S/GSK1349572 (GSK1349572, Dolutegravir) is a novel potent inhibitor of HIV integrase with an IC50 of 2.7 nM in vitro. Dolutegravir (DTG, GSK1349572) is metabolized primarily by uridine diphosphate glucuronyltransferase (UGT)1A1, with a minor role of cytochrome P450 (CYP)3A, and with renal elimination of unchanged compound being extremely low (< 1% of the dose). S/GSK1349572 is a next generation integrase inhibitor (INI) with low nM potency. Susceptibility to S/GSK1349572 and raltegravir (RAL) was determined for INI resistant clinical isolates from therapy experienced patients treated with RAL plus optimized background regimen.
|Cell lines||MT-4 cells|
|Preparation method||Antiviral assay in MT-4 cells. MT-4 cells growing exponentially at a density of 5 × 105 or 6 × 105/ml were 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 were then aliquoted to 96-well plates in the presence of varying concentrations of compounds. After incubation for 4 or 5 days, antiviral activity was determined by a cell viability assay that either measured bioluminescence with a CellTiter-Glo luminescent reagent (Promega Corporation, Madison, WI) or measured absorbance at 560 and 690 nm using the yellow tetrazolium MTT reagent [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide].|
|Concentrations||0.16, 0.8, 4, 20nM|
|Incubation time||4 or 5 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 60 mg/mL|
Cross-resistance profile of the novel integrase inhibitor Dolutegravir (S/GSK1349572) using clonal viral variants selected in patients failing raltegravir.
Canducci et al. J Infect Dis. 2011 Dec 1;204(11):1811-5. PMID: 21984737.
Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes.
Hightower et al. Antimicrob Agents Chemother. 2011 Oct;55(10):4552-9. PMID: 21807982.
Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572).
Hare et al. Mol Pharmacol. 2011 Oct;80(4):565-72. PMID: 21719464.
Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers.
Patel et al. J Antimicrob Chemother. 2011 Jul;66(7):1567-72. PMID: 21493648.
Prevalence of resistance mutations related to integrase inhibitor S/GSK1349572 in HIV-1 subtype B raltegravir-naive and -treated patients.
Malet et al. J Antimicrob Chemother. 2011 Jul;66(7):1481-3. PMID: 21474479.
|Related Integrase Products|
S/GSK1349572 (GSK1349572) is a two-metal-binding HIV integrase inhibitor with IC50 of 2.7 nM, modest activity against raltegravir-resistant signature mutants Y143R, Q148K, N155H, and G140S/Q148H.
MK-2048 is a potent inhibitor of integrase (IN) and INR263K with IC50 of 2.6 nM and 1.5 nM, respectively.
Raltegravir (MK-0518) is a potent integrase (IN) inhibitor for WT and S217Q PFV IN with IC50 of 90 nM and 40 nM, respectively.
Elvitegravir (EVG) is a HIV integrase inhibitor with IC50 of 0.7 nM, 2.8 nM and 1.4 nM for HIV-1 IIIB, HIV-2 EHO and HIV-2 ROD, respectively.
BMS-707035 is an HIV-1 integrase (IN) inhibitor. HIV-1 integrase (IN) represents a therapeutically advantageous viral target to treat HIV/AIDS in the clinic.
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