Antiviral Strategies Using Natural Source-Derived Sulfated Polysaccharides in the Light of the COVID-19 Pandemic and Major Human Pathogenic Viruses

Abstract

Only a mere fraction of the huge variety of human pathogenic viruses can be targeted by the currently available spectrum of antiviral drugs. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the urgent need for molecules that can be deployed quickly to treat novel, developing or re-emerging viral infections. Sulfated polysaccharides are found on the surfaces of both the susceptible host cells and the majority of human viruses, and thus can play an important role during viral infection. Such polysaccharides widely occurring in natural sources, specifically those converted into sulfated varieties, have already proved to possess a high level and sometimes also broad-spectrum antiviral activity. This antiviral potency can be determined through multifold molecular pathways, which in many cases have low profiles of cytotoxicity. Consequently, several new polysaccharide-derived drugs are currently being investigated in clinical settings. We reviewed the present status of research on sulfated polysaccharide-based antiviral agents, their structural characteristics, structure-activity relationships, and the potential of clinical application. Furthermore, the molecular mechanisms of sulfated polysaccharides involved in viral infection or in antiviral activity, respectively, are discussed, together with a focus on the emerging methodology contributing to polysaccharide-based drug development.

Keywords: antiviral activities and mechanisms; antiviral efficacy; drug structure-activity relationship; emerging viral infections; heparin mimetics; in vivo studies; major human pathogenic viruses; sulfated polysaccharides; virus entry as a target.

Figure 1

Schematic representation of the production of arabinoxylan sulfates from P. ovata seed husk using SO₃.Pyr reagent in DMF at 60 °C [46]. Notably, drawings are not intended to be representative of the full sample composition.

Figure 2

Comparison of antiviral activity of sulfated (A) ulvans against HSV-1 [45], (B) glucans against HCMV [47], (C) pectins against HSV-1 [259] and (D) arabinogalactans against HSV-1 [44], having different molecular masses (MSs). Antiviral activity was performed by plaque reduction assay in HEp-2 cells (human larynx epithelial cells carcinoma, ATCC CCL-23) (A,C), in Vero cells (ATCC CCL-81) (D) and by GFP-based replication assay in primary human fibroblasts (B).

Figure 3

Comparison of antiviral activity of sulfated (A) alginic acids against HSV-1 [74,76], (B) ulvans against HSV-1 [45], (C) fucoidans against HSV-1 [77], (D) fucoidans against HSV-1 [73], (E) xylans against HSV-1 [97], (F) linear and branched β-1,4-xylans having same degrees of sulfation against HSV-1 [46,97], (G) xylomannans against HSV-1 [98] and (H) glucans against HCMV and HSV-1 [275] having different degrees of sulfation. Antiviral activity was performed by plaque reduction assay in RC-37 cells (African green monkey kidney cells) (A,C), in HEp-2 cells (human larynx epithelial cells carcinoma, ATCC CCL-23) (B), in Vero cells (D–G) and by GFP-based replication assay in primary human fibroblasts (H).

Figure 4

The preparation of 3-O-sulfated octasaccharide by 3-O-sulfotransferase. 2S, 2-O-sulfated; 3S, 3-O-sulfated; 6S, 6-O-sulfated; NS, N-sulfated. (Adapted from [310]).