The short version of fatty diacid chain fits in a sentence. The long version — which is the one that helps — is below.
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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。
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.
| 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 |
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.
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.
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.
Some previous disputes, such as the Pedra Branca dispute, have been resolved by the International Court of Justice. Piracy in the Strait of Malacca has been a cause of concern for all three countries. Close economic ties exist with Brunei, and the two share a pegged currency value, through a Currency Interchangeability Agreement between the two countries which makes both Brunei dollar and Singapore dollar banknotes and coins legal tender in either country. The first diplomatic contact with China was made in the 1970s, with full diplomatic relations established in the 1990s. China has been Singapore's largest trading partner since 2013, after surpassing Malaysia. Singapore and the United States share a long-standing close relationship, in particular in defence, the economy, health, and education. Singapore has also increased co-operation with ASEAN members and China to strengthen regional security and fight terrorism, and participated in ASEAN's first joint maritime exercise with China in 2018. It has also given support to the US-led coalition to fight terrorism, with bilateral co-operation in counter-terrorism and counter-proliferation initiatives, and joint military exercises. As Singapore has diplomatic relations with both the United States and North Korea, and was one of the few countries that have relationships with both countries, in June 2018, it hosted a historic summit between US President Donald Trump and North Korean leader Kim Jong-un, the first-ever meeting between the sitting leaders of the two nations.
== Further reading == Brandoni, Diego; Scillato Yané, Gustavo J.; Miño Boilini, Ángel R.; Favotti, Emmanuel (2016). "Los Tardigrada (Mammalia, Xenarthra) de Argentina: diversidad, evolución y biogeografía" (PDF). Contribuciones del MACN. _: 263–274. Retrieved 2018-10-08. Cuvier, G. (1796): Notice sur le squelette d'une très grande espèce de quadrupède inconnue jusqu'à présent, trouvé au Paraguay, et déposé au cabinet d'histoire naturelle de Madrid. Magasin encyopédique, ou Journal des Sciences, des Lettres et des Arts (1): 303–310; (2): 227–228. De Iuliis, G. & Cartelle, C. (1999): A new giant megatheriine ground sloth (Mammalia: Xenarthra: Megatheriidae) from the late Blancan to early Irvingtonian of Florida. Zool. J. Linn. Soc. 127(4): 495–515. Harrington, C.R. (1993): Yukon Beringia Interpretive Center - Jefferson's Ground Sloth. Retrieved 2008-JAN-24. Hogan, C.M. (2008): Cueva del Milodon, Megalithic Portal. Retrieved 2008-APR-13 Kurtén, Björn and Anderson, Elaine (1980): Pleistocene Mammals of North America. Columbia University Press, New York. ISBN 0-231-03733-3 McKenna, Malcolm C. & Bell, Susan K. (1997): Classification of Mammals Above the Species Level. Columbia University Press, New York. ISBN 0-231-11013-8 Nowak, R.M. (1999): Walker's Mammals of the World (Vol. 2). Johns Hopkins University Press, London. White, J.L. (1993): Indicators of locomotor habits in Xenarthrans: Evidence for locomotor heterogeneity among fossil sloths. Journal of Vertebrate Paleontology, 13(2): 230–242. White, J.L.; MacPhee, R.D.E. (2001).
=== Firing of employee that filed suit (2010) === A federal lawsuit was filed by a scientist claiming she got an infection by a genetically modified lentivirus while working for Pfizer, resulting in intermittent paralysis. A judge dismissed the case citing a lack of evidence that the illness was caused by the virus but the jury ruled that by firing the employee, Pfizer violated laws protecting freedom of speech and whistleblowers and awarded her $1.37 million.
== Occurrence == The compound is produced by human pathogens such as Aspergillus fumigatus, and also by species of Trichoderma and Penicillium. Gliotoxin has also been reported from yeasts of the genus Candida, but results from other studies have cast doubt on the production of this metabolite by Candida fungi. Gliotoxin is not produced by nonpathogenic A. fischeri although A.fischeri contains a gene cluster that is homologous to the gliotoxin gene cluster found in the pathogenic A. fumigatus. Gliotoxin contributes to the pathogenicity of opportunistic fungi by suppressing the immune system response of its host. Gliotoxin additionally possesses fungicidal and bacteriostatic properties, which indicates that it likely plays an important self defense role against bacteria and other fungi for the fungi that produce gliotoxin. Exposure of A. fumigatus to exogenous gliotoxin resulted in aberrant protein expression, especially in those strains that lacked the self-protection protein GliT. There is additional evidence for differential gliotoxin sensitivities amongst fungi including Aspergillus flavus, Fusarium graminearum, and Aspergillus oryzae.
Sources: en.wikipedia.org
Vitamin A is found in many foods. Vitamin A in food exists either as preformed retinol – an active form of vitamin A – found in animal liver, dairy and egg products, and some fortified foods, or as provitamin A carotenoids, which are plant pigments digested into vitamin A after consuming carotenoid-rich plant foods, typically in red, orange, or yellow colors. Carotenoid pigments may be masked by chlorophylls in dark green leaf vegetables, such as spinach. The relatively low bioavailability of plant-food carotenoids results partly from binding to proteins – chopping, homogenizing or cooking disrupts the plant proteins, increasing provitamin A carotenoid bioavailability. Vegetarian and vegan diets can provide sufficient vitamin A in the form of provitamin A carotenoids if the diet contains carrots, carrot juice, sweet potatoes, green leafy vegetables such as spinach and kale, and other carotenoid-rich foods. In the U.S., the average daily intake of β-carotene is in the range 2–7 mg. Some manufactured foods and dietary supplements are sources of vitamin A or β-carotene.
=== Mice === Mouse FPR receptors localize to chromosome 17A3.2 in the following order: Fpr1, Fpr-rs2 (or fpr2), Fpr-rs1 (or LXA4R), Fpr-rs4, Fpr-rs7, Fpr-rs7, Fpr-rs6, and Fpr-rs3; Pseudogenes ψFpr-rs2 and ψFpr-rs3 (or ψFpr-rs5) lie just after Fpr-rs2 and Fpr-rs1, respectively. All of the active mouse FPR receptors have ≥50% amino acid sequence identity with each other as well as with the three human FPR receptors. Based on its predominantly intracellular distribution, mFpr-rs1 correlates, and therefore may share functionality, with human FPR3; However, the large number of mouse compared to human FPR receptors makes it difficult to extrapolate human FPR functions based on genetic (e.g. gene knockout or forced overexpression) or other experimental manipulations of the FPR receptors in mice.
==== Lymphatic system ==== The circulatory system processes an average of 20 litres of blood per day through capillary filtration, which removes plasma from the blood. Roughly 17 litres of the filtered blood are reabsorbed directly into the blood vessels. The lymphatic system provides an accessory return route to the blood for the remaining three litres of interstitial fluid.
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 is a synthetic peptide of 31 amino acids, built to resemble the natural incretin hormone GLP-1. Because of its size and composition it is handled analytically like other therapeutic peptides, using chromatographic and mass spectrometric methods rather than the techniques typical of small organic drugs.