Botryosphaeran and sulfonated derivatives as novel antiviral agents for herpes simplex and dengue fever

Sulfated polysaccharides are known to display activity against enveloped viruses, such as herpes and dengue. The aim of this work was to assess the antiviral activity of botryosphaeran, a fungal exocellular (1 → 3)(1 → 6)-β-d-glucan devoid of sulfate groups, and its chemically sulfonated derivatives, against herpes simplex virus (HSV), dengue virus (DENV) and poliovirus (PV). The natural parent polysaccharide inhibited acyclovir-sensitive HSV (HSV-KOS) infection in Vero cells (IC₅₀ of 39.3 μg mL^-1), while the IC₅₀ against acyclovir-resistant HSV (HSV-AR) was 47.5 μg mL^-1. Botryosphaeran was derivatized by sulfonylation with chlorosulfonic acid to prepare two sulfonated derivatives, S1 and S2, with degrees of substitution (DS) of 0.4 and 1.1, respectively. Antiviral evaluation of S1 and S2 gave the IC₅₀ of 3.0 and 2.4 μg mL^-1 against HSV-KOS, and 7.3 and 2.7 μg mL^-1 against HSV-AR, respectively. This study demonstrated for the first time that native botryosphaeran inhibited HSV infection, albeit moderately, while its sulfonated derivatives developed high activity against viral infection. DENV inhibition was weak for botryosphaeran, but remarkably stronger for S1 and S2. All compounds were inactive against PV, as it lacked a viral envelope. The presence of sulfate groups and the DS were confirmed to be important features for antiviral activity.