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| Targets |
The primary targets of K-11777 include cysteine proteases such as cruzipain (from Trypanosoma cruzi), cathepsin B, and cathepsin L. It is a potent, irreversible, covalent inhibitor of mammalian cathepsin L and other cysteine proteases of clan CA. K-11777 also acts as a selective CCR4 antagonist. By inhibiting these targets, the compound disrupts essential viral replication processes and pathogen survival. It inhibits SARS-CoV and EBOV pseudovirus entry with IC₅₀ values of 0.68 nM and 0.87 nM, respectively.
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| ln Vitro |
K777 (K11777) can block entry caused by various viral envelope proteins, such as filoviruses (Glycoproteins of EBOV, SUDV, TAFV, RESTV), BEBOV, and MARV, or HIV-based pseudotyped viruses with coronavirus spikes (SARS-CoV, HCoV-229E, NL63, and MERS-CoV). K777, with IC50 values of 0.68 nM, 1.48 nM, 6.78 nM, 46.12 nM, and so on, blocks the entry of SARS-CoV, HCoV-229E, NL63, MERS-CoV, EBOV, SUDV, TAFV, RESTV, BEBOV, MARV, and Nipah pseudovirus. 1,14, 2.26, 3.37, 5.91, 1.9, 0.42, 1.87, and 2.26 nM. On the other hand, alphavirus (CHIKV), rhabdovirus (VSV), flavivirus (HCV), retroviruses MLV-A and XMRV, and two arenaviruses, Lassa virus and Junin virus, were not inhibited by 100 nM K777. glycoprotein-mediated membrane infection [1]. K777 by itself demonstrated a 70% reduction in 229E-mediated transduction. When K777 and camostat were used together, the inhibition rate rose to almost 90%. The human intestinal epithelial cell line Caco-2, which expresses endogenous TMPRSS2 and cathepsins, was used to generate a comparable pattern of inhibition [1]. In Hut78 cells, K777 reduces both CCL17-induced chemotaxis and CCL17 binding (IC50 57 nM and 8.9 nM, respectively). K777-mediated chemotaxis inhibition was still effective even when CCL17 concentrations were ten times greater. K777 decreases cell surface CCR4 by around 50% and causes CCR4 internalization. K777 does not inherently trigger Ca2+ mobilization, nor does it block CXCR4-induced chemotaxis or internalization [3].
In vitro, K-11777 is a potent, irreversible, covalent inhibitor of mammalian cathepsin L and other cysteine proteases of clan CA. It inhibits SARS-CoV and EBOV pseudovirus entry with IC₅₀ values of 0.68 nM and 0.87 nM, respectively. The compound also irreversibly inhibits cruzain as well as cathepsins B and L. As a potent cysteine protease inhibitor, K-11777 has broad-spectrum antiviral activity. It is also a selective CCR4 antagonist. |
| ln Vivo |
K777 (K11777; 35-105 mg/kg; oral dose; twice daily; for 10 days; C57BL/6 IFN-γR-KO mice) therapy protected mice from otherwise deadly infections [4].
In vivo, K-11777 is orally active and has anticancer and antiviral activities. As a broad-spectrum antiviral that targets cathepsin-mediated cell entry, it would be expected to inhibit viral replication in vivo. The compound's oral bioavailability makes it suitable for convenient administration in preclinical studies. However, specific in vivo efficacy data from animal models is not detailed in the available sources. |
| Enzyme Assay |
For cysteine protease inhibitors, standard cell-free assays involve measuring the protease activity of recombinant cathepsin L, cathepsin B, or cruzain using fluorogenic peptide substrates (e.g., Z-FR-AMC or Z-RR-AMC). The compound is incubated with the enzyme and substrate, and the release of fluorescent product is measured to determine IC₅₀ values.
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| Cell Assay |
For antiviral compounds, standard cellular assays involve infection of susceptible cell lines with pseudovirus or live virus in the presence or absence of the test compound. Viral entry or replication is measured by luciferase reporter assays, qPCR, or plaque reduction assays to determine IC₅₀ values. Cytotoxicity is assessed using MTT or CellTiter-Glo assays.
