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Maraviroc

MCE China：Maraviroc

Brand：MedChemExpress (MCE)

Cat. No.HY-13004

CAS：376348-65-1

Synonyms：UK-427857

Purity：99.88%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month

Shipping：Room temperature in continental US; may vary elsewhere.

Description：Maraviroc (UK-427857) is a selective CCR5 antagonist with activity against human HIV.

In Vitro：Maraviroc (UK-427857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity. Maraviroc inhibits the downstream event of chemokine-induced intracellular calcium redistribution, with IC50s ranging from 7 to 30 nM obtained against MIP-1β, MIP-1α and RANTES.Maraviroc (UK-427857) is active (IC90) at low nanomolar concentrations against HIV-1 Ba-L (a lab-adapted R5 strain) when measured in a 5-day antiviral assay using either isolated multiple (pooled) donor PBMC (IC90, 3.1 nM), single-donor PBMC (IC90, 1.8 nM) or PM-1 cells (IC90, 1.1 nM)[1].

In Vivo：Clearance values are moderate to high in both rat and dog species following i.v. administration (74 and 21 mL/min/kg, respectively). Maraviroc also has a moderate volume of distribution in both species (4.3 to 6.5 liters/kg). The half-life values of maraviroc are 0.9 h in the rat and 2.3 h in the dog. Following oral administration (2 mg/kg) to the dog, the Cmax(256 ng/mL) occurs 1.5 h. post-dose, and the bioavailability is 40%. For the rat, investigation of the concentrations obtain in the portal vein following oral administration indicated that approximately 30% of the administered dose is absorbed from the intestinal tract[1]. In the DSS/TNBS colitis and in the transfer model, Maraviroc attenuates development of intestinal inflammation by selectively reducing the recruitment of CCR5 bearing leukocytes[2]

Animal Administration：Rats and Dogs[1] Preclinical pharmacokinetic studies are carried out with maraviroc following a single intravenous and oral administration to both male Sprague-Dawley rats (1 mg/kg of body weight given intravenously [i.v.] and 10 mg/kg given orally [p.o.]; n=2) and male beagle dogs (0.5 mg/kg i.v. and 2 mg/kg p.o; n=4). Plasma samples are taken for up to 24 h postdose, and the concentrations of unchanged maraviroc are determined using a specific high-performance liquid chromatography-tandem mass spectrum assay. Mice[2] Splenocytes are collected from 6-10 week old CCR5-/- mice or wild-type controlmice (n=8 per group) and naive CD4+ CD45RBhigh T-cells are isolated by cell sorting. A total of 3×105 CD45RBhigh cells are then injected intravenously into Rag1-/- mice that are subsequently weighed and assessed for fecal score every 20 days to evaluate IBD development. To investigate whether Maraviroc rescues from intestinal inflammation induced by transfer colitis, Rag1-/- mice are injected with CD4+ CD45RB-/- T-cells and 34 days later randomized into either a control group (no further treatment, n=6) or treatment with Maraviroc, 50 mg/kg/d Maraviroc per os (n=4) for 3 weeks, 5 d/week.

Cell Assay：HEK-293 cell aliquots (100 μL at 1×106 cells/mL) are plated into poly-D-lysine-coated plates and incubated at 37°C overnight. A 1:1 mix of soluble recombinant human CD4 (sCD4) (diluted to 4.5 nM in culture medium) and HIV-1 gp120 is incubated at room temperature for 15 min prior to its addition to PBS-washed cells in the presence of dilutions of maraviroc to enable IC50 determination. The assay plates are incubated at 37°C for 1 h and washed. Eu3+-labeled anti-gp120 antibody (1/500 dilution in assay buffer) is added to each well (50 μL) and incubated for 1 h. The plate is washed three times with wash buffer prior to the addition of enhancement solution (200 μL/well) and measurement of Eu3+ fluorescence (Victor2multilabel counter; “Europium” protocol). Nonspecific binding is taken as the fluorescence measured for gp120 incubated with cells in the absence of preincubation with sCD4[1].

Kinase Assay：Binding of 125I-labeled MIP-1α, MIP-1β, and RANTES to CCR5 is measured essentially using intact HEK-293 cells stably expressing the receptor or membrane preparations thereof. Briefly, cells are resuspended in binding buffer (50 mM HEPES containing 1 mM CaCl2, 5 mM MgCl2, and 0.5% bovine serum albumin [BSA] and adjusted to pH 7.4) to a density of 2×106 cells/mL. For membrane preparations, phosphate-buffered saline (PBS)-washed cells are resuspended in lysis buffer (20 mM HEPES, 1 mM CaCl2, 1 tablet COMPLETE per 50 mL, pH 7.4; Boehringer) prior to homogenization in a Polytron hand-held homogenizer, ultracentrifugation (40,000× g for 30 min), and resuspension in binding buffer to a protein concentration of 0.25 mg/mL (12.5 μg of membrane protein is used in each well of a 96-well plate). 125I-radiolabeled MIP-1α, MIP-1β, and RANTES are prepared and diluted in binding buffer to a final concentration of 400 pM in the assay. Appropriate maraviroc dilutions are added to each well to a final volume of 100 μL, the assay plates incubated for 1 h, and the contents filtered through preblocked and washed Unifilter plates which are counted following overnight drying[1].

IC50 & Target：MIP-1α-CCR5 3.3 nM (IC50, in HEK-293 cell membrane) RANTES-CCR5 5.2 nM (IC50, in HEK-293 cell membrane) MIP-1β-CCR5 7.2 nM (IC50, in HEK-293 cell membrane) HIV-1 (Ba-L) 1.1 nM (IC50, in PM-1 cells)

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References：

[1]. Dorr P, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005 Nov;49(11):472  [Content Brief]

[2]. Mencarelli A, et al. Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis. Sci Rep. 2016 Aug 5;6:30802.  [Content Brief]

[3]. Romero-Sánchez MC, et al. Effect of maraviroc on HIV-disease progression-related biomarkers. Antimicrob Agents Chemother. 2012 Nov;56(11):5858-64.  [Content Brief]

[4]. Huilin Mou, et al. NRSF and CCR5 Established Neuron-glia Communication during Acute and Chronic Stresses. Journal of Drug Metabolism & Toxicology. January 10, 2016.