Ceestatin, a Novel Small Molecule Inhibitor of Hepatitis C Virus Replication, Inhibits 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase

Abstract

Ceestatin therefore exerts its anti-HCV effects through inhibition of HMG-CoA synthase. It may prove useful as an antiviral agent, as a probe to study HCV replication, and as a cholesterol-lowering agent. The logical stepwise process employed to discover the mechanism of action of ceestatin can serve as a general experimental strategy to uncover the targets on which novel uncharacterized anti-HCV compounds act.

Identification of proteins that mediate the pro-viral functions of the interferon stimulated gene 15 in hepatitis C virus replication

“…It has been demonstrated, that Hmgcs1 possesses a prolonged expression in HCV infected humanized mice (Walters et al, 2006). Further, it has been shown that blocking the mevalonate pathway with Hmgcr inhibitors (statins) (Ye et al, 2003) or with the Hmgcs1 inhibitor ceestatin, leads to suppression of HCV replication (Delang et al, 2009;Peng et al, 2011). The siRNA-mediated knockdown of Hmgcs1 in our study had no direct effect on HCV replication; however, the Hmgcs1 knockdown has been described to suppress HCV replication in alternative HCV cell culture systems (OR6 cells and JFH1) (Peng et al, 2011).…”

“…Further, it has been shown that blocking the mevalonate pathway with Hmgcr inhibitors (statins) (Ye et al, 2003) or with the Hmgcs1 inhibitor ceestatin, leads to suppression of HCV replication (Delang et al, 2009;Peng et al, 2011). The siRNA-mediated knockdown of Hmgcs1 in our study had no direct effect on HCV replication; however, the Hmgcs1 knockdown has been described to suppress HCV replication in alternative HCV cell culture systems (OR6 cells and JFH1) (Peng et al, 2011). Idh1, as well as the mevalonate pathway, is sterol-controlled and activated by sterol regulatory element binding proteins (Srebps) (Shechter et al, 2003).…”

HCV and Host Lipids: An Intimate Connection

“…Blocking the mevalonate pathway at this more proximal step has also been demonstrated to block HCV replication. 74 The role of the mevalonate pathway has been elucidated to involve the important geranylgeranylation of FBL2, a host protein, which interacts with NS5A to promote replication. 75 The Bloch pathway of cholesterol biosynthesis has also been implicated in HCV replication, but its exact function has yet to be clearly elucidated.…”

Theoretical basis of a beneficial role for vitamin D in viral hepatitis

“…Higher serum triglycerides, total cholesterol and LDL levels were correlated with higher HCV RNA levels [83] . Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase in a dose-dependent manner [84] . Polyunsaturated liposomes are reported to be antiviral against hepatitis B and C viruses by decreasing cholesterol levels in infected cells [85] .…”