product name Dolutegravir (GSK1349572)
Description: Dolutegravir (also known as GSK1349572, S/GSK1349572) is a novel and potent two-metal-binding HIV integrase inhibitor with IC50 of 2.7 nM in a cell-free assay, it demonstrated modest activity against raltegravir-resistant signature mutants Y143R, Q148K, N155H, and G140S/Q148H. It is used for the treatment of HIV-infected adults who have never received any HIV therapy (treatment-naïve) and HIV-infected adults who have previously taken HIV therapy (treatment-experienced).
References: AIDS. 2010 Nov 13;24(17):2753-5; Antimicrob Agents Chemother. 2011 Feb;55(2):813-21.
419.38
Formula
C20H19F2N3O5
CAS No.
1051375-16-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 83 mg/mL (197.9 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
S/GSK1349572
other peoduct :
| In Vitro |
In vitro activity: S/GSK1349572 shows the potent inhibitory effect on nine clinical isolates from integrase inhibitor-naive HIV-2-infected patients with EC50 ranging from 0.2 nM -1.4 nM. In vitro, S/GSK1349572 inhibits recombinant HIV-1 integrase-catalyzed strand transfer with IC50 of 2.7 nM. Furthermore, S/GSK1349572 potently inhibits HIV replication in cells such as peripheral blood mononuclear cells (PBMCs), MT-4 cells and CIP4 cells infected with a self-inactivating PHIV lentiviral vector with EC50 of 0,51 nM, 0.71 nM and 2.2 nM, respectively. In vitro, S/GSK1349572 exhibits potent activity against five different nonnucleoside reverse transcription inhibitor–resistant or nucleoside reverse transcription inhibitor–resistant viruses with EC50 ranging from 1.3 nM -2.1 nM. Similarly to that against wild-type virus, S/GSK1349572 shows equivalent activity against two protease inhibitor-resistant viruses with EC50 of 0.36 nM and 0.37 nM, respectively. Kinase Assay: The inhibitory potencies of S/GSK1349572 and other INIs are measured in a strand transfer assay using recombinant HIV integrase. A complex of integrase and biotinylated preprocessed donor DNA-streptavidin-coated Acintillation proximity assay (SPA) beads is formed by incubating 2 μM purified recombinant integrase with 0.66 μM biotinylated donor DNA-4 mg/mL streptavidin-coated SPA beads in 25 mM sodium morpholinepropanesulfonic acid (MOPS) (pH 7.2), 23 mM NaCl, and 10 mM MgCl2 for 5 minutes at 37 °C. These beads are spun down and preincubated with diluted INIs for 60 minutes at 37 °C. Then a 3H-labeled target DNA substrate is added to give a final concentration of 7 nM substrate, and the strand transfer reaction mixture is incubated at 37 °C for 25 to 45 minutes, which allows for a linear increase in the strand transfer of donor DNA to radiolabeled target DNA. The signal is read using a Wallac MicroBeta scintillation plate reader. Cell Assay: MT-4 cells growing exponentially at a density of 500000 or 600000 /mL are infected with HIV-1 strain IIIB at a viral multiplicity of infection of 0.001 or a 50% tissue culture infective dose of 4 to 10. The cells are then aliquoted to 96-well plates in the presence of varying concentrations of S/GSK1349572. After incubation for 4 or 5 days, antiviral activity is determined by a cell viability assay that either measured bioluminescence with a CellTiter-Glo luminescent reagent or measured absorbance at 560 and 690 nm using the yellow tetrazolium MTT reagent [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide]. |
|---|---|
| In Vivo | In C57BL/6 mice, S/GSK1349572 significantly increases serum creatinine, which is consistent with integrase inhibitors competitively inhibiting creatinine secretion. |
| Animal model | C57BL/6 mice |
| Formulation & Dosage | 2.7 mg/kg/day; administrated orally for two weeks. |
| References | AIDS. 2010 Nov 13;24(17):2753-5; Antimicrob Agents Chemother. 2011 Feb;55(2):813-21; Antivir Chem Chemother. 2015 Apr;24(2):72-6. |