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| Animal Protocol |
Animal/Disease Models: C57BL/6 IFN-γR-KO mice (6-8 weeks of age) injected with Cryptosporidium parvum[4]
Doses: 35 mg/kg, 70 mg/kg, and 105 mg/kg Route of Administration: Oral administration; twice a day; for 10 days Experimental Results: Rescued mice from otherwise lethal infections. For in vivo evaluation of antiviral compounds, standard animal models include SARS-CoV or EBOV infection models in mice. The compound is typically administered orally or intraperitoneally, and viral titers, disease severity, and survival are assessed. For anticancer applications, tumor xenograft models are used. |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
K-11777 Known human metabolites include N-demethyl K-11777, N-oxide K-11777, and β-hydroxy-homophenylalanine K11777. K-11777 is an orally active cysteine protease inhibitor. It has a molecular weight of 2138.5 and formula C₉₉H₁₄₈N₂₄O₂₅S₂. As a large molecule, it would have complex pharmacokinetic properties. Comprehensive PK studies would be required for therapeutic development. |
| Toxicity/Toxicokinetics |
Detailed toxicology data for K-11777 is not provided in the available sources. As a research compound targeting cysteine proteases, standard preclinical toxicology would be required for therapeutic development. The compound's irreversible inhibition of cathepsins may have effects on normal cellular processes, and comprehensive safety evaluation would be needed. The compound is for research use only and not for therapeutic applications.
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| References |
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| Additional Infomation |
K-11777 is a potent, orally active, and irreversible cysteine protease inhibitor. It inhibits SARS-CoV and EBOV pseudovirus entry with IC₅₀ values of 0.68 nM and 0.87 nM, respectively. The compound also irreversibly inhibits cruzain as well as cathepsins B and L. It is also a selective CCR4 antagonist. No regulatory approval has been identified.
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| Molecular Formula |
C32H38N4O4S
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| Molecular Weight |
574.73352
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| Exact Mass |
574.261
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| CAS # |
233277-99-1
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| Related CAS # |
502960-90-9;
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| PubChem CID |
9851116
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| Appearance |
White to off-white solid powder
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| LogP |
4.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
41
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| Complexity |
939
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CN1CCN(CC1)C(=O)NC(CC2=CC=CC=C2)C(=O)NC(CCC3=CC=CC=C3)C=CS(=O)(=O)C4=CC=CC=C4
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| InChi Key |
RHJLQMVZXQKJKB-FPHSVDBKSA-N
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| InChi Code |
InChI=1S/C32H38N4O4S/c1-35-20-22-36(23-21-35)32(38)34-30(25-27-13-7-3-8-14-27)31(37)33-28(18-17-26-11-5-2-6-12-26)19-24-41(39,40)29-15-9-4-10-16-29/h2-16,19,24,28,30H,17-18,20-23,25H2,1H3,(H,33,37)(H,34,38)/b24-19+/t28-,30-/m0/s1
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| Chemical Name |
N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]-4-methylpiperazine-1-carboxamide
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| Synonyms |
APC 3316 K-11777 K-777APC3316 K11777 K777APC-3316
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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 : ~100 mg/mL (~173.99 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.35 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 25.0 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: ≥ 2.5 mg/mL (4.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 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: ≥ 2.5 mg/mL (4.35 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 | 1.7399 mL | 8.6997 mL | 17.3995 mL | |
| 5 mM | 0.3480 mL | 1.7399 mL | 3.4799 mL | |
| 10 mM | 0.1740 mL | 0.8700 mL | 1.7399 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.
Link: https://clinicaltrials.gov/ct2/show/NCT06146374
Conditions:COVID-19Link: https://clinicaltrials.gov/ct2/show/NCT04843787
Conditions:Covid19Products are for research use only; We do not sell to patients
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