The short version of fatty diacid fits in a sentence. The long version — which is the one that helps — is below.
Reviewed 2026-01-24. 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。
Development began in the early 2010s with the goal of extending GLP-1 activity beyond the brief window achieved by native peptide infusion. The earliest approved formulation was a subcutaneous injection given once weekly. A later oral tablet pairs the peptide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, usually shortened to SNAC. That carrier lowers local pH and helps the peptide cross gastric tissue. Both routes deliver the same active molecule.
Semaglutide is a synthetic peptide analog of human glucagon-like peptide-1, a gut hormone released after meals. Its backbone retains the GLP-1 sequence but incorporates two substitutions that slow enzymatic breakdown by dipeptidyl peptidase-4. A short polyethylene glycol linker and a C18 fatty diacid are attached to the peptide chain, allowing the molecule to bind serum albumin and remain in circulation far longer than the native hormone. The result is a circulating half-life measured in days rather than the minutes typical of endogenous GLP-1.
Receptor activation occurs at GLP-1 receptors distributed across pancreatic islets, the hypothalamus, and the gastrointestinal tract. Binding triggers G protein signaling that raises cyclic AMP and enhances glucose-dependent insulin release. Because the effect depends on prevailing glucose levels, insulin secretion does not rise when blood sugar is already low. Signaling in the brain and gut also influences appetite and gastric emptying, which is why the compound appears in both metabolic and weight-related research literature.
| 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 |
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.
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.
Identity and purity are assessed with reversed-phase high-performance liquid chromatography, which separates the peptide from related impurities by hydrophobicity. Mass spectrometry confirms molecular weight and detects truncation or modification products. Peptide mapping after enzymatic digestion verifies the amino acid sequence. Quantitation is often performed by LC-MS/MS or by immunoassay, and the two approaches can give different values because they measure different things. Method validation parameters such as accuracy, precision, and limit of quantitation are reported alongside results.
Certificate of analysis documents from suppliers typically report purity by chromatographic area, water content, and counter-ion identity. Independent verification is advisable because reported values can be generated under differing conditions. Impurity profiles matter for research use, where aggregates, deamidation products, and residual solvents may influence experimental results. Container, lot, and chain-of-custody records support traceability. Analytical results are method-dependent, so comparisons between laboratories require the same procedure and reference standards.
Lyophilized peptide material is typically stored at or below -20 °C, with -80 °C used for longer-term archives. Vials should remain sealed and desiccated because moisture promotes aggregation and hydrolysis. Repeated freeze-thaw cycles are avoided since they can alter peptide conformation and reduce recovery. Once reconstituted, solutions are generally kept at 2-8 °C and used within a defined window. Stability beyond those windows depends on buffer composition and concentration, and exact limits are product-specific rather than universal.
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.
=== Prodomain processing === Legmains are produced as inactive precursor zymogens. their C-terminal domain binds over their active site (where a substrate would normally bind), inhibiting activity. Once in the acidic environment of the vacuole or lysosome, the prodomain is cleaved off to reveal the active enzyme.
