Sofosbuvir (PSI-7977; GS-7977)   中文名称: 索非布韦

HCV ( EC50 = 92±5 nM )

体外活性：作为 HCV NS5B 聚合酶抑制剂，PSI-7977 对 HCV RNA 复制表现出比 PSI-7976 更有效的抑制活性，EC50 为 92 nM vs 1.07 μM，EC90 为 0.29 μM vs 2.99 μM，与孵育克隆 A 细胞一致与 PSI-7977 孵育相比，与 PSI-7976 孵育的克隆 A 细胞相比，PSI-7409 浓度更高。 PSI-7977 是 CatA 形成 PSI-352707 的有效底物，其效力是 PSI-7976 的 18-30 倍。然而，与 GS-7976 不同的是，CES1 介导的 PSI-7977 水解并不以时间依赖性方式进行。 S282T NS5B 聚合酶突变而非 S96T 突变赋予 PSI-7977 抗性，EC90 从 0.42 μM 增加至 7.8 μM。在 8 天细胞毒性测定中进行评估时，即使浓度高达 100 μM，PSI-7977 对 Huh7、HepG2、BxPC3 和 CEM 细胞也没有显示出细胞毒性。 PSI-7977 处理 14 天显示，在 HepG2 细胞中抑制 mtDNA 和 rDNA 的 IC90 分别为 72.1 μM 和 68.6 μM。 PSI-7977 对基因型 (GT) 1a、1b 和 2a（菌株 JFH-1）复制子以及含有 GT 2a（菌株 J6）、2b 和 3a NS5B 聚合酶的嵌合复制子表现出有效的活性。 JFH-1 NS5B 区域的序列分析表明，在 S282T 出现之前和之后选择了额外的氨基酸变化，包括 T179A、M289L、I293L、M434T 和 H479P，这是赋予 PSI-7977 抗性所必需的。细胞测定：将细胞（Huh7、HepG2、BxPC3 和 CEM）暴露于不同浓度的 PSI-7977 中 8 天。在生长期结束时，将来自 CellTiter 96 AQueous One Solution 细胞增殖测定试剂盒的 MTS 染料添加到每个孔中，并将板再孵育 2 小时。使用仅培养基对照孔作为空白，用 Victor3 读板器读取 490 nm 处的吸光度。通过比较含有细胞和 PSI-7977 的孔与未处理的细胞对照孔中的吸光度来确定 50% 抑制值 (IC50)。

440 mg/kg/d 治疗组和 44 mg/kg/d 治疗组的人源化肝脏小鼠的平均血浆 ALT 水平低于正常上限，并且与媒介物治疗的人源化肝脏小鼠中测量的结果没有显着差异。在接受任一剂量的 PSI-7977 的对照小鼠或具有人源化肝脏的小鼠中，血浆乳酸水平也没有升高。

在 T75 烧瓶中，使用补充有 10% 胎牛血清、100 IU/mL 青霉素、和 100 μg/mL 链霉素。以类似的方式，使用细胞铺板培养基在每个烧瓶中接种约 5×10⁶ 人原代肝细胞。将细胞与 50 μM PSI-7851、PSI-7976 或 Sofosbuvir (PSI-7977) 在新鲜培养基中（对于克隆 A 细胞）或细胞维持培养基（对于原代肝细胞）在 37°C、5% CO2 中孵育长达 24 小时放置过夜后₂ 个大气压。在研究中使用放射性标记的 PSI-7851 时，遵循相同的方案，不同之处在于将 1×10⁶ 细胞接种到 6 孔板的每个孔中，然后将细胞孵育含有 5 μM [³H]PSI-7851。每隔预定的时间间隔取出培养基，并使用冷的磷酸盐缓冲盐水（PBS）清洗细胞层。胰蛋白酶消化后，计数细胞并以 1,200 rpm 离心 5 分钟。将细胞沉淀悬浮于 1 mL 冷的 60% 甲醇中后，在 -20°C 下放置过夜。将样品以 14,000 rpm 离心 5 分钟后，收集上清液，用 SpeedVac 浓缩器干燥，并保存在 -20°C 直至进行高效液相色谱 (HPLC) 分析。将残留物悬浮在 100 μL 水中后，将 50 μL 等份注入 HPLC。

