Raltegravir (MK-0518)

Catalog No.S2005

Raltegravir (MK-0518) Chemical Structure

Molecular Weight(MW): 444.42

Raltegravir (MK-0518) is a potent integrase (IN) inhibitor for WT and S217Q PFV IN with IC50 of 90 nM and 40 nM in cell-free assays, respectively. It shows greater than 1000-fold selectivity for HIV-1 IN over several related Mg2+-dependent enzyme such as HCV polymerase, HIV reverse transcriptase, HIV RNaseH and human α-, β-, γ-polymerases.

Size Price Stock Quantity  
In DMSO USD 210 In stock
USD 120 In stock
USD 210 In stock
USD 670 In stock
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2 Customer Reviews

  • a: HCV, hepatitis C virus; HBV, hepatitis B virus. B: PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; IN, integrase inhibitor. c: n=3. d: The EC50 for samatasvir in the presence of 45% human serum was 25 pM.

    Antimicrob Agents Chemother, 2014, 58(8): 4431-42. Raltegravir (MK-0518) purchased from Selleck.

    Vet Microbiol 2011 152(1-2), 165-8. Raltegravir (MK-0518) purchased from Selleck.

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Biological Activity

Description Raltegravir (MK-0518) is a potent integrase (IN) inhibitor for WT and S217Q PFV IN with IC50 of 90 nM and 40 nM in cell-free assays, respectively. It shows greater than 1000-fold selectivity for HIV-1 IN over several related Mg2+-dependent enzyme such as HCV polymerase, HIV reverse transcriptase, HIV RNaseH and human α-, β-, γ-polymerases.
Features The 1st approved human immunodeficiency virus type 1 (HIV-1) integrase inhibitor.
Targets
Integrase (S217Q PFV) [1]
(Cell-free assay)
Integrase (WT PFV) [1]
(Cell-free assay)
40 nM 90 nM
In vitro

PFV IN carrying the S217H substitution is 10-fold less susceptible to Raltegravir with IC50 of 900 nM. PFV IN displays 10% of WT activity and is inhibited by Raltegravir with an IC50 of 200 nM, indicating a ~twofold decrease in susceptibility to the IN strand transfer inhibitor (INSTI) compared with WT IN. S217Q PFV IN is as sensitive to Raltegravir as the WT enzyme. [1] Raltegravir is metabolized by glucuronidation, not hepatically. Raltegravir has potent in vitro activity against HIV-1, with a 95% inhibitory concentration of 31?0 nM, in human T lymphoid cell cultures. Raltegravir is also active against HIV-2 when Raltegravir is tested in CEMx174 cells, with an IC95 of 6 nM. Raltegravir metabolism occurs primarily through glucuronidation. Drugs that are strong inducers of the glucuronidation enzyme, UGT1A1, significantly reduce Raltegravir concentrations and should not be used. Raltegravir exhibits weak inhibitory effects on hepatic cytochrome P450 activity. Raltegravir does not induce CYP3A4 RNA expression or CYP3A4-dependent testosterone 6-β-hydroxylase activity. [2] Raltegravir cellular permeativity is reduced in the presence of magnesium and calcium. [3] Raltegravir and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs efficiently block viral replication. [4] In acutely infected human lymphoid CD4+ T-cell lines MT-4 and CEMx174, SIVmac251 replication is efficiently inhibited by Raltegravir, which shows an EC90 in the low nanomolar range. [5]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human MT4 cells MVLGeY5kfGmxbjDhd5NigQ>? M4DzOmFvfGm4aYLhcEBi[3Srdnn0fUBi\2GrboP0JGh2dWGwIHntcZVvd2SnZnnjbYVv[3lidnnyeZMhOSB|QjDpcoZm[3SnZDDpckBpfW2jbjDNWFQh[2WubIOgZZN{\XO|ZXSgZZMhcW6qaXLpeIlwdiCxZjD2bZJidCC{ZYDsbYNifGmxbjygSWM2OD1zLkSgcm0> Ml21NVg2PDF5Mk[=
human HOS cells M4q5bWZ2dmO2aX;uJIF{e2G7 NFOzPVdCdnSrdnnyZYwh[WO2aY\peJkh[WejaX7zeEBJUVZzIHjhdoJwemmwZzD3bYxlNXS7cHWgbY51\We{YYPlJIlv\mWldHXkJIlvKGi3bXHuJGhQWyClZXzsd{whTUN3ME20JI5O M2DlelIyPDl|ME[2
human MT2 cells NFn2N2ZHfW6ldHnvckBie3OjeR?= NFPZT3A2KGSjeYO= MUPBcpRqfmm{YXygZYN1cX[rdImgZYdicW6|dDDITXYyKDOEIHnu[oVkfGWmIHnuJIh2dWGwIF3UNkBk\WyuczDh[pRmeiB3IHThfZMh[nliY3jlcYltfW2rbnXzZ4Vv[2ViaX6gdJJme2WwY3Wgc4Yh\mW2YXygZo93cW6nIIPldpVuNCCHQ{WwQVQhdk1? MVKxPVI5PTN6OR?=
human HeLa cells MYLGeY5kfGmxbjDhd5NigQ>? M{\GSVQ5KGh? M3TiU2FvfGm4aYLhcEBi[3Srdnn0fUBi\2GrboP0JHZUXi2JIIDz[ZVld3S7cHXkJGhKXjFibHXueIl3cXKjbDDwZZJ1cWOuZYOgbY5n\WO2ZXSgbY4hcHWvYX6gTIVN[SClZXzsd{BqdmO3YnH0[YQh\m:{IES4JIhzeyCkeTDzdIVkfHKxZnz1c5JwdWW2comsJGlEPTB;MUCgcm0> MoTONlI5PTh|MEC=

