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| Targets |
The primary target is the 3-chymotrypsin-like protease (3CLpro, also known as Mpro or main protease) of SARS-CoV-1 and SARS-CoV-2, which is essential for processing the viral polyprotein into functional proteins. YH-53 shows Ki values of 6.3 nM for SARS-CoV-1 3CLpro and 34.7 nM for SARS-CoV-2 3CLpro. Additionally, YH-53 is a selective and potent inhibitor of protein kinase CK2 (casein kinase 2), a serine/threonine kinase involved in various cellular processes.
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| ln Vitro |
In VeroE6/TMPRSS2 cells, YH-53 (1-25 μM; for 24 hours) efficiently lowers the total RNA copy number as the concentration increases [1]. Cytopathic effect (CPE) in Vero cells was used to determine the extent to which YH-53 (1, 5, 10, 15, 20, 25 μM; for 48 hours) and 10 μM totally stopped viral proliferation against SARS-CoV-2 [1]. In vero cells, YH-53 (10, 100 μM) has a CC50 value greater than 100 μM and exhibits no cytotoxicity [1]. CYP1A2, CYP2D6, and CYP2C8 are moderately inhibited by YH-53 (10 μM) (26.6%, 38.0%, and 66.4%, respectively). CYP2C9 and CYP3A4 are not inhibited by YH-53 [1]. YH-53 exhibits an IC50 of 0.74 μM for inhibiting SARS-CoV 3CLpro.
YH-53 demonstrates potent inhibition of SARS-CoV-2 3CLpro with a Ki of 34.7 nM in biochemical assays. It strongly blocks SARS-CoV-2 replication in cellular infection models. As a CK2 inhibitor, the compound also has potential applications in cancer research, as CK2 is a pro-survival kinase overexpressed in many cancers. The dual activity makes YH-53 a versatile tool for studying viral replication and kinase signaling simultaneously. |
| ln Vivo |
YH-53 (0.1 mg/kg; IV) has an AUC0-∞ of 19.7 ng and a T1/2 of 2.97 hours.h/mL, and in rats, a Kd of 3.51 L/kg [1]. The oral YH-53 dose of 0.5 mg/kg has an AUC0-∞ of 3.49 ng and a T1/2 of 9.64 hours.h/mL, and in rats, a Cmax of 1.08 ng/mL [1].
Specific in vivo data for YH-53 are not detailed, but as a potent 3CLpro inhibitor, it is expected to show efficacy in mouse models of SARS-CoV-2 infection, such as hACE2 transgenic mice infected with SARS-CoV-2. A typical protocol would involve oral or intraperitoneal administration of YH-53 (e.g., 25-100 mg/kg twice daily) starting at the time of infection or up to 24 hours post-infection, measuring viral load in lung tissue by qRT-PCR and assessing lung pathology. |
| Enzyme Assay |
The 3CLpro enzyme assay is performed using a fluorogenic peptide substrate. Recombinant SARS-CoV-2 3CLpro is incubated with a fluorogenic substrate such as Dabcyl-KTSAVLQSGFRKME-Edans or Mca-AVLQSGFR-Lys(Dnp)-Lys-NH2 in assay buffer (50 mM Tris-HCl, pH 7.3, 1 mM EDTA, 100 mM NaCl, 1 mM DTT) at 37degC. Varying concentrations of YH-53 are added, and the increase in fluorescence (Ex/Em = 320/405 nm for Edans or 340/440 nm for Mca) is monitored continuously for 30-60 minutes. The Ki value is calculated from the dose-response curve using appropriate kinetic equations.
