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. 2023 Apr 5;104:105532. doi: 10.1016/j.jff.2023.105532

Sulfated polysaccharides act as baits to interfere with the binding of the spike protein (SARS-CoV-2) to the ACE2 receptor and can be administered through food

Jhonatas Rodrigues Barbosa 1,⁎, Lúcia de Fátima Henriques Lourenço 1
PMCID: PMC10073580  PMID: 37035109

Graphical abstract

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Keywords: COVID-19, ACE2 receptor, Functional foods, Heparin, Sulfated polysaccharides

Abstract

Human civilization is experiencing a global crisis involving an unprecedented viral pandemic, with a high mortality rate, uncontrolled spread, and few effective drugs for treatment. Here, we critically evaluate how sulfated polysaccharides can be applied via foods to reduce the infectious process and increase the chances of an adequate immune response. The approach is directed to the infectious process by SARS-CoV-2 and protein S as a therapeutic focus. We discuss the antiviral activities of certain natural and specific sulfated polysaccharides that bind tightly to protein S. Finally, we identified that sulfated polysaccharides act as baits to interfere with the binding of the spike protein (SARS-CoV-2) to the ACE2 receptor and can be administered through food.

1. Introduction

COVID-19 is the name given to the global pandemic caused by the SARS-CoV-2 virus and its mutated variants. The disease causes a series of problems related to the sulfated polysaccharide respiratory tract, and in more acute cases it can lead to systematic failures of the immune system leading to multiple organ failure and death. Globally as of February 3, 2023, there have been 754.018.841 confirmed cases of COVID-19, including 6.817.478 deaths reported to WHO. As of January 31, 2023, a total of 13.168.935.724 vaccine doses have been administered.

The current understanding of the SARS-CoV-2 virus and its variants suggests a highly pathogenic nature related to the binding affinity between the pathogen and the host cell. The SARS-CoV-2 virus efficiently circumvents and blocks the immune system's defensive maneuvers, inhibiting cytokine activity (interferon (IFN), and causing a series of immune system failures. Thus, the main questions that can help to elucidate the possible means for the treatment of COVID-19 are the understanding of tropism, replication, release, and transmission of viral load (Wang et al., 2020, Di Nardo et al., 2020).

The SARS-CoV-2 virus and its variant forms have specificity for binding to the angiotensin-converting enzyme 2 receptor and serine transmembrane protease 2. These receptors together with a mannose receptor via lipopolysaccharides (LPSs), toll-like receptors via LPS / proteins / RNA, and sialic acid (Sia) via hemagglutinin or segments of glucans can help to understand the infection process (Barbosa & de Carvalho Junior, 2021). Fig. 1 , summarizes the main steps associated with pattern recognition in the cell membrane and membrane cleavage associated with furin mechanisms, in addition to other cell proteases such as TMPRSS2 8 at the S1 / S2 site.

Fig. 1.

Fig. 1

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Summary of the main steps associated with the recognition of patterns in the cell membrane and membrane cleavage associated with furin mechanisms, in addition to other cell proteases, such as TMPRSS2 at the S1/S2 site.

The storm of cytokines common in severe cases of patients infected with SARS-CoV-2 is associated with constant failures of the immune system. The uncontrolled release of pro-inflammatory compounds triggers a series of failures in the immune system response, leading in many cases to systematic failures of the pulmonary alveoli, heart, liver, and death. The cytokine storm may help researchers understand the mechanisms by which nuclear capsid proteins and RNAs bypass the secretion induced by interferon pattern recognition (IFNs) in cells (Di Nardo et al., 2020).

Sulfated polysaccharides have been extensively studied for >50 years, and have already been applied in preclinical studies to inhibit viruses such as human papillomavirus (HPV), influenza B virus, and mumps. While others are in a very advanced clinical stage for infections such as hepatitis C (HCV), and human immunodeficiency virus (HIV). On the other hand, some sulfated polysaccharides such as heparin have been on the market since the 1930s, being the oldest anticoagulant used in clinical practice (Andrew & Jayaraman, 2021).

