Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral Spread

Herpes simplex virus (HSV-1) employs heparan sulfate (HS) as receptor for cell attachment and entry. During late-stage infection, the virus induces the upregulation of human heparanase (Hpse) to remove cell surface HS allowing viral spread. We hypothesized that inhibition of Hpse will prevent viral release thereby representing a new therapeutic strategy for HSV-1. A range of HS-oligosaccharides was prepared to examine the importance of chain length and 2-O-sulfation of iduronic moieties for Hpse inhibition. It was found that hexa- and octasaccharides potently inhibited the enzyme and that 2-O-sulfation of iduronic acid is tolerated. Computational studies provided a rationale for the observed structure-activity relationship. Treatment of human corneal epithelial cells (HCEs) infected with HSV-1 with the hexa- and octasaccharide blocked viral induced shedding of HS which significantly reduced spread of virions. The compounds also inhibited migration and proliferation of immortalized HCEs thereby providing additional therapeutic properties. A range of heparan sulfate (HS) oligossacharides was synthesized by a modular synthetic approach and evaluated as human heparanase (Hpse) inhibitors. Treatment of herpes simplex-1 virus (HSV-1) infected corneal epithelial cells with synthetic HS oligosaccharide inhibitors prevented shedding of cell-surface HS, thereby impeding viral release and spread to other cells.+image

Automated summary

Inhibition of human heparanase (Hpse) has been found to be a promising therapeutic strategy for preventing the spread of herpes simplex virus (HSV-1). The synthesis of hexa- and octasaccharide inhibitors of Hpse showed potent enzyme inhibition and the presence of 2-O-sulfation on iduronic acid was tolerated. These inhibitors not only blocked viral-induced shedding of cell-surface heparan sulfate (HS) but also inhibited cell migration and proliferation in corneal epithelial cells infected with HSV-1.