When given orally, sofosbuvir reaches its maximum plasma concentration in about 0.5 to 2 hours with a maximal concentration (Cmax) of 567 ng/mL.
Sofosbuvir is eliminated by three routes: urine ( 80%), feces (14%), and respiration (2.5%); however, elimination through the kidneys is the major route.
The volume of distribution for sofosbuvir has yet to be determined.
The clearance of sofosbuvir has yet to be determined.
Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 ug/mL to 20 ug/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of (14)C-sofosbuvir in healthy subjects, the blood to plasma ratio of (14)C-radioactivity was approximately 0.7.
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of SOVALDI, sofosbuvir was absorbed with a peak plasma concentration observed at approximately 0.5-2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or without pegylated interferon), geometric mean steady state AUC0-24 was 969 ng*hr/mL for sofosbuvir (N=838), and 6790 ng*hr/mL for GS-331007 (N=1695), respectively. Relative to healthy subjects administered sofosbuvir alone (N = 272), the sofosbuvir AUC0-24 was 60% higher; and GS-331007 AUC0-24 was 39% lower, respectively, in HCV-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg.
Following a single 400 mg oral dose of (14)C-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007.
Studies in pregnant rats showed that sofosbuvir crossed the placenta. Fetal blood and brain sofosbuvir derived radioactivity was higher than in dams, but fetal liver and kidney had lower levels than corresponding organs in dams. Sofosbuvir-derived radioactivity was also quantifiable in milk from day 2 postpartum rats, but nursing pups did not appear to be extensively exposed to drug-derived radioactivity. Milk to plasma ratios were 0.1 at 1 hour and 0.8 at 24 hours.
For more Absorption, Distribution and Excretion (Complete) data for Sofosbuvir (6 total), please visit the HSDB record page.

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In vitro studies in human liver microsomes showed that sofosbuvir was an efficient substrate for Cathepsin A (Cat A) and carboxyl esterase 1 (CES1). Sofosbuvir was cleaved by CatA and CES1 and subsequent activation steps included amino acid removal by histidine triad nucleotide-binding protein 1 (HINT1) and phosphorylation by uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase and nucleoside diphosphate (NDP) kinase. In vitro data indicated that Cat A preferentially hydrolysed sofosbuvir (the S-diastereomer) while CES1 did not exhibit stereoselectivity.
In vitro studies in human liver microsomes showed that sofosbuvir was an efficient substrate for Cathepsin A (Cat A) and carboxyl esterase 1 (CES1). There were no indications of metabolism via urdine diphosphate glucuronosyltransferases (UGTs) or flavin-containing monooxygenase (FMO). Sofosbuvir was cleaved by CatA and CES1 and subsequent activation steps included amino acid removal by histidine triad nucleotide-binding protein 1 (HINT1) and phosphorylation by uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase and nucleoside diphosphate (NDP) kinase. In vitro data indicated that Cat A preferentially hydrolysed sofosbuvir (the S-diastereomer) while CES1 did not exhibit stereoselectivity. This would be consistent with studies using GS-9851 showing a less efficient metabolism to the triphosphate in the hepatically-derived cell line containing the Clone A replicon and shown to exhibit low CES 1 activity, but high Cat A activity compared with primary human hepatocytes. Following incubation of hepatocytes from rat, dog, monkey and human GS-9851 was converted to the triphosphate GS-461203 in all species, most efficiently in human. Sofosbuvir was also readily converted to the triphosphate in dog liver after oral doses and was the dominant metabolite at all time points assessed with a long half-life of approx. 18 hours. The active metabolite GS-461203 could not be detected in monkey. Further while GS-461203 was detected in rat liver, it could not be measured in liver from mouse.
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro.
GS-331007 and GS-566500 were detected in all species with GS-331007 being the major drug related material in all species and all matrices. In plasma, urine and feces of all species administered sofosbuvir the primary metabolite detected was GS-331007 accounting for >80% of total exposure. In rat liver and plasma GS-566500 was also detected. The metabolite profile was overall comparable between non-pregnant, pregnant and postpartum rats and in milk of postpartum rats with GS-331007 and 2 sulfate conjugates of GS-331007 being the major metabolites.
In dog following a single oral dose of 20 mg/kg of sofosbuvir three metabolites in plasma were identified, GS-331007, GS-566500 and M4 (proposed glucuronidation product of GS-606965), accounting for 93.4%, 1.6% and 0.5%, respectively of total plasma AUC. Parent compound amounted to 4.5%. In dog (and mouse) the majority of a radioactive dose was recovered in urine within 8 to 12 hours.
For more Metabolism/Metabolites (Complete) data for Sofosbuvir (7 total), please visit the HSDB record page.

