长效肽设计 raises a handful of sensible questions. This page answers them in order, starting with the fundamentals and moving to applications.
This page was last updated on 2025-10-16 and is reviewed periodically as new material appears.
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.
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 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.
| Property | Value | Notes |
|---|---|---|
| Molecular class | Acylated GLP-1 receptor agonist | 31-residue synthetic peptide |
| Molecular formula | C187H291N45O59 | established for the free peptide |
| Appearance | White to off-white powder | as supplied before formulation |
| Solubility | Freely soluble in water | aqueous buffers near neutral pH |
| Typical storage | 2 to 8 degrees Celsius, protected from light | powder and solution forms differ in shelf life |
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.
皮下注射后吸收相对缓慢，绝对生物利用度约为百分之八十九，血药浓度峰值通常出现在给药后一到三天。与白蛋白结合使清除减慢，终末半衰期约为一百六十五小时，接近一周。连续给药约四到五周后达到稳态暴露水平。表观分布容积约为每千克零点二五升，血浆蛋白结合率超过百分之九十九。代谢以蛋白水解切割和脂肪二酸侧链的 β-氧化为主，相关产物主要经尿液与粪便排出。
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。
== Etymology of anesthesia == In ancient Greek texts, such as the Hippocratic Corpus and the dialogue Timaeus, the term ἀναισθησία (anaisthēsíā) is used, which translates to "without sensation". This term is derived from the prefix ἀν- (an-), meaning "without", and αἴσθησις (aisthēsis), which means "sensation". The concept of anaisthēsia is significant in understanding the historical foundations of anesthesia and its relevance in medical practices. In 1679, Steven Blankaart published Lexicon medicum graeco-latinum with the Latin term anaisthesia. In 1684, an English translation appeared titled A Physical Dictionary, with anesthesia defined as a "defect of sensation, as in paralytic and blasted persons". Subsequently, the term and variant spellings like anæsthesia are used in medical literature signifying "insensibility". In 1846, in a letter, Oliver Wendell Holmes proposed the term anesthesia to be used for the state induced by an agent and anesthetic for the agent itself. Holmes motivates this with earlier uses of anesthesia in medical literature to mean "insensibility", particularly to "objects of touch".
Napoleon's Wars: An International History, 1803–1815. Penguin Books. ISBN 978-0-14-311628-8. Ferguson, Niall (2008). The Ascent of Money: A Financial History of the World: 10th Anniversary Edition. Penguin. ISBN 978-1-4406-5402-2. Fremont-Barnes, Gregory (2014). The Napoleonic Wars (3): The Peninsular War 1807–1814. Bloomsbury Publishing. ISBN 978-1-4728-0975-9. Gates, David (1986). The Spanish Ulcer: A History of the Peninsular War. Allen & Unwin. ISBN 978-0-04-940079-5. Glover, Michael (1963). Wellington's Peninsular Victories: Busaco, Salamanca, Vitoria, Nivelle. Macmillan. Götz, Norbert (6 June 2014). "The Good Plumpuddings' Belief: British Voluntary Aid to Sweden During the Napoleonic Wars". The International History Review. 37 (3): 519–539. doi:10.1080/07075332.2014.918559. ISSN 0707-5332. Grab, Alexander (2003). Napoleon and the Transformation of Europe. Macmillan International Higher Education. ISBN 978-1-4039-3757-5. Grainger, John D. (2004). The Amiens Truce: Britain and Bonaparte, 1801–1803. Boydell Press. ISBN 978-1-84383-041-2. Gray, Colin S. (2007). War, Peace and International Relations: An Introduction to Strategic History. Routledge. ISBN 978-1-134-16951-1. Halévy, Elie (1924). A History of the English People ...: England in 1815. Harcourt, Brace. Haythornthwaite, Philip; et al. (Illustrations and graphics by Peter Dennis) (20 September 2012). Cowper, Marcus (ed.). Borodino 1812: Napoleon's great gamble. Campaign. Vol. 246. London, England, United Kingdom of Great Britain: Bloomsbury Publishing. ISBN 9781849086974.
=== Inequalities === People living with AD and other forms of dementia and their unpaid carers might face inequalities in access to and the quality of care and support services. These inequalities can depend on various factors, including socio-economic background, housing situation, education level, gender, and race. People might have differences in how easily they can access AD services based on where they live. On a global level, people in low-and middle-income countries have fewer available facilities and services, and have greater difficulties accessing these than people living in high-income countries. As a result of AD and other forms of dementia being less recognised and treated in the healthcare systems of these countries, the level of awareness of AD as something caused by disease is relatively lower. At the same time, the local socio-cultural understandings of aging, senility, and eldercare may have larger effects on care provision and the reception of medical services. On a national level, people with AD might have unequal access to care based on where they live. This can manifest on a regional level, with people in rural areas facing more difficulties than those in urban areas. Inequalities can also affect smaller local units as well, for example people living in the same city might receive different or less frequent care based on their postcodes or the street they live in. Inequalities also affect people with AD from ethnic minority groups.