{\displaystyle \varepsilon _{\rm {a}}(f)\approx \sum _{i=1}^{N}\left|{\frac {\partial f}{\partial x_{i}}}\right|\varepsilon _{\rm {a}}(x_{i})=\left|{\frac {\partial f}{\partial x_{1}}}\right|\varepsilon _{\rm {a}}(x_{1})+\left|{\frac {\partial f}{\partial x_{2}}}\right|\varepsilon _{\rm {a}}(x_{2})+\ldots +\left|{\frac {\partial f}{\partial x_{N}}}\right|\varepsilon _{\rm {a}}(x_{N})}
EMP, also known as estradiol 3-normustine 17β-phosphate or as estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate), is a synthetic estrane steroid and a derivative of estradiol. It is an estrogen ester; specifically, EMP is a diester of estradiol with a C3 normustine (nitrogen mustard–carbamate moiety) ester and a C17β phosphate ester. EMP is provided as the sodium or meglumine salt. EMP is similar as a compound to other estradiol esters such as estradiol sulfate and estradiol valerate, but differs in the presence of its nitrogen mustard ester moiety. Antineoplastic agents related to EMP, although none of them were marketed, include alestramustine, atrimustine, cytestrol acetate, estradiol mustard, ICI-85966, and phenestrol. Due to its hydrophilic phosphate ester moiety, EMP is a readily water-soluble compound. This is in contrast to most other estradiol esters, which are fatty acid esters and lipophilic compounds that are not particularly soluble in water. Unlike EMP, estramustine is highly lipophilic, practically insoluble in water, and non-ionizable. The phosphate ester of EMP was incorporated into the molecule in order to increase its water solubility and allow for intravenous administration. The molecular weight of EMP sodium is 564.3 g/mol, of EMP meglumine is 715.6 g/mol, of EMP is 520.4 g/mol, of estramustine is 440.4 g/mol, and of estradiol is 272.4 g/mol.
== Mechanism of action == Immunoliposomes use similar functionality as liposomes with the added measure of conjugating monoclonal antibodies and their fragments to the liposomes. The use of antibodies allow for easy targeting as they can recognize many different types of antigens. Diseased cells typically contain more antigens than healthy cells, which is how antibodies are able to appropriately target certain extracellular domains (depending on antigen overexpression) and kill diseased cells. Liposomal drug delivery combined with antibodies as a targeting ligand are what help immunoliposomes function as an effective drug carrier.
== Mass spectrometry == The tropylium ion is frequently encountered in mass spectrometry in the form of a signal at m/z = 91 and is used in mass spectrum analysis. This fragment is often found for aromatic compounds containing a benzyl unit. Upon ionization, the benzyl fragment forms a cation (PhCH+2), which rearranges to the highly stable tropylium cation (C7H+7).
Sources: en.wikipedia.org
== Pharmacology == Chlorpromazine is classified as a low-potency typical antipsychotic. Low-potency antipsychotics have more anticholinergic side effects, such as dry mouth, sedation, and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as haloperidol) have the reverse profile.
=== By honey bees === Honey is produced by bees who have collected nectar or honeydew. Bees value honey for its sugars, which they consume to support general metabolic activity, especially that of their flight muscles during foraging, and as a food for their larvae. To this end bees stockpile honey to provide for themselves during ordinary foraging as well as during lean periods, as in overwintering. During foraging bees use part of the nectar they collect to power their flight muscles. The majority of nectar collected is not used to directly nourish the insects but is instead destined for regurgitation, enzymatic digestion, and finally long-term storage as honey. During cold weather or when other food sources are scarce, adult and larval bees consume stored honey, which is many times more energy-dense as the nectar from which it is made. After leaving the hive, a foraging bee collects sugar-rich nectar or honeydew. Nectar from the flower generally has a water content of 70 to 80% and is much less viscous than finished honey, which usually has a water content around 18%. The water content of honeydew from aphids and other true bugs is generally very close to the sap on which those insects feed and is usually somewhat more dilute than nectar. One source describes the water content of honeydew as around 89%. Whether it is feeding on nectar or honeydew, the bee sucks these runny fluids through its proboscis, which delivers the liquid to the bee's honey stomach or "honey crop".
Acheta domesticus, commonly called the house cricket, is a species of cricket most likely native to Southwestern Asia, but between 1950 and 2000 it became the standard feeder insect for the pet and research industries and spread worldwide. They can be kept as pets themselves, as this has been the case in China and Japan.
