Lersivirine (UK-453061)

For research use only.

Catalog No.S8055

Lersivirine (UK-453061) Chemical Structure

CAS No. 473921-12-9

Lersivirine (UK-453061) is a potent and selective inhibitor of nonnucleoside reverse transcriptase (NNRTI) with IC50 of 0.119 μM.

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Biological Activity

Description Lersivirine (UK-453061) is a potent and selective inhibitor of nonnucleoside reverse transcriptase (NNRTI) with IC50 of 0.119 μM.
Targets
NNRT [2]
()
In vitro

Lersivirine binds to HIV-1 wt reverse transcriptase (RT) with Kd of 624 nM. Lersivirine is a very weak inhibitor of human DNA polymerase beta, with an extrapolated geometric mean IC50 of approximately 20 mM resulting in a predicted selectivity index of 166,000. Lersivirine is able to inhibit HIV-1 virus replication in MT-2 cells infected with wt NL4-3, with an EC50 ranging from 5 nM to 35 nM against an MOI ranging from 0.005 to 0.5. Lersivirine retains activity against 80% of viruses with genotypes containing K103N as a single NNRTI mutation (versus 7% for efavirenz), 57% of viruses with genotypes containing Y181C as a single NNRTI mutation (43% for efavirenz), and 46% of viruses with genotypes containing G190A as a single NNRTI mutation (0% for efavirenz). Lersivirine inhibits the replication of strain Ba-L in PBL, with a geometric mean EC50 equal to 3.38 nM (95% CI, 2.26 to 5.05 nM) and an EC90 equal to 9.87 nM (95% CI, 6.63 to 14.7 nM), with no cytotoxicity observed up to 50 μM. Combinations of lersivirine with drugs of the NRTI class (abacavir, didanosine, emtricitabine, lamivudine, tenofovir, and zidovudine) results in synergistic interactions. [1]

In vivo

Lersivirine is not teratogenic in mice.[3]

Protocol

Kinase Assay:

[1]

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RT enzyme assays:

The activities of lersivirine and efavirenz against wt RT (BH10 strain) are determined using a primer extension assay incorporating a DNA/RNA primer/template. The 5’biotinylated primer DNA is a 16mer oligo(dT), which is annealed to a poly(rA) template of approximately 300 bases in length. Incorporation of [3H]TTP(dTTP) by reverse transcription results in extension of the primer. During the reaction the primer/template is bound to a streptavidin-coated flashplate (NEN). The incorporated tritiated nucleotides can then stimulate the scintillant to produce a signal that is measured using a scintillation counter. Compounds that inhibit the RNA-dependent DNA polymerase activity of RT produce a reduced signal.
Cell Research:

[1]

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  • Cell lines: SupT1 cells
  • Concentrations: increasing concentrations from 5 nM
  • Incubation Time: Every 7 days
  • Method:

    For inhibitor escalation studies, SupT1 cells are initially infected with HIV-1 NL4-3 wt for 1 h at 37°C and the virus-infected cells are passaged weekly in SupT1 cells in the presence of increasing concentrations of lersivirine from a starting concentration of 5 nM (IC50 in this assay system) in 12-well plates (6 × 105 cells/well). Throughout the passaging period, ongoing virus replication is monitored weekly by observing cytopathic effects (syncytia). Every 7 days, virus supernatant is passaged onto fresh cells at the same density with fresh lersivirine-containing medium. The concentration of lersivirine is increased by 2-fold and 5-fold that of the previous concentration upon subsequent passage whenever evidence of viral replication is observed. Virus stocks for phenotypic characterization are produced in SupT1 cells in the absence of compound and are tested for their sensitivity to lersivirine in an antiviral assay using HeLaP4 cells.


    (Only for Reference)
Animal Research:

[3]

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  • Animal Models: Mated Crl:CD1(ICR) mice
  • Dosages: 150 mg/kg, 350 mg/kg, 500 mg/kg
  • Administration: Oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 62 mg/mL (199.77 mM)
Water Insoluble
Ethanol '''62 mg/mL

* 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 Information

Molecular Weight 310.35
Formula

C17H18N4O2

CAS No. 473921-12-9
Storage powder
in solvent
Synonyms N/A
Smiles CCC1=C(C(=NN1CCO)CC)OC2=CC(=CC(=C2)C#N)C#N

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01220232 Completed Drug: Abacavir/Lamivudine|Drug: Lersivirine Healthy Volunteers Pfizer|ViiV Healthcare November 2010 Phase 1
NCT01230385 Completed Drug: Lersivirine Healthy Volunteers Pfizer|ViiV Healthcare October 2010 Phase 1
NCT00925535 Completed Drug: Lersivirine|Drug: Rifabutin Healthy Volunteers Pfizer May 2010 Phase 1
NCT01050751 Completed Drug: Lersivirine Healthy Volunteers Pfizer February 2010 Phase 1

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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Reverse Transcriptase Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID