Marine-derived sulfated glycans display a potent virostatic mechanism to block herpes simplex virus type-1 (HSV-1) entry and spread

A naturally derived library of glycomimetic mimicking the structure-function of heparan sulfate (HS) remains an untapped reservoir for drug discovery against viral infections. In this work we screened a library of marine-derived sulfated glycans from seaweeds and sea cucumbers to investigate if they can compete for the ligand/receptor binding sites to prevent virus entry. Multiple promising candidates were identified, such as RPI-27 (IC₅₀: 1.51 μM), FCS-Pg (IC₅₀: 0.906 μM), FCS-Ib (IC₅₀: 0.725 μM), and Rhamnan sulfate (RS; IC₅₀: 0.499 μM) capable of preventing HSV-1 entry at non-toxic concentrations when pre-incubated with the target cells before infection. Interestingly, we noticed a significant improvement in the IC₅₀ values among the sulfated glycans [RPI-27 (IC₅₀: 0.008 μM), FCS-Pg (IC₅₀: 0.007 μM), FCS-Ib (IC₅₀: 0.003 μM), and RS (IC₅₀: 0.004 μM)] when they were pre-exposed to the virus before infecting to the target cell. The Surface Plasmon Resonance (SPR) spectroscopy established the library's efficacy for their high binding affinity for HSV-1 central envelope glycoprotein D (gD), implying the potent virostatic nature of the sulfated glycans. These findings offer a rationalized development of targeted and fine-tuned marine-derived carbohydrate-based molecules to prevent HSV-1 entry and virus replication using either prophylaxis and or treatment approaches.