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Sofosbuvir has a terminal half life of 0.4 hours.
The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively.

In large randomized controlled trials, serum enzymes elevations were uncommon in patients treated with sofosbuvir despite the fact that the patients being treated had chronic liver disease. In most situations, serum aminotransferase levels improved rapidly upon initiating sofosbuvir therapy, and de novo, late elevations of ALT above 3 times the upper limit of normal (ULN) were uncommon and less frequent than with placebo or no therapy. In multiple, large clinical trials sofosbuvir has not been linked to instances of clinically apparent liver injury with jaundice. Because sofosbuvir is always used with other antiviral agents, it is not always possible to separate the relative role of sofosbuvir from other drugs in causing adverse reactions.
Two rare and unusual forms of liver injury of uncertain relationship to sofosbuvir have been described in patients with receiving antiviral therapy for hepatitis C: sudden hepatic decompensation in patients with preexisting cirrhosis and reactivation of hepatitis B in patients with preexisting evidence of HBV infection.
A rare, but striking liver injury associated with sofosbuvir (and perhaps other potent agents active against HCV) is hepatic decompensation occurring in patients with preexisting cirrhosis. In several instances, decompensation occurred within 2 to 6 weeks of starting therapy (Case 1), while in others it occurred late during therapy or in the immediate posttreatment period. The typical pattern of onset was a progressive rise in bilirubin with signs of hepatic failure such as prolongation of the prothrombin time, decrease in serum albumin and appearance of ascites and hepatic encephalopathy. In many (but not all) instances, serum enzyme levels did not change or increased only slightly in comparison to pretreatment values. In all instances, sofosbuvir was being used in combination with other antiviral agents, such as peginterferon, simeprevir, daclatasvir or ledipasvir, and the specific role of sofosbuvir has been difficult to define. The decompensation usually coincided with rapid viral clearance and patients who survived the episode often had a sustained virological response. The cause of this decompensation is not clear, but it may represent a response to HCV viral eradication (on-target effect) rather than toxicity of the administered antiviral agents (off-target effect on the liver). Alternatively, the injury may be coincidental and unrelated to therapy.
A second form of liver injury that can occur with sofosbuvir therapy and perhaps other potent anti-HCV agents is reactivation of hepatitis B. More than 50 instances of clinically apparent hepatitis with rises in serum HBV DNA levels during therapy of patients for chronic hepatitis C. The majority of these patients were also HBsAg positive with no detectable or only low levels of HBV DNA before treatment (Case 2). Reactivation has also been described in patients who have anti-HBc without HBsAg in serum, a pattern that suggests previous recovery from hepatitis B. HBV reactivation typically arises within 2 to 8 weeks of starting therapy for hepatitis C and it can be clinically manifest with symptoms of acute hepatitis and marked elevations in serum aminotransferase levels and bilirubin. Instances of death from HBV reactivation have been reported with sofosbuvir therapy. The cause of reactivation is unclear, but it may be that HCV replication has a nonspecific suppressive effect on HBV replication, and eradication of HCV allows HBV replication to increase to levels that cause hepatitis. Alternatively, the change in immune reactivity with sudden clearance of HCV or as a result of a direct activity of the antiviral agents may alter the replicative status of HBV.
Likelihood score: A (well known cause of hepatic decompensation in patients with hepatitis C and cirrhosis and a rare cause of reactivation of hepatitis B in susceptible individuals).

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◉ Summary of Use during Lactation
Sofosbuvir has not been well studied in nursing mothers being treated for hepatitis C infection, although one infant was breastfed for 3 weeks and had no developmental abnormalities. If sofosbuvir alone or in combination with ledipasvir (Harvoni) is required by the mother, it is not a reason to discontinue breastfeeding. Some sources recommend against breastfeeding when sofosbuvir is used with ribavirin.
Hepatitis C is not transmitted through breastmilk and breastmilk has been shown to inactivate hepatitis C virus (HCV). However, the Centers for Disease Control recommends that mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding. It is not clear if this warning would apply to mothers who are being treated for hepatitis C.
Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended.
◉ Effects in Breastfed Infants
An infant was breastfed (extent not stated) for 3 weeks postpartum by a mother who took sofosbuvir 400 mg plus ledipasvir 90 mg daily for 12 weeks beginning at 31 weeks of gestation for her chronic hepatitis C infection. The infant was followed for 1 year and found to have normal growth and development.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Sofosbuvir is approximately 61-65% bound to human plasma proteins.

