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Review
. 2022 Jun 19;14(6):1337.
doi: 10.3390/v14061337.

Extracellular Polymeric Substances: Still Promising Antivirals

Raquel Bello-Morales  1   2 , Sabina Andreu  1   2 , Vicente Ruiz-Carpio  1 , Inés Ripa  1   2 , José Antonio López-Guerrero  1   2
Affiliations
Review

Extracellular Polymeric Substances: Still Promising Antivirals

Raquel Bello-Morales et al. Viruses. .

Abstract

Sulfated polysaccharides and other polyanions have been promising candidates in antiviral research for decades. These substances gained attention as antivirals when they demonstrated a high inhibitory effect in vitro against human immunodeficiency virus (HIV) and other enveloped viruses. However, that initial interest was followed by wide skepticism when in vivo assays refuted the initial results. In this paper we review the use of sulfated polysaccharides, and other polyanions, in antiviral therapy, focusing on extracellular polymeric substances (EPSs). We maintain that, in spite of those early difficulties, the use of polyanions and, specifically, the use of EPSs, in antiviral therapy should be reconsidered. We base our claim in several points. First, early studies showed that the main disadvantage of sulfated polysaccharides and polyanions is their low bioavailability, but this difficulty can be overcome by the use of adequate administration strategies, such as nebulization of aerosols to gain access to respiratory airways. Second, several sulfated polysaccharides and EPSs have demonstrated to be non-toxic in animals. Finally, these macromolecules are non-specific and therefore they might be used against different variants or even different viruses.

Keywords: SARS-CoV-2; antivirals; coronaviruses; extracellular polymeric substance; herpesviruses; polyanions; sulfated polysaccharides.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of antiviral action of microbial exopolymers. EPSs can exert their antiviral activity via different mechanisms. Virucidal agents act by inactivating viruses. Inactivation can occur not only by damaging the virions, but also by blocking them and impeding the adsorption of virions to cells (red cross). Some EPSs can wrap the virions via electrostatic interactions, thus preventing viral adsorption and, therefore, exerting a virucidal effect (1). Other EPSs exert an antiviral effect allowing the viral entry but later impeding the viral replication. Therefore, antivirals inhibit replication of viable viruses in the cells (2). EPSs can also exert antiviral effect by activating immune cells and inducing them to secrete immunomodulators (IMs) and to kill virus-infected cells (3).
Figure 2
Figure 2
Schematic diagram representing the mechanistic basis of the inhibitory effect of EPSs and other antiviral polyanions on viral adsorption. The figure represents a prototypical polymer interacting with a SARS-CoV-2 virion. The main inhibitory mechanisms include non-covalent and non-specific electrostatic interaction between the negatively charged moieties of the EPSs and the positively charged viral glycoproteins. Viral glycoproteins might also interact with H-bond acceptors of the polymer.
Figure 3
Figure 3
Alternative routes of administration of EPSs and other polyanions. (A) To overcome the low bioavailability of EPSs, new routes of administration should be tested, especially nebulization of aerosols to access pulmonary alveoli. (B) Aerial virions can be trapped by EPSs before attachment in the respiratory epithelium. To enter cells, viral glycoproteins must first attach to the host cell receptors. EPSs may block the viral glycoproteins and prevent viral entry (red cross).
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This research was funded by Fundación Severo Ochoa.