Telaprevir (VX-950)

Telaprevir (VX-950) is an HCV NS3-4A serine protease inhibitor with IC50 of 0.35 μM.

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Telaprevir (VX-950) Chemical Structure

Telaprevir (VX-950) Chemical Structure
Molecular Weight: 679.85

Validation & Quality Control

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Quality Control & MSDS

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Product Information

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Product Description

Biological Activity

Description Telaprevir (VX-950) is an HCV NS3-4A serine protease inhibitor with IC50 of 0.35 μM.
Targets HCV NS3-4A serine protease [1]
IC50 0.35 μM
In vitro Telaprevir inhibits the hepatitis C virus NS3-4A serine protease, leading to the block of viral polyprotein processing and subsequently decrease of viral RNA replication, total HCV RNA levels and protein levels in the Con1 (genotype 1b) subgenomic HCV replicon cells in a time- and dose-dependent manner. Telaprevir displays a significant time-dependent increase in inhibitory effect on the replication of HCV RNA with IC50 values of 0.574 μM, 0.488 μM, 0.210 μM and 0.139 μM for 24, 48, 72 and 120 hours incubation, respectively. Telaprevir displays an average IC50 of 0.354 μM and an average IC90 of 0.830 μM, respectively, from three independent experiments using the 48 hours incubation. Telaprevir has no significant cytotoxicity to HCV replicon cells, parental Huh-7 and HepG2 cells after 48 hours incubation. Telaprevir (17.5 μM) completely eradicates HCV RNA from replicon cells after 13 days incubation without rebound after Telaprevir is withdrawn. Telaprevir displays an additive to moderate synergistic effect on reduction of HCV RNA replication and suppression of resistance mutations without significant increase in cytotoxicity when in combination with IFN-α, compared to treatment with each agent alone. [1]
In vivo Oral administration of Telaprevir reduces HCV protease-dependent cleavage and subsequent secretion of SEAP from the liver into the blood in the mice model to 18.7% and 18.4% at dosage of 10 and 25 mg/kg, respectively. [2] Administration of Telaprevir at 200 mg/kg for 1 week results in a 1.9 log reduction of HCV RNA in genotype 1b HCV-infected human hepatocyte chimeric mice, and when treatment in combination with MK-0608 (50 mg/kg) for 4 weeks, viruses are eliminated from mice. [3]
Features Telaprevir is a covalent, reversible inhibitor of the NS3-4A protease (unlike BILN 2061which is a noncovalent inhibitor), with a slow-binding and slow-dissociation mechanism.

Protocol(Only for Reference)

Kinase Assay: [1]

Determination of anti-HCV activity Stable Huh-7 cells containing the self-replicating, subgenomic HCV replicon, which is identical in sequence to the I377neo/NS3-3'/wt replicon are used for anti-HCV assays. Replicon cells are incubated at 37 °C for the indicated period of time with Telaprevir serially diluted in DMEM plus 2% FBS and 0.5% dimethyl sulfoxide (DMSO). Total cellular RNA is extracted using an RNeasy-96 kit, and the copy number of HCV RNA is determined using a quantitative RTPCR (QRT-PCR) assay for the assessment of 50% inhibitory concentration (IC50

Cell Assay: [1]

Cell lines Huh-7, HepG2, and peripheral blood mononuclear cells (PBMC)
Concentrations Dissolved in DMSO, final concentration ~1 mM
Incubation Time 48 hours
Method Cells are incubated with various concentrations of Telaprevir for 48 hours. Cell viability is determined by using a tetrazolium (MTS)-based cell viability assay.

Animal Study: [2]

Animal Models SCID mice injected with recombinant adenovirus (Ad-WT-HCVpro-SEAP or Ad-MT-HCVpro-SEAP)
Formulation Formulated in polyvinylpyrrolidone (PVP) K-30 plus 2% sodium lauryl sulfate
Dosages ~300 mg/kg
Administration Oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Lin K, et al. Antimicrob Agents Chemother, 2006, 50(5), 1813-1822.

