AT-511
(Synonyms: AT-511) 目录号 : GC62320
A prodrug form of AT-9010
Cas No.:1998705-64-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
AT-511 is a prodrug form of the antiviral nucleoside analog AT-9010.1 It reduces the infectious virus yield in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome CoV (SARS-CoV), SARS-CoV-2, human CoV 229E (HCoV-229E), and HCoV-OC43 (EC90s = 37, 0.47, 2.8, 1.2, and 0.5 ?M, respectively).
1.Good, S.S., Westover, J., Jung, K.H., et al.AT-527, a double prodrug of a guanosine nucleotide analog, is a potent inhibitor of SARS-CoV-2 in vitro and a promising oral antiviral for treatment of COVID-19Antimicrob. Agents Chemother.65(4)e02479-02420(2021)
| Cas No. | 1998705-64-8 | SDF | |
| 别名 | AT-511 | ||
| 分子式 | C24H33FN7O7P | 分子量 | 581.53 |
| 溶解度 | DMSO : 100 mg/mL (171.96 mM; Need ultrasonic) | 储存条件 | 4°C, protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7196 mL | 8.598 mL | 17.196 mL |
| 5 mM | 0.3439 mL | 1.7196 mL | 3.4392 mL |
| 10 mM | 0.172 mL | 0.8598 mL | 1.7196 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19
Antimicrob Agents Chemother 2021 Mar 18;65(4):e02479-20.PMID:33558299DOI:10.1128/AAC.02479-20.
The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.47 μM, very similar to its EC90 against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 μM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 μM AT-511 (698 ± 15 and 236 ± 14 μM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.
Preclinical evaluation of AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis C virus
PLoS One 2020 Jan 8;15(1):e0227104.PMID:31914458DOI:10.1371/journal.pone.0227104.
Despite the availability of highly effective direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infections, sustained viral response (SVR) rates remain suboptimal for difficult-to-treat patient populations such as those with HCV genotype 3, cirrhosis or prior treatment experience, warranting development of more potent HCV replication antivirals. AT-527 is the hemi-sulfate salt of AT-511, a novel phosphoramidate prodrug of 2'-fluoro-2'-C-methylguanosine-5'-monophosphate that has potent in vitro activity against HCV. The EC50 of AT-511, determined using HCV laboratory strains and clinical isolates with genotypes 1-5, ranged from 5-28 nM. The active 5'-triphosphate metabolite, AT-9010, specifically inhibited the HCV RNA-dependent RNA polymerase. AT-511 did not inhibit the replication of other selected RNA or DNA viruses in vitro. AT-511 was approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV genotypes 1-5 and remained fully active against S282T resistance-associated variants, with up to 58-fold more potency than SOF. In vitro, AT-511 did not inhibit human DNA polymerases or elicit cytotoxicity or mitochondrial toxicity at concentrations up to 100 μM. Unlike the other potent guanosine analogs PSI-938 and PSI-661, no mutagenic O6-alkylguanine bases were formed when incubated with cytochrome P450 (CYP) 3A4, and AT-511 had IC50 values ≥25 μM against a panel of CYP enzymes. In hepatocytes from multiple species, the active triphosphate was the predominant metabolite produced from the prodrug, with a half-life of 10 h in human hepatocytes. When given orally to rats and monkeys, AT-527 preferentially delivered high levels of AT-9010 in the liver in vivo. These favorable preclinical attributes support the ongoing clinical development of AT-527 and suggest that, when used in combination with an HCV DAA from a different class, AT-527 may increase SVR rates, especially for difficult-to-treat patient populations, and could potentially shorten treatment duration for all patients.
A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents
Antiviral Res 2021 Aug;192:105122.PMID:34186107DOI:10.1016/j.antiviral.2021.105122.
There are, besides remdesivir, no approved antivirals for the treatment of SARS-CoV-2 infections. To aid in the search for antivirals against this virus, we explored the use of human tracheal airway epithelial cells (HtAEC) and human small airway epithelial cells (HsAEC) grown at the air-liquid interface (ALI). These cultures were infected at the apical side with one of two different SARS-CoV-2 isolates. Each virus was shown to replicate to high titers for extended periods of time (at least 8 days) and, in particular an isolate with the D614G in the spike (S) protein did so more efficiently at 35 °C than 37 °C. The effect of a selected panel of reference drugs that were added to the culture medium at the basolateral side of the system was explored. Remdesivir, GS-441524 (the parent nucleoside of remdesivir), EIDD-1931 (the parent nucleoside of molnupiravir) and IFN (β1 and λ1) all resulted in dose-dependent inhibition of viral RNA and infectious virus titers collected at the apical side. However, AT-511 (the free base form of AT-527 currently in clinical testing) failed to inhibit viral replication in these in vitro primary cell models. Together, these results provide a reference for further studies aimed at selecting SARS-CoV-2 inhibitors for further preclinical and clinical development.