Since the origin of the pandemic in 2019, sulfated polysaccharides have been widely investigated for their antiviral potential against Sars-Cov-2. Recently, some review articles revisited the use of sulfated polysaccharides and their antiviral potential. The articles can be consulted for a more in-depth analysis of polysaccharides of marine origin, structural and molecular characteristics, and a deeper analysis of the infection by Sars-Cov-2 (Shi et al., 2021, Hans et al., 2021, Andrew and Jayaraman, 2021). However, these articles addressed polysaccharides as potential drugs and were limited to discussing mechanisms and means by which they could be administered. Furthermore, little has been examined about the mechanisms associated with the interaction between protein S (Sars-Cov-2) and the sulfated polysaccharide.

As these polysaccharides are non-toxic and biocompatible, we believe they can be administered through food. Therefore, the objective of this analysis article is to contextualize the reader about the antiviral mechanisms of sulfated polysaccharides associated with protein S binding (Sars-Cov-2) and to expand the discussion to strategies for supplying sulfated polysaccharides through feeding and blocking the ACE2 membrane receptors on cells of the oral mucosa, stomach, small intestine, and colon.

2. Sulfated polysaccharides inhibit SARS-CoV-2 virus entry

Sulfated polysaccharides exhibit potent antiviral activity related to the blockade of receptors linked to Spike Sars-Cov-2 protein, inducing steric hindrance. We know that blocking depends on three sulfated polysaccharides binding positions in the Spike protein. Sulfated polysaccharides can block Spike protein by directly binding to receptors on Heparan sulfate proteoglycans (HSPGs). Can compete for Spike protein binding by blocking the Receptor Binding Domain (RBD). Or, can prevent furin-mediated cleavage of the Spike protein, associating with the S1/S2 sites (Kwon et al., 2020). In Table 1 , we recap the main sulfated polysaccharides, their characteristics, and the antiviral mechanisms associated with Spike Sars-Cov-2 protein binding.

Table 1.

List of some sulfated polysaccharides tested for binding to wild-type SARS-CoV-2 and some variants.

Sulfated polysaccharides Inhibitory concentration Efficiency Type of virus Comments Reference
Heparin 1 μM IC50 = 0.056 μM SARS-CoV-2 The polysaccharide acts at the S1/S2 proteolytic cleavage site. (Kim et al., 2020)
Heparin 1 μM IC50 = 5.99 μg/l SARS-CoV-2 Heparin binds to glycosaminoglycans such as heparan sulfate on the cell surface. (Tandon et al., 2021)
Heparin 500–1.000 μg/ml−1 IC50 = 125 μg mL− 1 BetaCoV/Netherlands/
01/NL/2020		 We demonstrated in vitro that heparin inhibits SARS-CoV-2 infection and acts as an anticoagulant and anti-inflammatory agent. (Conzelmann, Müller, & Perkhofer, 2020)
Heparin 63 nM 58% N501Y mutant Computer simulations suggest an influence of sulfation patterns of Fuc units on hydrogen bonding with GlcA. (Dwivedi et al., 2021)
Heparin 6.25 a 200 μg mL −1 80 % Italy/UniSR1/2020 Inhibition of viral infection likely arises from an overlap between heparin/HS binding sites on S1 RBD and angiotensin-converting enzyme 2. (Mycroft-West et al., 2020)
Enoxaparin 250 UI/ml – hCoV-19/Italy SARS-CoV-2 binds to epithelial cells via heparan sulfate proteoglycans, leading to ACE-2-dependent infection. (Bermejo-Jambrina et al., 2021)
Dalteparin 250 UI/ml – hCoV-19/Italy – (Bermejo-Jambrina et al., 2021)
TrisS HS >500 μg mL −1 IC50 = 5.0 μM SARS-CoV-2 The larger the oligosaccharide template used in docking studies, the stronger the binding. Specifically, octasaccharide binds more tightly than tetrasaccharide. (Kwon et al., 2020)
Mucopolysaccharide polysulfate 5 ng/mL IC50 = 9 nM SARS-CoV-2 – (Zhang et al., 2022)
Fucoidan RPI-27 >500 μg mL −1 IC50 = 9.1 μg mL−1 SARS-CoV-2 Fucoidan binds to glycoprotein S and prevents entry of SARS-CoV-2. (Song et al., 2020)
Iota-carrageenan >10 μg/ml IC50 = 2.6 μg mL− 1 SARS-CoV-2 A nasal spray containing iota-carrageenan has been shown to reduce the severity and duration of cold symptoms. (Morokutti-Kurz et al.,
2021)
Lambda-carrageenan 5 mg/kg EC50 = 0.9 μg mL− 1 (BetaCoV/Korea/-KCDC03/2020) Intranasal administration protected 60% of mice from virus-induced mortality. (Jang et al., 2021)
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Angiotensin-converting enzyme 2 (ACE2), widely distributed in cells, plays a critical role in virus attachment to host cells. Target sites for therapy include cells in the oral mucosa and nasopharynx, smooth muscle cells, and vascular endothelium in the stomach, small intestine, and colon. Smooth muscle cells in the muscular mucosa and enterocytes in the small intestine, including the duodenum, jejunum, and ileum (Morokutti-Kurz et al., 2021).

