Home Microbiology Reverse Transcriptase inhibitor Lersivirine (UK-453061) For research use only.

Lersivirine (UK-453061)

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

Lersivirine (UK-453061) Chemical Structure

Lersivirine (UK-453061) Chemical Structure

CAS No. 473921-12-9

Purity & Quality Control

Lersivirine (UK-453061) Related Products

Signaling Pathway

Reverse Transcriptase Signaling Pathways

Reverse Transcriptase Signaling Pathway

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
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]
Kinase Assay 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 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.
In Vivo
In vivo

Lersivirine is not teratogenic in mice.[3]
Animal Research Animal Models Mated Crl:CD1(ICR) mice
Dosages 150 mg/kg, 350 mg/kg, 500 mg/kg
Administration Oral gavage
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01220232 Completed
Healthy Volunteers
Pfizer|ViiV Healthcare
 November 2010 Phase 1
NCT01230385 Completed
Healthy Volunteers
Pfizer|ViiV Healthcare
 October 2010 Phase 1
NCT00925535 Completed
Healthy Volunteers
Pfizer
 May 2010 Phase 1
NCT01050751 Completed
Healthy Volunteers
Pfizer
 February 2010 Phase 1

Chemical Information & Solubility

Molecular Weight 310.35 Formula

C17H18N4O2
CAS No. 473921-12-9 SDF --
Smiles CCC1=C(C(=NN1CCO)CC)OC2=CC(=CC(=C2)C#N)C#N
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 62 mg/mL ( (199.77 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 62 mg/mL

Water : Insoluble


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In vivo
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Tech Support

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.

Handling Instructions

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