A heparan sulfate-mimetic derivative of botryosphaeran with antiviral activity against herpes simplex virus

Herpes is a viral disease with high worldwide prevalence. The lack of herpes vaccines and the growing viral resistance to acyclovir and its analogues create an urgent need for new treatment strategies. Anionic polysaccharides, especially sulfated derivatives, can inhibit herpes simplex virus (HSV) infection by interfering with viral attachment to heparan sulfate on host cells. Building on our previous work, we designed and prepared a heparan sulfate-mimetic derivative of botryosphaeran, a fungal β-glucan, by sequential oxidation and sulfonation. Firstly, oxidation converted approximately one-half of the C-6 primary hydroxyl groups into carboxyl groups, yielding BOT_OX. Subsequent sulfonation yielded the heparan sulfate mimetic (BOT_OX/SULF) with a degree of sulfonation of 0.3 and sulfate groups mainly at C-6 of the remaining glucose units. In vitro assays showed that BOT_OX/SULF had high anti-HSV-1 activity, while BOT_OX was inactive. The antiviral effect of BOT_OX/SULF was comparable to that of previously reported botryosphaeran sulfonated derivatives with a higher degree of sulfonation, suggesting that the combined presence of carboxylate and sulfate groups contributes to activity. These results support heparan sulfate mimicry as a promising strategy for designing entry inhibitors against enveloped viruses.