Recently, two strategies have been widely used to identify how sulfated polysaccharides block infection by Sars-Cov-2. Interactions between sulfated polysaccharides - Sars-Cov-2 are studied using surface plasmon resonance spectrometry (SPR) and structurally defined oligosaccharide sequences in a high-throughput microarray format. With these two experiments, it was possible to quickly screen several sulfated polysaccharides that compete for binding to the Spike protein receptor. Although there are differences between the studies given the methodology, we cannot generalize trends regarding sulfated polysaccharides - SARS-CoV-2 interactions (Jin et al., 2020).

Among all the sulfated polysaccharides studied, heparin was identified as having the strongest binding to SARS-CoV-2 receptors. When heparin is associated with metallic ions such as magnesium, an increase in antiviral activity is observed (Mese et al., 2021). Other sulfated polysaccharides like fucans and galactans showed high receptor binding affinity for SARS-CoV-2 but no protein S inhibition activity (Jin et al., 2020). Another study showed that iota-carrageenan has high antiviral activity, whereas kappa carrageenan and lambda-carrageenan were less effective (Morokutti-Kurz et al., 2021).

The chain length of sulfated polysaccharides is critical, as the greater the molecular weight of the chain, the greater the antiviral activity. Low molecular weight heparin is less effective when compared to unfractionated heparin. Short-chain sulfated polysaccharides fail to provide the essential steric hindrance to inhibit viral infection. Furthermore, long sulfated polysaccharide chains can interact with multiple target sites simultaneously (Paiardi et al., 2022). Recent evidence shows that high molecular weight heparin can bind protein S in both open and closed forms, inhibiting sites of infection (Clausen & Sandoval, 2020).

Sulfated polysaccharides that have branches with α-Fuc2,4S difucosyl unit in the terminal monosaccharide are good coadjuvants in the interaction of sulfated polysaccharide with SARS-CoV-2. The presence of ions such as iodine in the branched structure of sulfated polysaccharide enhances binding to SARS-CoV-2 receptors (Hao et al., 2021). The sulfation pattern is complex and suggests patterns of electrostatic interactions between protein S-SARS-CoV-2 and sulfated polysaccharide. Generally, studies define some sulfation sites as a prerequisite for sulfated polysaccharide binding to protein S target sites. Higher levels of sulfation have been shown to increase sulfated polysaccharide interactions with protein S target sites and reduce infection rates (Tandon et al., 2021).

3. Strategies for delivering sulfated polysaccharides through food

We know that the SARS-CoV-2 virus infects various cell tissues where ACE2 receptors are present, including the respiratory and gastrointestinal tracts. Therefore, a potential route for delivery of these sulfated polysaccharides is oral via functional foods. In Fig. 2 , we present a summary of possible paths for the delivery of sulfated polysaccharides.

Fig. 2.

Fig. 2

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(A) Graphic summary showing the competition of sulfated polysaccharides (SPOP) and COVID-19 viruses for membrane receptors. Sulfated polysaccharides inhibit the binding between protein S and ACE2 receptors in host cells. (B) We present a summary of potential routes for the delivery of sulfated polysaccharides.

