heparitin-sulfate and Hepatitis-C

Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. Although antiviral therapy has been markedly improved by the licensing of direct-acting antivirals, safety, resistance, high costs and difficult-to-treat patients remain important challenges.. This article focuses and comments on the recent development of synthetic anti-lipopolysaccharide peptides (SALPs) which bind to highly sulfated glycosaminoglycan/heparan sulfate (HS) on cell surface. HS serves as a primary docking site for several viruses to their respective host cells before the viruses interact with their cell surface receptor(s). In vitro studies have shown that SALPs inhibit entry of HCV without cell toxicity.. SALPs prevent viral infection in cell culture model systems. Treatment studies of established HCV infection in cell culture models as well as proof-of-concept and safety studies in animal models are needed to evaluate their potential for drug development. The mechanism of action of SALPs as entry inhibitors suggests a potential application for HCV-infected patients to prevent reinfection of the liver graft in liver transplantation. Potential limitations may include high doses to obtain an antiviral effect and a target which is widely expressed and has a key function in cell physiology.

Topics: Animals; Antiviral Agents; Cell Line; Cell Survival; Heparitin Sulfate; Hepatitis C; Humans; Lipopolysaccharides; Peptides; Protein Binding; Viral Envelope Proteins; Virus Internalization

Several putative cell surface receptors have been identified in the Hepatitis C virus (HCV) infection including CD81, low-density lipoprotein (LDL) receptor, scavenger receptor class B type I (SR-BI), and highly sulfated heparan sulfate (HS). In this study, we showed that the binding of soluble heparin to the envelope glycoprotein E2 (E2) of HCV was dependent on the dose and conformation of E2. On the other hand, the binding of E2 to the cell surface after treatment with soluble heparin was not markedly inhibited, what was different from other viruses utilizing cellular HS as the primary receptor. However, the enzymatic removal of HS from the cell surface led to a significant reduction in the binding of E2 to the cells. These facts imply that E2 was bound to cellular HS but might also have another route for cell attachment. Monoclonal antibodies with neutralizing activity against E2 did not completely block the binding of E2 to the cell surface, but their neutralization activity was greatly enhanced in the presence of soluble heparin. Taken together, the cellular HS could act as an alternative receptor for HCV and the interaction of E2 with HS could play a distinct role in escaping of HCV from the humoral immunity.

Topics: Cell Line; Hepacivirus; Heparitin Sulfate; Hepatitis C; Humans; Protein Binding; Receptors, Virus; Viral Envelope Proteins; Virus Attachment