[1]. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977.J Biol Chem. 2010 Nov 5;285(45):34337-47.

[2]. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother. 2012 Jun;56(6):3359-68.

[3]. Discovery of a β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem. 2010 Oct 14;53(19):7202-18.

[4]. Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism. Eur J Med Chem. 2018 Jan 1;143:1053-1065.

Sofosbuvir is a nucleotide conjugate that is used in combination with ledipasvir (under the trade name Harvoni) for the treatment of chronic hepatitis C genotype 1 infection. It has a role as a prodrug, an antiviral drug and a hepatitis C protease inhibitor. It is a L-alanyl ester, a phosphoramidate ester, a nucleotide conjugate, an organofluorine compound and an isopropyl ester. It is functionally related to a uridine 5'-monophosphate.
Sofosbuvir is an antiviral prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis C virus infection (HCV) in adults and children 3 years of age and older who meet specific requirements, as determined by a health care provider.
HCV infection can be an opportunistic infection (OI) of HIV.
Sofosbuvir (tradename Sovaldi) is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as sofosbuvir. As a prodrug nucleotide analog, Sofosbuvir is metabolized into its active form as the antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate (also known as GS-461203), which acts as a defective substrate for NS5B (non-structural protein 5B) [synthesis]. NS5B, an RNA-dependent RNA polymerase, is essential for the transcription of Hepatitis C viral RNA and for its high replicative rate and genetic diversity. Sofosbuvir and other direct acting antivirals are therefore very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid development of resistance has proven to be an important cause of therapeutic failure. In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Sofosbuvir as first line therapy in combination with other antivirals for all six genotypes of Hepatitis C. Depending on the genotype, sofosbuvir is often used in combination with other antivirals such as [DB09027], [DB11613], [DB09102], [DB06290], [DB11574], [DB11575], [DB00811], [DB00008], or [DB00022] with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality. Treatment with direct acting antivirals such as sofosbuvir is associated with very minimal side effects, with the most common being headache and fatigue. Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon- and ribavirin-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects. Since 2014, sofosbuvir has been available as a fixed dose combination product with [DB09027] (tradename Harvoni) used for the treatment of chronic Hepatitis C. Approved in October 2014 by the FDA, Harvoni is indicated for the treatment of HCV genotypes 1, 4, 5, and 6 with or without [DB00811] depending on the level of liver damage or cirrhosis. When combined together, ledipasvir and sofosbuvir as the combination product Harvoni has been shown to achieve a SVR between 93 and 99% after 12 weeks of treatment. Its use has also proven successful in the treatment of HCV in patients co-infected with HIV. Sofosbuvir is also available as a fixed dose combination product with [DB11613] as the commercially available product Epclusa. First approved in June 2016, Epclusa is the first combination HCV product indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis. Epclusa is also currently the most potent HCV antiviral medication on the market with a sustained virologic response (SVR) after 12 weeks of therapy of 93-99% depending on genotype and level of cirrhosis. Both Canadian and American guidelines list Epclusa as a first line recommendation for all genotypes of HCV. Notably, sofosbuvir has come under intense scrutiny since its release to market in 2013. With the price per pill set at $1000, a 12-week treatment can cost upwards of $84,000 per patient.
Sofosbuvir is a Hepatitis C Virus Nucleotide Analog NS5B Polymerase Inhibitor. The mechanism of action of sofosbuvir is as a RNA Replicase Inhibitor.
Sofosbuvir is an oral nucleoside analogue and potent inhibitor of the hepatitis C virus (HCV) RNA polymerase that is used in combination with other antiviral agents to treat chronic hepatitis C. Elevations in serum enzyme levels during sofosbuvir therapy are uncommon, and it has not been implicated convincingly in cases of clinically apparent liver injury with jaundice. Nevertheless, and for unknown reasons, successful antiviral therapy of hepatitis C with sofosbuvir and other direct acting agents in patients with cirrhosis is occasionally complicated by hepatic decompensation; furthermore, treatment can cause reactivation of hepatitis B in susceptible patients coinfected with the hepatitis B virus (HBV).
Sofosbuvir is an orally available nucleotide prodrug and a hepatitis C virus (HCV) NS5B polymerase inhibitor with potential HCV inhibiting activity. Upon oral administration, sofosbuvir is metabolized to 2'-deoxy-2'-alpha-fluoro-beta-C-methyluridine-5'-monophosphate, which is then converted into the active triphosphate nucleotide that inhibits the NS5B polymerase, thereby preventing viral replication. The HCV NS5B protein, an RNA-dependent RNA polymerase, is essential for the replication of the viral HCV RNA genome.
A uridine monophosphate analog inhibitor of HEPATITIS C VIRUS (HCV) polymerase NS5B that is used as an ANTIVIRAL AGENT in the treatment of CHRONIC HEPATITIS C.
See also: Ledipasvir; sofosbuvir (component of); Sofosbuvir; velpatasvir; voxilaprevir (component of); Sofosbuvir; velpatasvir (component of).