No Heat Applying heat to the injured area can cause blood flow and swelling to increase. No Alcohol Alcohol can inhibit the ability to feel if the injury is becoming more aggravated, as well as increasing blood flow and swelling. No Re-injury Avoid any activities that could aggravate the injury and cause further damage. No Massage Massaging an injured area can promote blood flow and swelling, and potentially cause more damage if done too early.
Sources: en.wikipedia.org
Yukio Ninagawa staged a production called Ohjo Media (王女メディア) in 1978, followed by a second version in 2005. In 1982, George Eugeniou at Theatro Technis London directed Medea as a barefooted unwanted refugee played with "fierce agility" and "dangerous passions" by Angelique Rockas. In 1983, kabuki Master Shozo Sato created Kabuki Medea uniting Euripides' play and classical Kabuki storytelling and presentation. It debuted at Wisdom Bridge Theater in Chicago. The 1990 play Pecong, by Steve Carter, is a retelling of Medea set on a fictional Caribbean island around the turn of the 20th century The play was staged at the Wyndham's Theatre in London's West End, in a translation by Alistair Elliot. The production opened on 19 October 1993. Chrysanthos Mentis Bostantzoglou makes a parody of this tragedy in his comedy Medea (1993). A 1993 dance-theatre retelling of the Medea myth was produced by Edafos Dance Theatre, directed by avant-garde stage director and choreographer Dimitris Papaioannou. John Fisher wrote a camp musical version of Medea entitled Medea the Musical that re-interpreted the play in light of gay culture. The production was first staged in 1994 in Berkeley, California. Christopher Durang and Wendy Wasserstein co-wrote a sketch version for the Juilliard School's Drama division 25th Anniversary. It premiered 25 April 1994, at the Juilliard Theater, New York City.
==== March 2024 ==== On 4 March, a Hezbollah anti-tank missile strike on Margaliot resulted in seven injuries as well as the death of an Indian national. The next day, an Israeli airstrike on Hula, in retaliation for the previous day's strike on Margaliot, killed three Lebanese citizens, a married couple and their child. Amongst the three killed, Hezbollah announced two as their members. On 9 March, five people, including three Hezbollah members, were killed and at least nine others were wounded in an IDF strike on a house in Khirbet Selm. In retaliation, the next day Hezbollah fired 37 Katyusha rockets at the Mount Meron in northern Israel; no injuries were reported.
Transuranic waste (TRUW) as defined by U.S. regulations is, without regard to form or origin, waste that is contaminated with alpha-emitting transuranic radionuclides with half-lives greater than 20 years and concentrations greater than 100 nCi/g (3.7 MBq/kg), excluding high-level waste. Elements that have an atomic number greater than uranium are called transuranic ("beyond uranium"). Because of their long half-lives, TRUW is disposed of more cautiously than either low- or intermediate-level waste. In the United States, it arises mainly from nuclear weapons production, and consists of clothing, tools, rags, residues, debris, and other items contaminated with small amounts of radioactive elements (mainly plutonium). Under U.S. law, transuranic waste is further categorized into "contact-handled" (CH) and "remote-handled" (RH) on the basis of the radiation dose rate measured at the surface of the waste container. CH TRUW has a surface dose rate not greater than 200 mrem per hour (2 mSv/h), whereas RH TRUW has a surface dose rate of 200 mrem/h (2 mSv/h) or greater. CH TRUW does not have the very high radioactivity of high-level waste, nor its high heat generation, but RH TRUW can be highly radioactive, with surface dose rates up to 1,000,000 mrem/h (10,000 mSv/h). The United States currently disposes of TRUW generated from military facilities at the Waste Isolation Pilot Plant (WIPP) in a deep salt formation in New Mexico.
Sources: en.wikipedia.org
Native GLP-1 is degraded within minutes by dipeptidyl peptidase-4 and neutral endopeptidases. Semaglutide carries a non-natural amino acid at position eight that blocks that cleavage, and a fatty diacid side chain that binds albumin. The result is a much longer duration of action than the native hormone.
The fatty diacid chain associates strongly with serum albumin, which keeps the peptide in circulation and shields it from rapid renal clearance. Bound peptide is released gradually, producing a sustained receptor signal. This mechanism also reduces the peak-to-trough variation seen with shorter-acting analogues.
The balance between peripheral receptor activation and signalling in the central nervous system is not fully resolved. The extent to which slowed gastric emptying accounts for reduced energy intake, compared with direct effects on appetite circuits, is debated. Long-term effects on lean mass and on tissues outside the gut and brain are still under study.
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.