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Antiviral activity of GS-5801 exhibits delayed kinetics.
No full textPHH from three donors (BCD, VUZ, and 8181) were infected with HBV for three days prior to initiation of GS-5801 treatment. PHH were dosed with vehicle or 10 μM GS-5801 every three to four days for a total of 30–32 days. At the timepoints shown, levels of secreted (A) HBeAg and (B) HBsAg were measured by immunoassay. Data are plotted as the percentage inhibition of HBeAg or HBsAg in GS-5801 treated PHH relative to vehicle treated PHH.</p
GS-5801 increases H3K4me3:H3 levels preferentially in liver tissue.
No full textSprague Dawley rats (A) and cynomolgus monkeys (B) were dosed once with 1 mg/kg or 2.5 mg/kg GS-5801 p.o., respectively. Amounts of pro-drug (GS-5801) and active parent (GS-080) were measured by LC-MS in liver tissue and plasma at the timepoints shown. (C) Cynomolgus monkeys were dosed p.o. once daily for seven days with 0.03, 0.1, 0.3, 1, 3, or 10 mg/kg of GS-5801. Twenty four hours after the last dose, amounts of H3K4me3 and H3 were measured by ELISA in liver, kidney, PBMCs, and lung. Data are displayed as the average H3K4me3:H3 ratio of GS-5801 treated monkeys relative to vehicle treated monkeys from n = 2–3 animals; error bars represent the standard deviation. (D) Sprague Dawley rats were dosed p.o. once daily for five days with 0.3, 1, 3, 10, or 30 mg/kg of GS-5801. Twentyfour hours after the last dose, amounts of H3K4me3 and H3 were measured by ELISA in liver, kidney, PBMCs, and lung. Data are displayed as the average H3K4me3:H3 ratio of GS-5801 treated rats relative to vehicle treated rats from n = 3 animals; error bars represent the standard deviation. (E–F) Wistar Han rats were dosed p.o. once daily for seven days with 10, 30, or 100 mg/kg of GS-5801 and a subset of rats from each dose group continued into a seven day off-treatment phase. (E) Twentyfour hours after the last dose or recovery day, amounts of H3K4me3 and H3 were measured by ELISA in the liver. Data are displayed as the average H3K4me3:H3 ratio of GS-5801-treated rats relative to vehicle treated rats from n = 3 animals during the dosing or recovery phases; error bars represent the standard deviation. (F) Transcript levels in rat liver tissue were quantified by RNA-seq (cpm). The number of genes differentially up or downregulated (differential by 2-fold log2; FDR < 0.05) in GS-5801-dosed rats compared to vehicle-treated rats are shown during the dosing phase (24 hours after once daily dosing for seven days) and recovery phase (24 hours after seven days off drug; F).</p
TP-5801 in vitro kinase screen data
Full text linkIn vitro kinase screen data for TP-5801 to accompany Chan and Egbert et al., Nature Communications, 2021 (in press
GS-5801 influences host and viral gene transcription.
No full textPHH from three donors (8130, 8181, and 4239) were infected with HBV for three days prior to initiation of GS-5801 treatment. PHH were treated continuously with vehicle, 0.03, 0.3, or 10 μM GS-5801 every three to four days for a total of 13 days. PHH were harvested at 1, 3, 10, and 13 days after initiation of GS-5801 dosing and mRNA was quantified by RNA-seq. (A) The number of sequencing reads mapping to the HBV genome were quantified in all samples (counts per million; cpm) and data are plotted as the percentage inhibition of HBV RNA (vRNA) in GS-5801 treated samples relative to vehicle treated samples at each timepoint. (B) The number of genes differentially up or downregulated (differential by 4-fold log2; FDR 2; FDR < 0.05) in PHH treated with 10 μM GS-5801 compared to vehicle treated PHH for Day 3 (n = 414 genes), Day 10 (n = 1131 genes), and Day13 (n = 1268 genes) after initiation of GS-5801 dosing. (D) Hallmark Gene Set. Data are displayed as the difference in average gene set score based on GSVA between each dose respective vehicle control, with upregulated gene sets in red and downregulated gene sets in blue. For comparison, downregulation of HBV mRNA for same dose and time regiment is shown at the top.</p
Antiviral activity of GS-5801 in HBV-infected PHH.
No full textAntiviral activity of GS-5801 in HBV-infected PHH.</p
A single dose of GS-5801 confers sustained HBV antiviral activity in PHH.
No full text(A) PHH from three donors (BCD, 7272, and 8181) were infected with HBV for three days prior to initiation of GS-5801 treatment. PHH were treated once for two hours with vehicle or 10 μM GS-5801. Compound was removed by replacing the medium with fresh medium without drug or vehicle. At the timepoints shown, levels of secreted HBeAg and HBsAg were measured by immunoassay for 12 days. Data are shown as the percentage inhibition of HBeAg or HBsAg in GS-5801 treated PHH relative to vehicle treated PHH. (B) PHH from donor BCD were infected with HBV for three days prior to initiation of GS-5801 treatment. PHH were treated once for two hours with vehicle or 10 μM GS-5801. Compound was removed by replacing the medium with fresh medium without drug or vehicle. At the timepoints shown, levels of secreted HBeAg and HBsAg were measured by immunoassay for 24 days. Data are shown as the average percentage.</p
Antiviral activity of GS-5801 across HBV genotypes.
No full textAntiviral activity of GS-5801 across HBV genotypes.</p
A retrospective investigation of HLA-B*5801 in hyperuricemia patients in a Han population of China
Full text linkHyperuricemia and gout have become increasingly prevalent in China. Allopurinol is an effective urate-lowering therapy but it has severe side-effects. HLA-B*5801 is highly associated with the allopurinol-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. In this retrospective report, we had genotyped HLA-B*5801 in 253 cases of hyperuricemia and gout patients in a Han population in Shenzhen and analyzed the clinical management of medications. We found 30 carriers of HLA-B*5801 allele in 253 cases of hyperuricemia or gout patients in the population (11.9%). Allopurinol was prescribed in both HLA-B*5801 positive and negative groups. The evaluation of four models with or without genetic screening and management of allopurinol or febuxostat indicated the HLA-B*5801 screening had significant cost benefit for clinical management. HLA-B*5801 allele should be screened in all patients with hyperuiciemia and gout in the Chinese population
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