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GRL0617 Sale

目录号 : GC39172

A SARS-CoV and SARS-CoV-2 PLpro inhibitor

GRL0617 Chemical Structure

Cas No.:1093070-16-6

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥2,695.00
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5mg
¥2,450.00
现货
10mg
¥4,550.00
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产品文档

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产品描述

GRL-0617 is an inhibitor of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 papain-like proteases (PLpros; IC50s = 0.6 and 1.5 ?M, respectively).1,2 It increases the viability of SARS-CoV-infected Vero E6 cells (EC50 = 14.5 ?M).1 GRL-0617 (6.25-50 ?M) reduces viral replication in SARS-CoV-2-infected Caco-2 cells.2

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) 2.Shin, D., Mukherjee, R., Grewe, D., et al.Papain-like protease regulates SARS-CoV-2 viral spread and innate immunityNature587(7835)657-662(2020)

Chemical Properties

Cas No. 1093070-16-6 SDF
Canonical SMILES O=C(N[C@@H](C1=C2C=CC=CC2=CC=C1)C)C3=CC(N)=CC=C3C
分子式 C20H20N2O 分子量 304.39
溶解度 DMSO: 125 mg/mL (410.66 mM) 储存条件 Store at -20°C
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1 mM 3.2853 mL 16.4263 mL 32.8526 mL
5 mM 0.6571 mL 3.2853 mL 6.5705 mL
10 mM 0.3285 mL 1.6426 mL 3.2853 mL
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Research Update

The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery

Nat Commun 2021 Jan 20;12(1):488.PMID:33473130DOI:10.1038/s41467-020-20718-8.

SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease (PLpro) has been implicated in playing important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses. The multiple functions of PLpro render it a promising drug target. Therefore, we screened a library of approved drugs and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising in vitro IC50 of 2.1 μM and an effective antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PLproC111S in complex with GRL0617 indicates that GRL0617 is a non-covalent inhibitor and it resides in the ubiquitin-specific proteases (USP) domain of PLpro. NMR data indicate that GRL0617 blocks the binding of ISG15 C-terminus to PLpro. Using truncated ISG15 mutants, we show that the C-terminus of ISG15 plays a dominant role in binding PLpro. Structural analysis reveals that the ISG15 C-terminus binding pocket in PLpro contributes a disproportionately large portion of binding energy, thus this pocket is a hot spot for antiviral drug discovery targeting PLpro.

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors

Protein Cell 2021 Nov;12(11):877-888.PMID:33864621DOI:10.1007/s13238-021-00836-9.

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

Identifying structural-functional analogue of GRL0617, the only well-established inhibitor for papain-like protease (PLpro) of SARS-CoV2 from the pool of fungal metabolites using docking and molecular dynamics simulation

Mol Divers 2022 Feb;26(1):309-329.PMID:33825097DOI:10.1007/s11030-021-10220-8.

The non-structural protein (nsp)-3 of SARS-CoV2 coronavirus is sought to be an essential target protein which is also named as papain-like protease (PLpro). This protease cleaves the viral polyprotein, but importantly in human host it also removes ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from interferon responsive factor 3 (IRF3) protein which ultimately downregulates the production of type I interferon leading to weakening of immune response. GRL0617 is the most potent known inhibitor for PLpro that was initially developed for SARS outbreak of 2003. The PLpro of SARS-CoV and CoV2 share 83% sequence identity but interestingly have several identical conserved amino acids that suggests GRL0617 to be an effective inhibitor for PLpro of SARS-CoV2. GRL0617 is a naphthalene-based molecule and interacts with Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro). To identify PLpro inhibitors, we prepared a library of secondary metabolites from fungi with aromatic nature and docked them with PLpro of SARS-CoV and SARS-CoV2. We found six hits which interacts with Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro). More surprisingly the top hit, Fonsecin, has naphthalene moiety in its structure, which recruits Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro) and has binding energy at par with control (GRL0617). Molecular dynamics (MD) simulation showed Fonsecin to interact with Tyr268 of SARS-CoV2-PLpro more efficiently than control (GRL0617) and interacting with a greater number of amino acids in the binding cleft of PLpro.

Crystal structure of SARS-CoV-2 papain-like protease

Acta Pharm Sin B 2021 Jan;11(1):237-245.PMID:32895623DOI:10.1016/j.apsb.2020.08.014.

The pandemic of coronavirus disease 2019 (COVID-19) is changing the world like never before. This crisis is unlikely contained in the absence of effective therapeutics or vaccine. The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays essential roles in virus replication and immune evasion, presenting a charming drug target. Given the PLpro proteases of SARS-CoV-2 and SARS-CoV share significant homology, inhibitor developed for SARS-CoV PLpro is a promising starting point of therapeutic development. In this study, we sought to provide structural frameworks for PLpro inhibitor design. We determined the unliganded structure of SARS-CoV-2 PLpro mutant C111S, which shares many structural features of SARS-CoV PLpro. This crystal form has unique packing, high solvent content and reasonable resolution 2.5 Å, hence provides a good possibility for fragment-based screening using crystallographic approach. We characterized the protease activity of PLpro in cleaving synthetic peptide harboring nsp2/nsp3 juncture. We demonstrate that a potent SARS-CoV PLpro inhibitor GRL0617 is highly effective in inhibiting protease activity of SARS-CoV-2 with the IC50 of 2.2 ± 0.3 μmol/L. We then determined the structure of SARS-CoV-2 PLpro complexed by GRL0617 to 2.6 Å, showing the inhibitor accommodates the S3-S4 pockets of the substrate binding cleft. The binding of GRL0617 induces closure of the BL2 loop and narrows the substrate binding cleft, whereas the binding of a tetrapeptide substrate enlarges the cleft. Hence, our results suggest a mechanism of GRL0617 inhibition, that GRL0617 not only occupies the substrate pockets, but also seals the entrance to the substrate binding cleft hence prevents the binding of the LXGG motif of the substrate.

In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542

Front Pharmacol 2023 Feb 15;14:1067408.PMID:36874001DOI:10.3389/fphar.2023.1067408.

The SARS-CoV-2 pandemic requires a new therapeutic target for viral infection, and papain-like protease (Plpro) has been suggested as a druggable target. This in-vitro study was conducted to examine the drug metabolism of the GRL0617 and HY-17542, Plpro inhibitors. Metabolism of these inhibitors was studied to predict the pharmacokinetics in human liver microsomes. The hepatic cytochrome P450 (CYP) isoforms responsible for their metabolism were identified using recombinant enzymes. The drug-drug interaction potential mediated by cytochrome P450 inhibition was estimated. In human liver microsomes, the Plpro inhibitors had phase I and phase I + II metabolism with half-lives of 26.35 and 29.53 min, respectively. Hydroxylation (M1) and desaturation (-H2, M3) of the para-amino toluene side chain were the predominant reactions mediated with CYP3A4 and CYP3A5. CYP2D6 is responsible for the hydroxylation of the naphthalene side ring. GRL0617 inhibits major drug-metabolizing enzymes, including CYP2C9 and CYP3A4. HY-17542 is structural analog of GRL0617 and it is metabolized to GRL0617 through non-cytochrome P450 reactions in human liver microsomes without NADPH. Like GRL0617 and HY-17542 undergoes additional hepatic metabolism. The in-vitro hepatic metabolism of the Plpro inhibitors featured short half-lives; preclinical metabolism studies are needed to determine therapeutic doses for these inhibitors.