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Danoprevir (ITMN-191)

Name: Danoprevir (ITMN-191)
Brand: Selleck Chemicals
SKU: S1183
Rating: 5 (14 reviews)

Catalog No.S1183 Synonyms: RG7227

For research use only.

Danoprevir (ITMN-191, RG7227) is a peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV) with IC50 of 0.2-3.5 nM, inhibition effect for HCV genotypes 1A/1B/4/5/6 is ~10-fold higher than 2B/3A. Phase 2.

Danoprevir (ITMN-191) Chemical Structure

CAS No. 850876-88-9

Selleck's Danoprevir (ITMN-191) has been cited by 14 publications

Purity & Quality Control

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HCV Protease Signaling Pathway Map

Biological Activity

Description

Features

A peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV).

Targets

HCV NS3/4A protease ^[1]

0.2 nM-3.5 nM

In vitro

Danoprevir (0.29 nM) inhibits the reference genotype 1 NS3/4A protease half-maximally, but a high dose of Danoprevir (10 μM) shows no appreciably inhibition in a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Danoprevir remains bound to and inhibits NS3/4A for more than 5 hours after its initial association. Danoprevir (45 nM) eliminates a patient-derived HCV genotype 1b replicon from hepatocyte-derived Huh7 cells with an EC50 of 1.8 nM. ^[1] In HCV subgenomic replicon cell lines containing the individual mutations, V36M, R109K, and V170A substitutions confer little or no resistance to Danoprevir, but the R155K substitution confers a high level (62-fold increase) of resistance to Danoprevir. ^[2] In Huh7.5 cells transfected with chimeric recombinant virus, Danoprevir shows antiviral inhibition effects against HCV genotypes 1, 4 and 6 with IC50 of 2-3 nM, which are >100-fold lower than genotypes 2/3/5 (280-750 nM). ^[3]

In vivo

Danoprevir (30 mg/kg) administered to rats or monkeys shows that its concentrations in liver 12 hours after dosing exceed the Danoprevir concentration required to eliminate replicon RNA from cells. ^[1]

Protocol (from reference)

Kinase Assay:^[1]	Continuous fluorescent resonance energy transfer (FRET) assay: The assay buffer contains 25 μM NS4A peptide, 50 mM Tris-HCl, pH 7.5, 15% (vol/vol) glycerol, 0.6 mM lauryldimethylamine N-oxide, 10 mM dithiothreitol, and 0.5 μM fluorescein/QXL520-labeled FRET substrate {Ac-DE-Dap(QXL520)-EE-Abu-ψ-[COO]-AS-Cys(5-FAMsp)-NH2}. K2040 enzyme (50 pM) is added to initiate the reaction. Reactions are set up in black 96-well plates, and fluorescence data is collected. Control reactions lacking inhibitors and enzyme are included. Initial rates are calculated from the linear phase of the reaction (up to 1 hour) and are used to obtain IC50. Recovery of activity from preformed Danoprevir-NS3/4A complex is assessed by preincubating 10 nM NS3/4A with a two-fold excess of Danoprevir in 1× assay buffer for 15 min, followed by a rapid 200-fold dilution of the preformed complex into assay buffer containing substrate. A control reaction with the same final conditions without preincubation of NS3/4A and Danoprevir is initiated by the addition of enzyme to an otherwise-complete reaction mixture. Additional control reactions lack either Danoprevir or NS3. The progress of the reactions is followed over 5 hours.
Cell Research:^[1]	Cell lines: Huh7 cells harboring HCV replicon Concentrations: 5 pM - 100 nM Incubation Time: 48 hours Method: Serially diluted Danoprevir is added to Huh7 cells harboring the K2040 replicon 1 day after cell plating. For antiviral assays, after a 48-hour incubation, intracellular RNA is extracted, and the level of HCV replicon RNA is quantified by reverse transcription (RT)-PCR assay with the primers (5'-CACTCCCCTGTGAGGAACTACTG-3' and 5'-AGGCTGCACGACACTCATACT-3') and a probe (5'-6-FAM-CTTCACGCAGAAAGCGTCTAGCCATGG-MGBNFQ-3' using an ABI Prism 7900 sequence detection system. Here, FAM is 6-carboxyfluorescin and MGBNFQ is a molecular-groove binding non-fluorescence quencher specific to the HCV 5' untranslated region. Single-tube reactions are performed using the TaqMan Gold RT-PCR kit. Triplicate reactions for the RNA standards and samples are performed in 50 μL with 5 μL intracellular RNA (50 ng). RT is carried out at 48 °C for 30 min followed by 10 min at 95 °C. The PCR is run as follows: 15 seconds at 95 °C and 1 min at 60 °C for 40 cycles. Each RNA concentration is determined in triplicate. The absolute concentration of replicon RNA is calculated based on its signal relative to that of a standard curve generated by known concentrations of an in vitro-transcribed RNA corresponding to a genotype 1b 5' untranslated region. Replicon levels in the presence of Danoprevir are fitted to a four-parameter logistic function to obtain EC50.
Animal Research:^[1]	Animal Models: Sprague-Dawley rats, Cynomolgus monkeys Dosages: 30 mg/kg Administration: Oral gavage

References

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight	731.83
Formula	C₃₅H₄₆FN₅O₉S
CAS No.	850876-88-9
Storage	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
Smiles	CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(NC(=O)C3CC(CN3C1=O)OC(=O)N4CC5=C(C4)C(=CC=C5)F)C(=O)NS(=O)(=O)C6CC6

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In vivo Formulation Calculator (Clear solution)

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Clinical Trial Information

NCT Number	Recruitment	Interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT01714154	Completed	Drug: danoprevir\|Drug: ritonavir\|Drug: setrobuvir	Healthy Volunteer	Hoffmann-La Roche	November 2012	Phase 1
NCT01592318	Completed	Drug: danoprevir\|Drug: ritonavir	Healthy Volunteer	Hoffmann-La Roche	May 2012	Phase 1
NCT01588002	Completed	Drug: danoprevir\|Drug: efavirenz\|Drug: ritonavir	Healthy Volunteer	Hoffmann-La Roche	April 2012	Phase 1
NCT01519336	Completed	Drug: danoprevir\|Drug: darunavir\|Drug: ritonavir	Healthy Volunteer	Hoffmann-La Roche	February 2012	Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

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