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Sofosbuvir is used in combination therapy with other antiviral medications to treat chronic hepatitis C virus (HCV) infected patients with HCV genoptypes 1-6, and to treat HCV and HIV co-infected patients. Depending on the level of cirrhosis or decompensation, combination therapy can also include either ribavirin alone or ribavirin and peg-interferon alfa. When used in combination with [DB09027], sofosbuvir has the following indications: treatment of genotypes 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis; in combination with [DB00811] for genotype 1 infection with decompensated cirrhosis; or in combination with [DB00811] for the treatment of genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis. When used in combination with [DB11613] as the combination product Epclusa, sofosbuvir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis, or in combination with [DB00811] if associated with decompensated cirrhosis. Resistance: Reduced susceptibility to sofosbuvir has been associated with the NS5B substitution mutation S282T.
Sovaldi is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients aged 3 years and above (see sections 4. 2, 4. 4 and 5. 1). For hepatitis C virus (HCV) genotype specific activity, see sections 4. 4 and 5. 1. Sovaldi is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults and paediatric patients aged 3 years and above (see sections 4. 2, 4. 4 and 5. 1). For hepatitis C virus (HCV) genotype specific activity, see sections 4. 4 and 5. 1.
Treatment of chronic hepatitis C

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Sofosbuvir is nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator [synthesis, A7533]. More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material.
Sofosbuvir is a direct-acting antiviral agent (pan-genotypic polymerase inhibitor) against the hepatitis C virus. HCV RNA replication is mediated by a membrane-associated multiprotein replication complex. The HCV polymerase (NS5B protein) is an RNA-dependent RNA polymerase (RdRp). It is the essential initiating and catalytic subunit of this replication complex and is critical for the viral replication cycle. There is no human homolog for HCV NS5B RdRp. Sofosbuvir is a monophosphorylated pyrimidine nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203). GS-461203 competes with natural nucleotides for incorporation (by HCV NS5B) into the nascent RNA strand during replication of the viral genome. GS-461203 differs from endogenous pyrimidine nucleotides in that it has been modified at the 2' position with the addition of a methyl and a fluoro functional group. Incorporation of GS-461203 into nascent RNA strongly reduces the efficiency of further RNA elongation by RdRp, resulting in premature termination of RNA synthesis. The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

C22H29FN3O9P

529.45

529.162

C, 49.91; H, 5.52; F, 3.59; N, 7.94; O, 27.20; P, 5.85

1190307-88-0

45375808

White solid powder

1.4±0.1 g/cm3

1.573

1.62

167.99

3

11

11

36

913

6

O=C1N([C@H]2[C@]([C@H](O)[C@@H](CO[P@](OC3=CC=CC=C3)(N[C@@H](C)C(OC(C)C)=O)=O)O2)(C)F)C=CC(N1)=O

TTZHDVOVKQGIBA-IQWMDFIBSA-N

InChI=1S/C22H29FN3O9P/c1-13(2)33-19(29)14(3)25-36(31,35-15-8-6-5-7-9-15)32-12-16-18(28)22(4,23)20(34-16)26-11-10-17(27)24-21(26)30/h5-11,13-14,16,18,20,28H,12H2,1-4H3,(H,25,31)(H,24,27,30)/t14-,16+,18+,20+,22+,36-/m0/s1

propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 1.67 mg/mL (3.15 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 16.7 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 1.67 mg/mL (3.15 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 16.7mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 1.67 mg/mL (3.15 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 16.7 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 4.55 mg/mL (8.59 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。