) Prolonged QT interval Respiratory Hypoxia Hypercapnia Hyperventilation Myxedema of the larynx Pleural effusion Gastrointestinal Abdominal distention Abdominal pain Anasarca Anorexia and nausea Decreased motility Fecal impaction and constipation Gastrointestinal atony or ileus Myxedema or toxic megacolon—late Neurogenic oropharyngeal dysphagia ileus Neurological Altered mentation Coma Confusion and obtundation Delayed tendon reflexes Depression Poor cognitive function Psychosis Seizures Renal and urinary function Bladder dystonia and distension Fluid retention Appearance and dermatological Alopecia Coarse, sparse hair Dry, cool, doughy skin Myxedematous face Generalized swelling Goiter Macroglossia Non-pitting edema Ptosis Periorbital edema Surgical scar from prior thyroidectomy Hypothermia (often marked: usually < 35 °C/ 95 °F) Laboratory features in myxedema coma:
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。
It belongs to the incretin mimetic class and acts as a long-acting glucagon-like peptide-1 receptor agonist. The class includes several peptides with different half-lives and routes of administration.