生物活性

• 靶点	HIV Integrase IC50:2.7nM

• 描述The HIV integrase (IN) enzyme can help to transfer the virally genomic encoded DNA into the host chromosome. Dolutegravir (DG) is a next-generation HIV IN inhibitor with the IC50 value of 2.7nM. Besides, the EC50s of DG against HIV-1 were 0.51nM and 0.71nM in PBMCs and MT-4 cells, respectively. It showed 50% cytotoxicity to IM-9, U-937, MT-4, and Molt-4 cells at concentrations ranging in 4.8-15μM, but at 52μM in stimulated PBMCs. DG demonstrated a substitution of T124A with a proportion of 40% in wild-type HIV-1 IIIB. Then, the T124A/S153F substitution was observed followed by T124A/S153Y and L101I/T124A/S153F, which could remain or showed a low fold change (4.1-fold max). Furthermore, in a screening of 50 INI-resistant site-directed mutant construction, Dolutegravir displayed a mean fold change of EC50 ranging in 0.26 to 19, most of which located within 3 to 10 fold, compared to wild-type virus. This suggested a moderate reduction in potency against this mutants. Meanwhile, DG is potent against all single mutants. In combination studies with 8 HIV antiretrovirals, DG served as either an additive or synergistic with stavudine, abacavir, efavirenz and nevirapine. Furthermore, a median EC50 value of 0.8nM with a rang from 0.2 to 1.4 nM, similarly as the reference strain, was shown in HIV-2 virus isolates from nine HIV-2-infected patients following with Dolutegravir treatment in vitro. In integrase-mutated variants, treatment of Dolutegravir demonstrated an increasing EC50 values with different folds, for example, it was 13-fold for samples with double variants G140S and Q148R .
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  MDCK2 cells	-	Function assay	-	Inhibition of human OCT2 expressed in MDCK2 cells using [14C]metformin as substrate by liquid scintillation counting analysis	23132334

• 动物研究
  剂量	Rat: ≤500 mg/kg[3] (p.o.) Monkey: 50 mg/kg - 500 mg/kg[3] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[4] Monkeys[4] Dose 1 mg/kg (i.v.) 5 mg/kg (p.o.) 1 mg/kg (i.v.) 3 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. F 34.2% (p.o.) 68.3% (p.o.) AUC0-inf 74.3 μg·h/ml (i.v.) 127 μg·h/ml (p.o.) T1/2 6.18 h (i.v.) 6.00 h (i.v.) AUC0→inf 7.91 μg·h/ml (i.v.) 16.2 μg·h/ml (p.o.) Tmax 1.33 h (p.o.) 2.2 h (p.o.) CLp 0.23 ml/min/kg (i.v.) 2.12 ml/min/kg (i.v.) Cmax 9.66 μg/ml (p.o.) 2.97 μg/ml (p.o.) Vss 0.10 L/kg (i.v.) 0.28 L/kg (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00867152	Healthy Volunteer	Phase 1	Completed	-	United States, New York ... more >> GSK Investigational Site Buffalo, New York, United States, 14202 Collapse <<
  NCT00858455	Healthy Volunteer	Phase 1	Completed	-	United States, New York ... more >> GSK Investigational Site Buffalo, New York, United States, 14202 Collapse <<
  NCT01302847	HIV Infections	Phase 1 Phase 2	Recruiting	June 30, 2023	-

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