Aib substitution 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.
Updated 2025-09-10. Numbers and descriptions here follow the published literature rather than marketing material.
Pharmacological activity arises from agonism at the glucagon-like peptide-1 receptor, a G protein-coupled receptor expressed in the pancreas, the gastrointestinal tract, and the brainstem. Receptor activation raises intracellular cyclic adenosine monophosphate and enhances insulin release in a glucose-dependent manner, an effect that diminishes when blood glucose concentration is low. Other effects include slowed gastric emptying and hypothalamic satiety signalling. These pathways are described well. Receptor desensitisation rates across tissues, relative to the endogenous hormone, are still under investigation, and reported findings differ between laboratories.
The company that developed the compound filed it as a long-acting analogue, and it gained first approval in 2017 for type 2 diabetes. Later authorisations from several regulators extended the indication to chronic weight management, and the World Health Organization added the glucagon-like peptide-1 receptor agonist drug class to its model list of essential medicines in 2023. Production uses solid-phase peptide synthesis followed by side-chain conjugation and chromatographic purification. Supply constraints and cost differences across regions are well documented. Literature on long-term outcomes continues to grow, with many trials reporting surrogate endpoints rather than hard clinical endpoints.
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。
| Property | Value | Notes |
|---|---|---|
| Molecular class | 31-amino-acid peptide | Modified glucagon-like peptide-1 analogue |
| Molecular mass | approximately 4114 Da | Calculated for the free peptide backbone |
| Appearance | white to off-white powder | Typical of purified lyophilised peptide batches |
| Solubility class | freely soluble in water | Aqueous solubility improves at slightly alkaline pH |
| Typical storage | -20 degrees Celsius, dry, dark | Protect from repeated freeze-thaw cycles |
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.
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.
== Ligands == The main ligand for α2β1 integrin is collagen, and thus, it is considered one of the main receptors for collagen on mammalian cells. The receptor interacts highly with fibrillar collagen types, especially type I collagen, which is plentiful in connective tissues including skin, tendon, and bone. It also recognizes type IV collagen, which is an important part of basement membranes and permits cells to associate with different ECM components. Even though collagen is its primary ligand, there are several other proteins with which α2β1 integrin interacts, such as Laminin; however, the affinity in these cases is usually lower. The ligand binding occurs due to the presence of the inserted αI (I) domain that is located in the extracellular domain of the α2 subunit. The MIDAS domain of the protein binds divalent cation, magnesium ions (Mg²⁺) and manganese ions (Mn²⁺), required for the ligand binding. Changes in conformation control the binding affinity of the receptor towards the extracellular ligands and help α2β1 integrin to change from an inactive to an active state under the influence of both extracellular and intracellular stimuli. The interaction between α2β1 integrin and collagen anchors cells to the extracellular matrix and initiates intracellular signaling pathways that regulate cellular behavior.
== Pathology == Mutations in the human collagen XVII gene, COL17A1, lead to the absence or structural alterations and mutations of collagen XVII. The functional consequences include diminished epidermal adhesion and skin blistering in response to minimal shearing forces. The disorder caused by biallelic COL17A1 mutations and is called junctional epidermolysis bullosa, an autosomal recessive skin disease with variable clinical phenotypes. Morphological characteristics of junctional epidermolysis bullosa are rudimentary hemidesmosomes and subepidermal tissue separation. Clinical hallmarks, in addition to blisters and erosions of the skin and mucous membranes, include nail dystrophy, loss of hair, and dental anomalies. Collagen XVII also plays a role as an autoantigen in Bullous pemphigoid (BP) and herpes gestationis (HG), both acquired subepithelial blistering disorders. Most immunodominant epitopes lie within the NC16A domain, and the binding of the autoantibodies perturbs adhesive functions of the collagen XVII, and this (together with inflammation-related processes) leads to epidermal-dermal separation and skin blistering. Other mutations make the epithelium of the cornea in the eye brittle, which results in dominantly inherited recurrent corneal erosion dystrophy (ERED). Whole-exome sequencing first identified a heterozygous mutation (c.2816C>T, p.T939I) that segregated with ERED in a large Swedish pedigree dating back 200 years.
== Early life == James Rowley French was born on September 23, 1928, in Pasadena, California, to Mabelle (née Rowley) and James Forrest French. French got his first job in radio as a teenager, on the Pasadena AM station KXLA. French enlisted in the U.S. Army in 1945 and was stationed in allied-occupied Japan, where he worked for the Armed Forces Radio. He attended the Pasadena City College following his discharge.
Sources: en.wikipedia.org
== Etymology and pronunciation == The word purpura () comes from Latin purpura, "purple", which came from ancient Greek πορφύρα. Purpura is a mass noun naming the condition or state, not the name of an individual spot (thus there is no *purpurum, *purpura or *purpura, *purpurae count declension).