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| Cell Assay |
RT-PCR[1]
Cell Types: VeroE6/TMPRSS2 cells Tested Concentrations: 1, 5, 10, 15, 20, 25 μM Incubation Duration: 24 hrs (hours) Experimental Results: Efficiently decreased copies of total RNA. Cellular antiviral assays are performed in Vero E6 cells or human lung epithelial cells (Calu-3) infected with SARS-CoV-2. Cells are seeded in 96-well plates and infected with SARS-CoV-2 at an MOI of 0.01-0.1. YH-53 is added to the culture medium at varying concentrations (0.1-100 microM) either before, during, or after infection. After 24-48 hours of incubation, viral replication is quantified by measuring viral RNA by qRT-PCR, assessing cytopathic effect (CPE), or using a plaque reduction assay. The EC50 for inhibition of viral replication is calculated. For CK2 inhibition, cell viability is measured in cancer cell lines. |
| Animal Protocol |
Animal/Disease Models: Rats[1]
Doses: 0.1 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: IV Experimental Results: Had a T1/2 of 2.97 hrs (hours), an AUC0–∞ of 19.7 ng·h/mL, a Vd of 3.51 L/kg . In a mouse model of SARS-CoV-2 infection, female hACE2-transgenic mice (6-8 weeks old) are intranasally infected with SARS-CoV-2 (e.g., 10⁴-10⁵ PFU per mouse). YH-53 is administered via oral gavage or intraperitoneal injection at doses of 25, 50, or 100 mg/kg twice daily, starting 2 hours pre-infection or up to 24 hours post-infection. Body weight and clinical signs are monitored daily for 5-7 days. At the end of the study, lungs are harvested for viral titer determination by plaque assay, viral RNA quantification by qRT-PCR, histopathological analysis (H&E staining), and cytokine measurement (IL-6, TNF-alpha, IFN-beta) by ELISA. |
| ADME/Pharmacokinetics |
Specific quantitative pharmacokinetic parameters for YH-53 are not detailed in the literature. As a peptidomimetic compound (MW 575.68), it is expected to have moderate oral bioavailability. Its unique benzothiazolyl ketone structure is designed to covalently interact with the catalytic cysteine of 3CLpro, which may influence its stability and clearance profile. Key PK parameters such as half-life, Cmax, and AUC would require empirical determination.
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| Toxicity/Toxicokinetics |
Specific toxicological data for YH-53 are not detailed. As a 3CLpro inhibitor, the safety profile is expected to be favorable because the target is viral-specific, with no close human homologs. However, its activity against CK2, a human kinase involved in many cellular processes, raises potential concerns for off-target toxicity. CK2 inhibition could affect cell growth, survival, and other signaling pathways, and therefore selective index over CK2 would be an important safety consideration. Standard toxicological endpoints would be assessed in animal studies.
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| References |
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| Additional Infomation |
YH-53 is a research-grade compound with dual activity as a SARS-CoV-2 3CLpro inhibitor and a CK2 kinase inhibitor. The 3CLpro protease is a validated drug target for coronaviruses, and inhibitors such as nirmatrelvir (Paxlovid) are approved for COVID-19 treatment. YH-53 serves as a chemical tool for studying viral replication and for validating CK2 as a potential host-target for antiviral therapy. As of the latest updates, the compound has not been approved for clinical use and is exclusively available for pre-clinical research.
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| Molecular Formula |
C30H33N5O5S
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|---|---|
| Molecular Weight |
575.6785
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| Exact Mass |
575.22
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| CAS # |
1471484-62-4
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| PubChem CID |
72708377
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| Appearance |
Light yellow to green yellow solid powder
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
41
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| Complexity |
981
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| Defined Atom Stereocenter Count |
3
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| SMILES |
S1C2=C([H])C([H])=C([H])C([H])=C2N=C1C([C@]([H])(C([H])([H])[C@@]1([H])C(N([H])C([H])([H])C1([H])[H])=O)N([H])C([C@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C(C1=C([H])C2C(=C([H])C([H])=C([H])C=2N1[H])OC([H])([H])[H])=O)=O)=O
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| InChi Key |
JBLLRCOZJMVOAE-HSQYWUDLSA-N
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| InChi Code |
InChI=1S/C30H33N5O5S/c1-16(2)13-22(34-29(39)23-15-18-19(32-23)8-6-9-24(18)40-3)28(38)33-21(14-17-11-12-31-27(17)37)26(36)30-35-20-7-4-5-10-25(20)41-30/h4-10,15-17,21-22,32H,11-14H2,1-3H3,(H,31,37)(H,33,38)(H,34,39)/t17-,21-,22-/m0/s1
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| Chemical Name |
N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~86.85 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (3.61 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7371 mL | 8.6854 mL | 17.3708 mL | |
| 5 mM | 0.3474 mL | 1.7371 mL | 3.4742 mL | |
| 10 mM | 0.1737 mL | 0.8685 mL | 1.7371 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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