== SAR and the SAR paradox == The basic assumption for all molecule-based hypotheses is that similar molecules have similar activities. This principle is also called Structure–Activity Relationship (SAR). The underlying problem is therefore how to define a small difference on a molecular level, since each kind of activity, e.g. reaction ability, biotransformation ability, solubility, target activity, and so on, might depend on another difference. Examples were given in the bioisosterism reviews by Patanie/LaVoie and Brown. In general, one is more interested in finding strong trends. Created hypotheses usually rely on a finite number of chemicals, so care must be taken to avoid overfitting: the generation of hypotheses that fit training data very closely but perform poorly when applied to new data. The SAR paradox refers to the fact that it is not the case that all similar molecules have similar activities.
=== Special classes === Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition). These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously. The permissive conditions may be temperature, certain chemicals, light or mutations in other parts of the genome. In vivo mechanisms like transcriptional switches can create conditional mutations. For instance, association of Steroid Binding Domain can create a transcriptional switch that can change the expression of a gene based on the presence of a steroid ligand. Conditional mutations have applications in research as they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms. DNA Recombinase systems like Cre-Lox recombination used in association with promoters that are activated under certain conditions can generate conditional mutations.
Sources: en.wikipedia.org
== S == Secondary ion mass spectrometry Supercritical fluid chromatography (SFC) Scanning transmission electron microscopy (STEM) Scanning tunneling microscope (STM) Scanning electron microscope (SEM)
By using temperature variations in their surroundings, or by remaining cold when they do not need to move, reptiles can save considerable amounts of energy compared to endothermic animals of the same size. A crocodile needs from a tenth to a fifth of the food necessary for a lion of the same weight and can live half a year without eating. Lower food requirements and adaptive metabolisms allow reptiles to dominate the animal life in regions where net calorie availability is too low to sustain large-bodied mammals and birds. It is generally assumed that reptiles are unable to produce the sustained high energy output necessary for long distance chases or flying. Higher energetic capacity might have been responsible for the evolution of warm-bloodedness in birds and mammals. However, investigation of correlations between active capacity and thermophysiology show a weak relationship. Most extant reptiles are carnivores with a sit-and-wait feeding strategy; whether reptiles are cold blooded due to their ecology is not clear. Energetic studies on some reptiles have shown active capacities equal to or greater than similar sized warm-blooded animals.
== Further reading == "Chapter 12: Electrical Bursting, Calcium Oscillations, and Synchronization of the Pancreatic Islets by Richard Bertram, Arthur Sherman, and Leslie S Satin". The islets of Langerhans. Md. Shahidul Islam. Dordrecht: Springer. 2010. ISBN 978-90-481-3271-3. OCLC 663096203.
The Na+/I− symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodide ion. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I− against its concentration gradient. This is called iodide trapping. Sodium is cotransported with iodide from the basolateral side of the membrane into the cell, and then concentrated in the thyroid follicles to about thirty times its concentration in the blood. I− is moved across the apical membrane into the colloid of the follicle by pendrin. Hydrogen peroxide is also introduced into the follicle by the action of DUX (Dual Oxidase). Iodide is non-reactive, and the reactive I2 species is required for the next step. Thyroid peroxidase (TPO) reduces hydrogen peroxide to water by transferring one electron from two I− atoms that react to form I2. Iodine (I2) is converted into HOI, by hydration with water. Both I2 and HOI iodinate specific tyrosyl residues of the thyroglobulin within the colloid to form 3-monoiodityrosyl (MIT-yl) and 3,5-diiodityrosyl (DIT-yl) residues—introducting iodine atoms at one or both locations ortho to the hydroxyls of tyrosine. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid. TPO also converts tyrosyl, MIT-yl, and DIT-yl residues into their free radical forms. These forms attack other MIT-yl and DIT-yl residues. When a DIT-yl radical attacks a DIT, T4-yl (peptidic T4) is formed. When a MIT-yl radical attacks a DIT, T3-yl is formed.
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 circulating enzymes. The synthetic version carries substitutions at positions that block enzymatic cleavage, plus a fatty acid side chain that promotes albumin binding. These two changes together extend circulation time from minutes to roughly a week.