[2] Perni RB, et al. Antimicrob Agents Chemother, 2006, 50(3), 899-909.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-06-27)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02333292 Recruiting Chronic Hepatitis C Infection Valme University Hospital December 2014 --
NCT02087111 Not yet recruiting Hepatitis C Queen Mary University of London|Janssen-Cilag Ltd.|Barts  ...more Queen Mary University of London|Janssen-Cilag Ltd.|Barts & The London NHS Trust|St Georges Healthcare NHS Trust|Bradford Teaching Hospitals NHS Foundation Trust|Nottingham University Hospitals NHS Trust April 2014 Phase 4
NCT02006745 Recruiting HIV St Stephens Aids Trust January 2014 Phase 3
NCT01994486 Completed Hepatitis C, Chronic University of Florida|Vertex Pharmaceuticals Incorporated December 2013 Phase 2
NCT01890772 Withdrawn Hepatitis C Timothy Morgan, MD|Vertex Pharmaceuticals Incorporated|So  ...more Timothy Morgan, MD|Vertex Pharmaceuticals Incorporated|Southern California Institute for Research and Education August 2013 Phase 2|Phase 3

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Chemical Information

Download Telaprevir (VX-950) SDF
Molecular Weight (MW) 679.85
Formula

C36H53N7O6

CAS No. 402957-28-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms LY-570310, MP-424
Solubility (25°C) * In vitro DMSO 136 mg/mL (200.04 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)-octahydrocyclopenta[c]pyrrole-1-carboxamide

Customer Product Validation (4)


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Rating
Source Antimicrob Agents Chemother 2014 10.1128/AAC.04220-14. Telaprevir (VX-950) purchased from Selleck
Method Crystal violet
Cell Lines HCV replicon genotype 1b cells
Concentrations 0.6, 1.5, 3, 6 uM
Incubation Time 28 days
Results The presence of miravirsen resulted in the decrease in the rate of cell expansion and a reduction in HCV RNA without the emergence of distinct clonal populations following the initial 25 days of passage at concentrations up to 20-fold the average EC50 (10 uM). In contrast, selection in the presence of telaprevir resulted in the decrease in the rate of cell expansion with the appearance of distinct individual resistant clonal populations.

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Rating
Source Virology 2013 435(2), 385-94. Telaprevir (VX-950) purchased from Selleck
Method Coimmunoprecipitation analysis
Cell Lines 293 cells
Concentrations 0.2 mM
Incubation Time 1 days
Results These results suggest that DDB1 is a bona fide cellular substrate of NS3/4A. To confirm that DDB1 is cleaved by NS3/4A protease activity, we constructed a N-terminal and a C-terminal Flag-tagged DDB1 expression plasmid respectively. We found that NS3/4A cleavage resulted in a ~45 kDa N-terminal fragment and a ∼82 kDa C-terminal fragment. The added molecular size of these two fragments is consistent with the expected size of 127 kDa of the full-length DDB1. The cleavage of DDB1 by NS3/4A was inhibited by the NS3/4A inhibitor VX-950.

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Rating
Source PLoS One 2013 8(12), e82094. Telaprevir (VX-950) purchased from Selleck
Method CBB staining
Cell Lines HCV replicon genotype 1b cells
Concentrations 0-500 uM
Incubation Time 28 days
Results It tested the effect of VX950, a specific inhibitor of NS3/4A protease, on C4 cleavage by NS3/4A protease and inhibition of complement activation. As shown in Figure, under a condition in which more than 80% of 32-kDa C4γ was processed into 17- and 15-kDa fragments in the presence of NS3/4A protease (lanes 5), pretreatment of the protease with 1 uM VX950 moderately inhibited the cleavage of C4γ (lanes 4). The NS3/4A-mediated processing of C4γ into 17- and 15-kDa fragments was almost completely blocked by VX950 at ≥10 uM (lanes 1-3).

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Source 2011 Dr. Julie Sheldon,Dr Esteban Domingo and Dr Celia Perales. Telaprevir (VX-950) purchased from Selleck
Method MTT assays
Cell Lines
Concentrations 50 μM
Incubation Time 72 h
Results The 50% cytotoxic concentration (CC50) of VX-950 was 22 ± 3.2 μM.

Product Use Citation (10)

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