PLpro inhibitor
(Synonyms: 5-(乙酰氨基)-2-甲基-N-[(1R)-1-(1-萘基)乙基]苯甲酰胺) 目录号 : GC36939
A SARS-CoV PLpro inhibitor
Cas No.:1093070-14-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
HY-17542 is an inhibitor of the severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro; IC50 = 2.6 ?M).1 It increases the viability of SARS-CoV-infected Vero E6 cells (EC50 = 13.1 ?M).
1.Ratia, K., Pegan, S., Takayama, J., et al.A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replicationProc. Natl. Acad. Sci. USA105(42)16119-16124(2008)
| Cas No. | 1093070-14-4 | SDF | |
| 别名 | 5-(乙酰氨基)-2-甲基-N-[(1R)-1-(1-萘基)乙基]苯甲酰胺 | ||
| Canonical SMILES | O=C(C1=CC(NC(C)=O)=CC=C1C)N[C@H](C)C2=C(C=CC=C3)C3=CC=C2 | ||
| 分子式 | C22H22N2O2 | 分子量 | 346.42 |
| 溶解度 | DMSO: ≥ 42 mg/mL (121.24 mM) | 储存条件 | Store at -20°C |
| 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 | 2.8867 mL | 14.4333 mL | 28.8667 mL |
| 5 mM | 0.5773 mL | 2.8867 mL | 5.7733 mL |
| 10 mM | 0.2887 mL | 1.4433 mL | 2.8867 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。
Inhibitors of SARS-CoV-2 PLpro
Front Chem 2022 Apr 26;10:876212.PMID:35559224DOI:10.3389/fchem.2022.876212.
The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now ∼30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.
Discovery of small molecule PLpro inhibitor against COVID-19 using structure-based virtual screening, molecular dynamics simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) calculation
Struct Chem 2021;32(2):879-886.PMID:33106741DOI:10.1007/s11224-020-01665-y.
COVID-19 is spreading in a global pandemic that is endangering human life and health. Therefore, there is an urgent need to target COVID-19 to find effective treatments for this emerging acute respiratory infection. Viral Papain-Like cysteine protease (PLpro), similar to papain and the cysteine deubiquitinase enzyme, has been a popular target for coronavirus inhibitors, as an indispensable enzyme in the process of coronavirus replication and infection of the host. Combined structure-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) free energy calculation approaches were utilized for identification of PLpro inhibitors. Four compounds (F403_0159, F112_0109, G805_0497, D754_0006) with diverse chemical scaffolds were retrieved as hits based on docking score and clustering analysis. Molecular dynamics simulations indicated that the contribution of van der Waals interaction dominated the binding free energies of these compounds, which may be attributed to the hydrophobicity of active site of PLpro from COVID-19. Moreover, all four compounds formed conservative hydrogen bonds with the residues Asp164, Gln269, and Tyr273. We hoped that these four compounds might represent the promising chemical scaffolds for further development of novel PLpro inhibitors against COVID-19.
Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV
ACS Chem Biol 2015 Jun 19;10(6):1456-65.PMID:25746232DOI:10.1021/cb500917m.
The Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) blocking loop 2 (BL2) structure differs significantly from that of SARS-CoV PLpro, where it has been proven to play a crucial role in SARS-CoV PLpro inhibitor binding. Four SARS-CoV PLpro lead inhibitors were tested against MERS-CoV PLpro, none of which were effective against MERS-CoV PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-CoV PLpro, were replaced by T274 and A275 in MERS-CoV PLpro, making critical binding interactions difficult to form for similar types of inhibitors. High-throughput screening (HTS) of 25 000 compounds against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. Mode of inhibition studies by enzyme kinetics and competition surface plasmon resonance (SPR) analyses suggested that this compound acts as a competitive inhibitor with an IC50 of 6 μM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC50 of 11 μM. These results raised the possibility that inhibitor recognition specificity of MERS-CoV PLpro may differ from that of SARS-CoV PLpro. In addition, inhibitory activity of this compound was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologues, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3).