MK-2048 is a second generation integrase inhibitor for integrase (IN) and INR263K with an IC50 of 2.6 and 1.5 nM, respectively.MK-2048 inhibits subtype B and subtype C integrase activities with IC50 of 75 and 80 nM, respectively. Disintegration is prevented by high concentrations of MK-2048 to a comparable extent with both subtype B and C enzymes. Mutation at the site of R263K slightly increases integrase susceptibility to MK-2048. G118R translates into a decrease in integrase activity and confers resistance to MK-2048. MK-2048 inhibits S217H intasome with an IC50 of 900 nM. By contrast, MK2048 remains fully active against the N224H intasome with an IC50 of 25 nM. MK2048 displays substantially lower dissociation rates compared with raltegravir, another integrase inhibitor. The subsequent selection of E138K partially restores replication capacity to approximately 13% of wt levels and increased resistance to MK-2048 to approximately 8-fold. MK-2048 is active against viruses resistant to RAL and EVG. Exposure to MK-2048 leads to the selection of G118R as a possible novel resistance mutation after 19 weeks. Continued pressure with MK-2048 subsequently leads to an additional substitution after 29 weeks at position E138K, within the IN gene. Although the G118R mutation alone confers only slight resistance to MK-2048 but not to RAL or EVG, its presence arouses a dramatic reduction in viral replication capacity compared to wild-type NL4-3. E138K both partially restores viral replication capacity and also contributes to increased levels of resistance against MK-2048.
|Cell lines||PM1 cells|
|Preparation method||A total of 7.5×104 PM1 cells per well are infected with clonal NL4-3 virus containing the integrase mutations G118R, E138K, or G118R and E138K or with wild-type viruses (45 ng p24 virus per well) by spinoculation at 1,200 × g for 2 hours at 37 °C. Washing cells two times to remove unbound virus and then resuspends in RPMI growth medium alone or containing various concentrations of MK-2048, ranging from 0.0256 nM to 2 μM. Experiments are performed, each in duplicate. Mearsure supernatant reverse transcriptase (RT) activity at 72 hours postinfection as an indicator of virus replication. Normalize data based on uninfected and no-drug controls included in each experiment. Using the same methodology as that used to determine EC50s to determing viral replication capacity in PM1 cells, by comparing levels of supernatant RT activity of each mutant virus to those of wild-type virus in the absence of MK-2048.|
|Concentrations||0.0256 nM to 2 μM|
|Incubation time||72 hours|
|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.
|Related Integrase Products|
Bictegravir (GS-9883) is a novel, potent inhibitor of HIV-1 integrase with an IC50 of 7.5 nM.
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.
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.
S/GSK1349572 (Dolutegravir) is a novel integrase inhibitor with an IC50 of 2.7 nM.
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