== External links == Emil Fischer on Nobelprize.org including his Nobel Lecture Nobel Lecture, 12 December 1902 Syntheses in the Purine and Sugar Group Eminent Chemists of Our Time By Benjamin Harrow pages 216–239, published 1920 by Von Nostrand Company at books.google.com. Aders Plimmer, R. H. (July 1907). "The work of Emil Fischer and his school on the chemistry of the proteins". Science Progress in the Twentieth Century. 2 (5): 88–120. Guide to the Emil Fischer Papers at The Bancroft Library Text-book of Physiological Chemistry in Thirty Lectures by Emil Abderhalden, translated by William Thomas Hall and George Defren; published 1908 by Wiley Company, has many technical references to Fischer's work in Chemistry. American Journal of Diseases of Children 1911 volume 2 by the American Medical Association also refers to Fischer's work. An Introduction to the History of Medicine: With Medical Chronology by Fielding Hudson Garrison, page 708 refers to Fischer and Merings discovery of the drugs veronal(1904) and proponal(1905), published 1921 by Saunders Company. 1914 Year Book of the American Pharmaceutical Association, page 438 abstracts Fischer and Strauss's work on Phenol-Glucosides – Synthetic Production from Berlin d.D Chem. Germany, page 45(1912) No. 12. Texts on Wikisource: "Fischer, Emil". New International Encyclopedia. 1905. "Fischer, Emil". Encyclopædia Britannica (11th ed.). 1911. "Fischer, Emil". Encyclopedia Americana. 1920.
=== Misinformation === Naloxone has been subject to much inaccurate media reporting and many urban legends about it have become prevalent. One such myth is that naloxone makes the recipient violent. Another is that events called "Lazarus parties" have taken place, in which people reportedly took fatal overdoses in anticipation of being treated with naloxone; in reality this was a fiction spread by the police. Yet another is the claim that people have indulged in "yo-yoing", whereby they would take naloxone and opioids simultaneously to enjoy an extreme "high" and subsequent revival; the idea is scientifically nonsensical.
=== November === 1 November – Sinn Féin and the Social Democratic and Labour Party say they will support a motion of no confidence in Paul Givan, Stormont's Education Minister, after he took part in a six-day visit to Israel along with other unionist politicians. 2 November – Former SNP Cabinet Secretary for Health Jeane Freeman blames failures faced by NHS Scotland on successive governments including her own. 4 November – In a pre-budget speech from Downing Street, Chancellor Rachel Reeves Chancellor Rachel Reeves says she will make "necessary choices" in the forthcoming budget after the "world has thrown more challenges our way". 5 November – MSPs vote 85–25 in favour of the Land Reform (Scotland) Bill that aims to reduce the concentration of rural land ownership among a small number of people. Charges against former SDLP leader Colum Eastwood in relation to his attendance at a pro-Palestine rally are dropped after he accepted a formal caution. 6 November – Culture Secretary Lisa Nandy is found to have "unknowingly" breached public appointment rules with her choice to be the boss of England's new football watchdog. 7 November – The Labour Whip is restored to Chris Hinchliff, Neil Duncan-Jordan, Brian Leishman and Rachael Maskell following their suspension for voting against the government's Welfare Reform Bill in July. Deputy First Minister of Northern Ireland Emma Little-Pengelly turns down an invite to the inauguration of President of Ireland Catherine Connolly.
Sources: en.wikipedia.org
=== Micronutrient metabolism === Riboflavin, FMN, and FAD are involved in the metabolism of niacin, vitamin B6, and folate. The synthesis of the niacin-containing coenzymes, NAD and NADP, from tryptophan involves the FAD-dependent enzyme, kynurenine 3-monooxygenase. Dietary deficiency of riboflavin can decrease the production of NAD and NADP, thereby promoting niacin deficiency. Conversion of vitamin B6 to its coenzyme, pyridoxal 5'-phosphate, involves the enzyme, pyridoxine 5'-phosphate oxidase, which requires FMN. An enzyme involved in folate metabolism, 5,10-methylenetetrahydrofolate reductase, requires FAD to form the amino acid, methionine, from homocysteine. Riboflavin deficiency appears to impair the metabolism of the dietary mineral, iron, which is essential to the production of hemoglobin and red blood cells. Alleviating riboflavin deficiency in people who are deficient in both riboflavin and iron improves the effectiveness of iron supplementation for treating iron-deficiency anemia.
Unlike terrestrial silos that maintain value for decades, the imminent expiration of orbital weapons creates a fiscal “use it or lose it" pressure, potentially incentivizing commanders to expend these assets in gray zone conflicts rather than allowing billions of dollars of hardware to burn up in the atmosphere. Ultimately, the deployment of such systems creates a state of "orbital ambiguity" that destabilizes traditional deterrence. Because a Starshield satellite carrying defensive interceptors is indistinguishable on radar from a commercial Starlink satellite or one carrying offensive hypersonic gliders, adversaries are forced to treat the entire constellation as a potential nuclear-equivalent first-strike platform. Strategic theorists such as Forrest Morgan (RAND) and James Acton (Carnegie Endowment) argue that this "warhead ambiguity" creates a “reciprocal fear of surprise attack," incentivizing adversaries to execute massive "blinding" strikes against the constellation or its launch infrastructure at the onset of any crisis, thereby ensuring that a limited conflict immediately escalates to the strategic level.
Special care must be taken when supplementing the medium with FBS (fetal bovine serum), as it also contains small metabolites used for the biosynthesis of nucleosides. The use of dialyzed FBS is therefore advisable when defined labeling of all nucleosides is desired.
Sources: en.wikipedia.org
It is a glucagon-like peptide-1 receptor agonist, often grouped with the incretin mimetics. Its backbone is modified from the human hormone to resist enzymatic degradation and to bind albumin. These two features distinguish it from the native peptide.
No. It shares high sequence identity but carries non-natural modifications that alter its stability and clearance. The naturally occurring hormone is broken down within minutes, while the synthetic analogue circulates far longer.
Attachment to serum albumin reduces renal filtration of the peptide and shields it from enzymatic breakdown. The consequence is a much longer interval between administrations than unmodified peptides allow. The precise contribution of binding affinity to overall duration is still being quantified.
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。