NA808

NA808 is an Serine Palmitoyltransferase (SPT) inhibitor. NA808 reduces sphingomyelin synthesis, inhibits its activation in hepatic stellate cells, and decreases the expression of α-SMA protein and mRNA, as well as collagen 1A1 mRNA (IC₅₀ 0.16, 0.12, and 0.11 μM, respectively). NA808 inhibits HCV replication and reduces NS3 and RdRp protein expression in HCV replicon cells without significant cytotoxicity and exhibits almost no immunosuppressive effect at effective concentrations. NA808 demonstrates broad-spectrum antiviral activity in humanized chimeric liver mice infected with various HCV genotypes, and dose-dependently reduces serum and hepatic HCV RNA levels. NA808 can be used for research on non-alcoholic steatohepatitis and hepatitis C virus infection^[1][2][3][4]. In Vitro:NA808 (12.3-1000 nM; 4 days) concentration-dependently inhibits de novo synthesis of Cer, Glc Cer, and SM in E14C12 cells, with sub-maximum inhibition for Cer and GlcCer at 37 nM and for SM at 111 nM^[1].
NA808 (7 days) concentration-dependently reduces α-SMA protein levels (IC₅₀ = 0.16 μM) as well as α-SMA and collagen 1A1 mRNA expression (IC₅₀ = 0.12 and 0.11 μM, respectively) in E14C12 cells without cytotoxicity^[1].
NA808 (1-100 μM; 1-4 h) shows substrate characteristics for OATP1B1 and MRP2 in OATP1B1-MRP2 double-transfected MDCK II cells (Papp ratios 24.2-70.2, decreasing with increasing concentration), shows Papp ratios of approximately 1.0 in OATP1B1-BCRP double-transfected cells, and shows Papp ratios of approximately 1.0-1.1 in OATP1B1 single-transfected cells (no active transport)^[2].
NA808 (0-250 nM) inhibits HCV replication in HCV genotype 1b subgenomic replicon cells (FLR3-1) with an IC₅₀ of 0.84 µmol/L, without apparent cytotoxicity^[3][4].
NA808 (5-25 nM; 0.25-72 h) shows noncompetitive inhibition of SPT enzymatic activity in FLR3-1 cell lysates and replicon cells^[3][4].
NA808 (0-100 nM) dose-dependently inhibits de novo sphingolipid synthesis in FLR3-1 cells^[3][4].
NA808 (48-72 nM, i.e., 4-6 × IC₅₀; 14 passages) does not induce resistance mutations in HCV genotype 1b replicon cells (R6 FLR-N), with IC₅₀ values remaining stable during passaging: 18.9 nM for untreated, 14.3 nM for 4 × IC₅₀ treatment, and 19.8 nM for 6 × IC₅₀ treatment^[3].
NA808 shows little to no inhibitory effect on human peripheral blood T-cell proliferation at concentrations that suppress HCV replication^[4].
NA808 (0-250 nM; 96 h) reduces HCV NS3 protein and RdRp (NS5B) protein expression levels in FLR3-1 replicon cells^[4].
NA808 (0-1 μM) decreases sphingomyelin levels in the detergent-resistant membrane (DRM) fraction required for HCV replication, disrupting the association between RdRp and SM, thereby inhibiting HCV replication^[4]. In Vivo:NA808 (5 mg/kg; i.v.; once daily; for 14 days) shows broad-spectrum antiviral activity in humanized liver chimeric mice infected with HCV genotypes 1a, 1b, 2a, 3a, and 4a, synergistically enhances antiviral efficacy when combined with PegIFN (HY-108839), RO-9187 (HY-10870), HCV-796 (HY-14775), or Telaprevir (HY-10235), reduces serum HCV RNA in triple combination with telaprevir and HCV-796, but shows no significant effect on serum HBV DNA levels in an HBV genotype C infection model^[3][4].
NA808 (5-10 mg/kg; i.v.; once daily; for 14-21 days) dose-dependently reduces serum HCV RNA levels and hepatic HCV RNA and core protein levels in humanized liver chimeric mice infected with HCV genotype 1a or 2a, without apparent toxicity. NA808 at 5 mg/kg for 21 days reduces serum HCV RNA to below the detection limit in 2 out of 5 mice^[4].