Using a 3-O-sulfated heparin octasaccharide to inhibit the entry of herpes simplex virus type 1.
Heparan sulfate (HS) is a highly sulfated polysaccharide and is present in large quantities on the cell surface and in the extracellular matrix. Herpes simplex virus type 1 (HSV-1) utilizes a specialized cell surface HS, known as 3-O-sulfated HS, as an entry receptor to establish infection. Here, we exploit an approach to inhibiting HSV-1 infection by using a 3-O-sulfated octasaccharide, mimicking the active domain of the entry receptor. The 3-O-sulfated octasaccharide was synthesized by incubating a heparin octasaccharide (3-OH octasaccharide) with HS 3-O-sulfotransferase isoform 3. The resultant 3-O-sulfated octasaccharide has a structure of Delta UA2S-GlcNS6S-IdoUA2S-GlcNS6S-IdoUA2S-GlcNS3S6S-IdoUA2S-GlcNS6S (where Delta UA is 4-deoxy-alpha-L-threo-hex-4-enopyranosyluronic acid, GlcN is D-glucosamine, and IdoUA is L-iduronic acid). Results from cell-based assays revealed that the 3-O-sulfated octasaccharide has stronger activity in blocking HSV-1 infection than that of the 3-OH octasaccharide, suggesting that the inhibition of HSV-1 infection requires a unique sulfation moiety. Our results suggest the feasibility of inhibiting HSV-1 infection by blocking viral entry with a specific oligosaccharide.
Copeland
Ronald
R
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Balasubramaniam
Arun
A
Tiwari
Vaibhav
V
Zhang
Fuming
F
Bridges
Arlene
A
Linhardt
Robert J
RJ
Shukla
Deepak
D
Liu
Jian
J
D000998:Antiviral Agents / Q000737:chemistry*; D002240:Carbohydrate Sequence; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D005944:Glucosamine / Q000737:chemistry; D006367:HeLa Cells; D006493:Heparin / Q000737:chemistry; D006497:Heparan Sulfate / Q000737:chemistry*; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011134:Polysaccharides / Q000737:chemistry*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization
D000998:Antiviral Agents; D005944:Glucosamine; D006493:Heparin; D006497:Heparan Sulfate; D011134:Polysaccharides; D011994:Recombinant Proteins