BACKGROUND & AIMS: Host cell lipid rafts form a scaffold required for 
replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) 
produce sphingolipids, which are essential components of the lipid rafts that 
associate with HCV nonstructural proteins. Prevention of the de novo synthesis 
of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and 
thereby inhibits HCV replication. We investigated the ability of the SPT 
inhibitor NA808 to prevent HCV replication in cells and mice.
METHODS: We tested the ability of NA808 to inhibit SPT's enzymatic activity in 
FLR3-1 replicon cells. We used a replicon system to select for HCV variants that 
became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory 
concentration, after 14 rounds of cell passage. We assessed the ability of NA808 
or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in 
mice with humanized livers (transplanted with human hepatocytes). NA808 was 
injected intravenously, with or without pegylated interferon alfa-2a and HCV 
polymerase and/or protease inhibitors.
RESULTS: NA808 prevented HCV replication via noncompetitive inhibition of SPT; 
no resistance mutations developed. NA808 prevented replication of all HCV 
genotypes tested in mice with humanized livers. Intravenous NA808 significantly 
reduced viral load in the mice and had synergistic effects with pegylated 
interferon alfa-2a and HCV polymerase and protease inhibitors.
CONCLUSIONS: The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 
1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It 
might be developed for treatment of HCV infection or used in combination with 
pegylated interferon alfa-2a or HCV polymerase or protease inhibitors.