YL1004
YL1004 is a potent, selective and orally active noncovalent inhibitor of SARS-CoV-2 papain-like protease (PLpro). YL1004 shows an IC50 of 17.5 nM and a Ki of 2.3 nM against PLpro, with an in vitro anti-SARS-CoV-2 EC50 of 0.08 μM-1.37 μM. YL1004 suppresses the proteolytic activity of PLpro and blocks its deubiquitinating and deISGylating effects to restore host innate antiviral immune signaling. YL1004 inhibits the replication of wild-type, Delta, Omicron variants and nirmatrelvir-resistant strains of SARS-CoV-2. YL1004 can be used for the research of COVID-19 (SARS-CoV-2 infection).
For research use only. We do not sell to patients.
- Formula: C31H37N5O3
- Molecular Weight:527.66
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
- Protocols
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
Description
In Vitro
YL1004 (range; 10 min preincubation at room temperature) inhibits SARS-CoV-2 PLpro-mediated polyprotein cleavage with an IC50 of 17.5 nM and a Ki of 2.3 nM; inhibits SARS-CoV-2 PLpro-mediated deubiquitination with an IC50 of 22.9 nM and a Ki of 4.2 nM; inhibits SARS-CoV-2 PLpro-mediated deISGylation with an IC50 of 43.6 nM and a Ki of 39.3 nM[1].
YL1004 (72 h) exhibits low cytotoxicity in mammalian cell lines, with a CC50 of 226.90 μM in VeroE6 cells and 296.33 μM in Calu3 cells[1].
YL1004 directly binds to SARS-CoV-2 PLpro, as demonstrated by a ΔTm of 18.07°C in a DSF assay[1].
YL1004 (0.001-10 μM; 36 h) dose-dependently inhibits SARS-CoV-2 PLpro-mediated deubiquitination in HEK293T cells[1].
YL1004 (0.1-10 μM; co-treated with PLpro following 48 h IFN-α stimulation) dose-dependently inhibits SARS-CoV-2 PLpro-mediated deISGylation[1].
YL1004 (0.002-10 μM; co-treated with TNF-α (HY-P7058) stimulation) restores TNF-α-induced NF-κB activation in PLpro-expressing HEK293T cells with an EC50 of 44.1 nM, and restores ISRE activation with an EC50 of 265.3 nM[1].
YL1004 (0.002-10 μM; co-treated with poly (I:C) (HY-107202) stimulation) restores poly (I:C)-induced IFNB1 and IRF3 activation in PLpro-expressing HEK293T cells, with EC50 values of 26.5 nM and 206.9 nM, respectively[1].
YL1004 (18-24 h after treatment alongside poly (I:C) stimulation) restores transcription of PLpro-repressed genes involved in innate immunity, autophagy, and mitochondrial stress response in poly (I:C)-stimulated HEK293T cells[1].
YL1004 (0.039-10 μM; 22 h for wildtype/Delta/JN.1, 46 h for KP.3/NSP5-E166V) dose-dependently reduces SARS-CoV-2 sgE RNA levels in infected Calu3 cells[1].
YL1004 (48 h for wildtype/Delta, 72 h for JN.1/KP.3/NSP5-E166V post-infection) potently inhibits infectious SARS-CoV-2 replication, with EC50 values ranging from 0.08 μM to 1.37 μM across wildtype, Delta, Omicron JN.1, Omicron KP.3, and nirmatrelvir-resistant NSP5-E166V recombinant strains[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:HEK293T cells
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Concentration:0.01, 0.05, 0.1, 0.25, 0.5, 1, 10 μM
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Incubation Time:36 h
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Result:Restored ubiquitinated protein levels in a dose-dependent manner.
Showed greater potency than 10 μM of a reference compound at suppressing PLPRO-mediated deubiquitination when used at 1 μM.
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Cell Line:HEK293T cells
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Concentration:0.1, 1, 10 μM
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Incubation Time:with or without IFN-α for 48 h
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Result:Reversed PLPRO-mediated reduction of ISG15-conjugated proteins in a dose-dependent manner.
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Cell Line:Calu3 cells infected with SARS-CoV-2 wildtype, Delta, Omicron JN.1, Omicron KP.3, and NSP5-E166V recombinant strains
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Concentration:0.039, 0.16, 0.63, 2.5, 110 μM
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Incubation Time:24 h (WT, Delta, JN.1); 48 h (KP.3, NSP5-E166V mutant)
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Result:Dose-dependently reduced SARS-CoV-2 sgE RNA levels; inhibited replication of WT, Delta, Omicron JN.1/KP.3 and nirmatrelvir-resistant strain.
Parmacokinetics
In Vivo
YL1004 (100 mg/kg; p.o.; twice per day) starting 1 hour post-challenge confers 100% survival and reduces body weight loss in SARS-CoV-2 Delta-challenged K18-hACE2 mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:K18-hACE2 transgenic (8-12-week-old; male and female; intranasal inoculation with SARS-CoV-2 Omicron JN.1)[1]
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Dosage:100 mg/kg
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Administration:p.o.; twice per day
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Result:Decreased viral sgE RNA loads in nasal turbinates by 3.6-fold compared to vehicle controls.
Decreased viral sgE RNA loads in lung tissues by 26.1-fold compared to vehicle controls.
Lowered infectious viral titers in nasal turbinates by 21-fold compared to vehicle controls.
Lowered infectious viral titers in lung tissues by 13.4-fold compared to vehicle controls.
Rarely detected viral antigen in treated mouse lungs.
Significantly alleviated virus-induced pathological changes, with only mild alveolar deformation observed.
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Animal Model:K18-hACE2 transgenic (8-12-week-old; female; intranasal inoculation with SARS-CoV-2 Delta)[1]
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Dosage:100 mg/kg
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Administration:p.o.; twice per day
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Result:Reduced body weight loss significantly compared to vehicle controls.
Achieved 100% survival (10/10 mice) at 14 days post-infection, compared to 10% survival (1/10 mice) in vehicle controls.
Chemical Information
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Molecular Weight 527.66
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Formula C31H37N5O3
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SMILES
O=C(C1=C(N)C=C2OC[C@@](CN(C)CC3)([H])N3C2=C1)NC4(C5=C6C=CC=CC6=C(NC7CCOCC7)C=C5)CC4
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocols
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Research Protocol for Infectious Diseases
Infectious-disease experiments test how pathogens interact with host barriers, innate immune receptors, inflammatory signaling, pathogen replication, and tissue injury; pattern-recognition receptors such as TLRs, RIG-I-like receptors, NOD-like receptors, and inflammasomes detect microbial molecules and activate NF-κB, interferon, and cytokine responses. The central hypothesis is that infection severity reflects the balance between pathogen burden and host response: protective inflammation restricts pathogen growth, whereas excessive or mislocalized inflammation contributes to tissue damage and disease phenotype. Unresolved questions include which host pathways are protective versus pathogenic, why some infection models fail to translate to human disease, and which combined readouts best predict clinically relevant infection outcomes.
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
YL1004 Related Classifications
HY-181661 Related Classifications
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