The epithelial cells of the stomach are rich in ACE2 and other receptors that are the gateway to the binding with the Spike (S) protein of SARS-CoV-2. Using foods rich in sulfated polysaccharides may be the key to blocking the link between the virus and receptors. Sulfated polysaccharides can be used in the formulation of edible gums. For example, small doses of sulfated polysaccharide can be added to starch or gelatin gums. Similar products, such as starch gums containing vitamin C and other phytochemicals, are found on the market. Gums are an attractive option, as they remain in the mouth for a long time and are tasted, providing the controlled release of sulfated polysaccharide throughout the larynx and esophagus (Gómez, Pérez-García, Alemán, Vázquez, & Montero, 2022).

ACE2 participates in homeostasis, mediated through the regulation of the activity of the K-RAS gene in the intestine by regulating the microbiota and the uptake of amino acids and antiviral peptides. The binding of SARS-CoV-2 to ACE2 blocks biochemical signals related to the regulation of the intestine microbiota, leading to colon inflammation, alteration of the endothelium, and reduced responsiveness to damage. Sulfated polysaccharides inhibit the connection of the SARS-CoV-2 virus to ACE2 through chemical competition mechanisms (Kim et al., 2020). A small dosage of polysaccharides acts directly on the cell membrane without passing through the bloodstream and activates the biochemical signaling pathways of defense cells (Table 1).

The intestine has the highest expression for ACE2, followed by smooth muscle cells and endothelium of the stomach and colonic vessels, in addition to smooth muscle cells from the mucosa and enterocytes from all parts of the small intestine, including the duodenum, jejunum, and ileum. SARS-CoV-2 infection leads to severe changes in all these cellular tissues, including multiple organ failures linked to physiological functionality (Tandon et al., 2021). Κ-carrageenan exposes sulfated groups in casein-containing systems during digestion and interacts with receptors present in the stomach. Systems containing dairy beverages can use κ-carrageenan as active functional agents (Guo et al., 2023). Functional beverages containing fucoidan and other sulfated polysaccharides exhibit antioxidant, anticoagulant, antiviral, anticancer, and anticoagulant activity (Yoo et al., 2019, Chen et al., 2021).

Food emulsions have also been prepared with sulfated fucan, ι-carrageenan, κ-carrageenan, and alginate, which act as foaming agents and emulsion stabilizers being released during digestion (Shi, Chang, Shen, Chen, & Xue, 2023). Bovine albumin and fucoidan conjugates improve the physical stability of emulsions, including in the gastric phase, and show high bioaccessibility of bioactive compounds (Kim & Shin, 2021).

Gels and hydrogels are also an option for delivering sulfated polysaccharides and can be flavored and consumed in liquid form (Srivastava & Choudhury, 2023). In addition, hydrogels may contain other active ingredients, such as antioxidants and anti-inflammatory agents (Shu et al., 2023). Tian et al. (2021) efficiently produced an edible hybrid base of beeswax carrageenan-xanthan to transport lychee ink for 3D food printing. We evaluated that hybrid gelator systems are attractive materials for applications in functional foods, mainly considering the stability, precision, and reliability of products after 3D printing.

Sulfated polysaccharides are promising as active agents for food packaging and edible sachets. Studies conducted before the COVID-19 pandemic have extensively investigated the benefit of κ-carrageenan and alginate in antiviral film production (Shojaee-Aliabadi et al., 2014, Azarakhsh et al., 2014). New studies must advance in the formulation of films containing heparin and other artificially sulfated polysaccharides and validate their application with in vitro and in vivo studies.

4. Conclusions

Sulfated polysaccharides reduce viral load, inhibit the viral cycle, and help boost immunity through immunomodulatory effects. Sulfated polysaccharides with a high degree of branching, sulfation, and molecular weight inhibit and compete for connections with the Spike (S) protein, reducing the entry of SARS-CoV-2 into the cellular environment. Different strategies can be applied to release sulfated polysaccharides through feeding. The most promising are edible packaging, gums, and beverage.

5. Ethics statement

The authors declare not to have violated any ethical principles.

CRediT authorship contribution statement

Jhonatas Rodrigues Barbosa: Conceptualization, Investigation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing. Lúcia de Fátima Henriques Lourenço: Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

The authors would like to thank the Federal University of Pará for the infrastructure for carrying out the literature review.

Data availability

Data will be made available on request.

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Data Availability Statement

Data will be made available on request.

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