... Click to View More Cell Line Experimental Data

In vivo Raltegravir induces viro-immunological improvement of nonhuman primates with progressing SIVmac251 infection. One non-human primate shows an undetectable viral load following Raltegravir monotherapy. [5]

Protocol

Kinase Assay:

[1]

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PFV integration assay:

For quantitative strand transfer assays, donor DNA substrate is formed by annealing HPLC grade oligonucleotides 5′-GACTCACTATAGGGCACGCGTCAAAATTCCATGACA and 5′-ATTGTCATG GAATTTTGACGCGTGCCCTATAGTGAGTC. Reactions (40 μL) contains 0.75 μM PFV IN, 0.75 μM donor DNA, 4 nM (300 ng) supercoiled pGEM9-Zf(−) target DNA, 125 mM NaCl, 5 mM MgSO4, 4 μM ZnCl2, 10 mM DTT, 0.8% (vol/vol) DMSO, and 25 mM BisTris propane–HCl, pH 7.45. Raltegravir is added at indicated concentrations. Reactions are initiated by addition of 2 μL PFV IN diluted in 150 mM NaCl, 2 mM DTT, and 10 mM Tris-HCl, pH 7.4, and stopped after 1 hour at 37 °C by addition of 25 mM EDTA and 0.5% (wt/vol) SDS. Reaction products, deproteinized by digestion with 20 μg proteinase K for 30 minutes at 37 °C followed by ethanol precipitation, are separated in 1.5% agarose gels and visualized by staining with ethidium bromide. Integration products are quantified by quantitative real-time PCR, using Platinum SYBR Green qPCR SuperMix and three primers: 5′-CTACTTACTCTAGCTTCCCGGCAAC, 5′-TTCGCCAGTTAATAGTTTGCGCAAC, and 5′-GACTCACTATAGGGCACGCGT. PCR reactions (20 μL) contained 0.5 μM of each primer and 1 μL diluted integration reaction product. Following a 5-min denaturation step at 95 °C, 35 cycles are carried out in a CFX96 PCR instrument, using 10 seconds denaturation at 95 °C, 30 seconds annealing at 56 °C and 1 minutes extension at 68 °C. Standard curves are generated using serial dilutions of WT PFV IN reaction in the absence of INSTI.
Cell Research:

[5]

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  • Cell lines: Human MT-4 cells
  • Concentrations: 0.0001-1 μM
  • Incubation Time: 5 days
  • Method:

    Human MT-4 cells are infected for 2 hours with the SIVmac251, HIV-1 (IIIB) and HIV-2 (CDC 77618) stocks at a multiplicity of infection of, approximately, 0.1. Cells are then washed three times in phosphate buffered saline, and suspended at 5 × 105/mL in fresh culture medium (to primary cells 50 units/mL of IL-2 are added) in 96-well plates, in the presence or absence of a range of triplicate raltegravir concentrations (0.0001 μM -1 μM). Untreated infected and mock-infected controls are prepared too, in order to allow comparison of the data derived from the different treatments. Viral cytopathogeniciy in MT-4 cells is quantitated by the methyl tetrazolium (MTT) method (MT-4/MTT assay) when extensive cell death in control virus-infected cell cultures is detectable microscopically as lack of capacity to re-cluster. The capability of MT-4 cells to form clusters after infection. Briefly, clusters are disrupted by pipetting; and, after 2 hours of incubation at 37 °C, the formation of new clusters is assessed by light microscopy (100 × magnification). Cell culture supernatants are collected for HIV-1 p24 and HIV-2/SIVmac251 p27 core antigen measurement by ELISA. In CEMx174-infected cell cultures, which show a propensity to form syncytia induced by the virus envelope glycoproteins, syncytia are counted, in blinded fashion, by light microscopy for each well at 5 days following infection.


    (Only for Reference)

Solubility (25°C)

In vitro DMSO 88 mg/mL (198.01 mM)
Water slightly soluble or insoluble
Ethanol slightly soluble or insoluble
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 Information

Molecular Weight 444.42
Formula

C20H21FN6O5

CAS No. 518048-05-0
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01867320 Recruiting HTLV-I Infection National Institute of Neurological Disorders and Stroke (NINDS)|National Institutes of Health Clinical Center (CC) May 6, 2013 Early Phase 1
NCT02437110 Enrolling by invitation Amyotrophic Lateral Sclerosis National Institute of Neurological Disorders and Stroke (NINDS)|National Institutes of Health Clinical Center (CC) April 23, 2015 Phase 1
NCT02655471 Not yet recruiting HTLV-I Infections|Tropical Spastic Paraparesis Universidad Peruana Cayetano Heredia|Merck Sharp & Dohme Corp. March 2016 Early Phase 1
NCT02150993 Recruiting HIV-2 Infection French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS) January 2016 Phase 2|Phase 3
NCT02336074 Recruiting HIV Imperial College London|Medical Research Council|University of Oxford|University of Cambridge|Chelsea and Westminster NHS Foundation Trust|Royal Free Hospital NHS Foundation Trust|Brighton and Sussex University Hospitals NHS Trust|Guys and St Thomas NHS Foundation Trust|Central and North West London NHS Foundation Trust November 2015 Phase 2
NCT02577042 Recruiting Aging-related Inflammation in HIV-infected Patients Fundacio Lluita Contra la SIDA October 2015 Phase 4

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID