Carbohydrate Polymers 272 (2021) 118526

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Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol

Review

Recent advances in antiviral activities and potential mechanisms of

sulfated polysaccharides
Wenjing Lu *, Zhifeng Yang, Juan Chen, Di Wang, Yu Zhang
Shaanxi Academy of Traditional Chinese Medicine, Xi'an 710003, China

A R T I C L E I N F O A B S T R A C T

Keywords: Natural polysaccharides derived from plants, fungi and animals are well known as ideal functional products with
Sulfated polysaccharide multiple biological activities and few side effects. Among them, natural occurring sulfated polysaccharides and
Sulfation those from synthetic origin are increasingly causing more attention worldwide, as they have been proved to
Viral infection
possess broad-spectrum antiviral activities. The focus of this review is on analyzing the current state of
Molecular structure
knowledge about the origin of sulfated polysaccharides, more importantly, the potential connection between the
Mechanism
structure and their antiviral mechanisms. Sulfated polysaccharide may interfere with a few steps in the virus life
cycle (i.e. adsorption, invasion, transcription and replication) and/or improve the host antiviral immune
response. Moreover, their antiviral activity was affected by degree of substitution, substitution position, mo­
lecular weight, and spatial conformation. This review may provide approach for the development of novel and
potent therapeutic agents.

1. Introduction
Polysaccharides are a structurally diverse group of biopolymers
existing in an enormous structural diversity as they are produced by
microbes, algae, plants, and animals (Ullah et al., 2019). They partici­
pate in various life activities, and display great potential for various
biological properties, such as antiviral, immune-modulating, antimi­
crobial, anticoagulant, anti-diabetic, antioxidant, and antitumor activ­
ities (Chen, Liu, et al., 2018; Kalinina et al., 2020; Li et al., 2016;
Mirzadeh et al., 2020; Zhang et al., 2017; Zhao et al., 2019).
In particular, sulfated polysaccharides offer interesting pharmaco­
logical perspectives for antiviral drug development (He et al., 2020).
Sulfated polysaccharides, referring to natural and semi-synthetic acidic
polysaccharides, are formed by the substitution of hydroxyl groups on
the monosaccharide in the macromolecular chain with sulfate groups.
Studies have shown that, whether they are directly extracted or chem­
ically modified, the antiviral activity is one of the most important bio­
logical activities of sulfated polysaccharides. They have significant
inhibitory effects against viruses such as influenza A virus (IAV) (Kim
et al., 2012), human immunodeficiency virus (HIV) (Thuy et al., 2015),
dengue virus (DENV) (Pujol et al., 2012), herpes simplex virus (HSV)
(Mandal et al., 2008), hepatitis B virus (HBV) (Jiang et al., 2003), and
also effective on the 2019-coronavirus (SARS-CoV-2) (Mycroft-West
et al., 2020) (Table 1). Besides, sulfated polysaccharides exert low
cytotoxicity and drug resistance, good biocompatibility, less side effects,
and also possess immune-stimulating perspectives (Huang, Shen, et al.,
2019; Witvrouw & Clercq, 1997), which lead to the potential for new
food supplements and antiviral drugs.
In addition, the biological activity of sulfated polysaccharides is
closely related to the molecular structure. With the introduction of
sulfate groups, the original molecular chain conformation of the poly­
saccharides is changed. Thus, in-depth study on the biological activity,
physical and chemical properties and structure-activity relationships of
polysaccharides is conducive to the development of potential antiviral
drugs. This review summarized and analyzed recent advances of the
source, antiviral activity, as well as the structure-activity relationship of
sulfated polysaccharides, aiming to provide reference and guidance for
the future investigations.
2. Source of sulfated polysaccharides
2.1. Natural polysaccharides
Many sulfated polysaccharides with high antiviral activity are
extracted from algae or microorganisms. Due to the long-term exposure
to high-pressure, high-salt, low-temperature, and oligotrophic

* Corresponding author at: Shaanxi Academy of Traditional Chinese Medicine, No.4 Xihuamen, Xi’an 710003, Shaanxi, PR China.
E-mail address: lwjcici@hotmail.com (W. Lu).

https://doi.org/10.1016/j.carbpol.2021.118526
Received 19 May 2021; Received in revised form 31 July 2021; Accepted 1 August 2021
Available online 5 August 2021
0144-8617/© 2021 Elsevier Ltd. All rights reserved.
W. Lu et al. Carbohydrate Polymers 272 (2021) 118526

Table 1 Table 1 (continued )

Antiviral activities of sulfated polysaccharides from different sources. Polysaccharide Source Virus type Mechanism References
Polysaccharide Source Virus type Mechanism References name
name
Ascophyllum HIV, HBV, Inhibit the early (Ueno
p-KG03 Gyrodinium H1N1, Inhibit virus (Kim et al., nodosum HCV step of virus et al.,
impudium H3N2 attachment, 2012) infection 2019)
penetration into sABPS Achyranthes PRRSV Inhibit viral (Liu et al.,
cells and, early bidentata adsorption and 2013)
viral replication replication
Fucoidans Sargassum HIV Block the early (Thuy sRCP Cyathula HSV-2 Interfere with (Liu et al.,
mcclurei, steps of HIV et al., officinalis the virus 2004)
Sargassum entry into target 2015) adsorption
polycystum, cells process
Turbinara sAPS Astragalus IBDV Combine with (Huang
ornata membranaceus virus or cells, et al.,
GiWE, GiF3 Grateloupia DENV-2 Interfere virus (Pujol interdict virus 2008)
indica adsorption and et al., adsorption or
internalization 2012) inhibit some
ShWE Scinaia hatei HSV-1/-2 Inhibit viral (Mandal step of virus
replication et al., replication after
2008) entered cell
Heparin SARS-CoV- Bind to the (Mycroft- KW Kjellmaniella IAV Bind to viral (Wang
2 Spike protein West et al., crassifolia neuraminidase et al.,
receptor 2020) (NA) and 2017)
binding domain inhibit the
and induce activity of NA to
conformational block the viral
change release
911 HBV Inhibit the (Jiang
replication of et al.,
virus DNA 2003) environments, marine organisms, especially algae, are rich in sulfated
DS-1, DS-2e, Cryptonemia HMPV Inhibit virus (Mendes polysaccharides which have been found to possess unique structures and
DS-3 seminervis replication by et al.,
exert virucidal effects on various viruses. Gerber and colleagues firstly
binding to the 2014)
viral particle; reported in 1958 about the inhibition effects of influenza B virus and
inhibit the mumps virus by highly sulfated polysaccharides from marine algae
recognition of Gelidium cartiagenium, suggesting algae-derived polysaccharides as
cell receptor by potent source of antiviral agents (Gerber et al., 1958).
HMPV and
penetration to
At present, the extraction of sulfated polysaccharides from algae has
the host cell become an important way to obtain natural sulfated polysaccharides.
PAE Entermorpha RSV, IBV, (Wang These natural polysaccharides all exhibit antiviral activities in varying
intestinalis HSV-1/-2, et al., extents (Ahmadi et al., 2015) (Fig. 1). Sulfated fucoidans derived from
enterovirus 2019)
several brown seaweeds such as Sargassum mcclurei, Sargassum poly­
71
P1S, P2S Azadirachta HSV-1 Interfere the (Faccin- cystum, Turbinara ornate, Dictyota bartayesiana and Turbinaria decurrens
indica early stages of galhardi displayed similar antiviral activities and low cell toxicity in comparison
virus et al., with other conventional drugs commonly used (Sanniyasi et al., 2019;
replication, 2019) Thuy et al., 2015). Sulfated DL-hybrid galactans obtained from the red
including
adsorption
seaweed Cryptonemia seminervis showed anti-human metapneumovirus
sBSRPS Bush sophora DHAV-1 Inhibit virus (Chen, (HMPV) activity (Mendes et al., 2014). A sulfated polysaccharide from
root protein Yang, the green algae Entermorpha intestinalis (Wang et al., 2019) had a sig­
translation and et al., nificant anti-respiratory syncytial virus (RSV) activity, and its IC50 value
RNA synthesis 2018)
was only 1.63 μg/mL; in addition, it also had varying degrees of inhib­
SCPPS-1 Codonopsis HSV-1 Occupy the (Wang
pilosula receptor et al., itory effects on influenza A virus (A/Aichi/2/68), influenza B virus (B/
binding sites, 2015) Hongkong/5/72), HSV-1, HSV-2 and enterovirus 71. Ulvan (1068.2
resulting in the kDa) and ulvan-F1 (38.5 kDa) from Ulva pertusa with relatively high
decrease of molecular weight showed potency of inhibiting the infection and repli­
virus
adsorption;
cation of vesicular stomatitis virus (VSV) (Chi et al., 2020).
affect the
functions of
some key
2.2. Artificially sulfated polysaccharides
enzymes of
virus It has been observed that the molecular modification of poly­
replication saccharides can enhance the antiviral activity. Sulfated modification
Iota- HRV, Bind and (Ciejka
(Fig. 2) refers to the introduction of sulfate groups into the backbones of
carrageenan H1N1, inactivate virus et al.,
hCoV, particles; block 2019; natural polysaccharides that lack intrinsic sulfate groups to endow them
hMPV viral release Morokutti- with the change of the three-dimensional conformation. Hence, these
from infected kurz & polysaccharides with weak or no biological activities could enhance
cells Prieschl- their analogous activity or obtain new activity within living organisms.
grassauer,
2017)
Also, they can be used as building blocks for drug carriers and medical
Ascophyllan implants (Zeng et al., 2019).
At present, the commonly used methods for sulfation include
Nagasawa method (Concentrated sulfuric acid method), Wolfrom

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W. Lu et al. Carbohydrate Polymers 272 (2021) 118526

OH
OH -
O3SO
OSO3- O
COO- O
O O
HO O O O
HO O
O OH
NH OSO3-
- n
OSO3 n

heparan sulfate ι-carrageenan

HO OSO3-
HOOC
H3 C O O O O
OH HO O
O OH
- NHCOCH3
O3SO
n
n

fucoidan chondroitin sulfate C

Fig. 1. Examples of natural occurring sulfated polysaccharides with antiviral activities.

1) conc. H2SO4, pyridine

OH OSO3-
2) ClSO3H, pyridine
O O O
O O
HO O RO
OH OR
3) SO3•pyridine
n n

Fig. 2. Scheme and general methods for the synthesis of sulfated polysaccharides. R = H/SO3− .

method (chlorosulfonic acid-pyridine method), SO3⋅pyridine method sinkiangensis polysaccharide (FSP), Morus nigra polysaccharide (MP) and
(Bedini et al., 2017; Dimassi et al., 2018; Huang et al., 2020) (Table 2). their sulfated modifiers, turned out the post-adding polysaccharide
Nagasawa method is usually used for furan polysaccharides, while group had the best antiviral effect, and the sulfated MP with 2.5%
Wolfrom method is used for pyran polysaccharides. substitution showed the strongest anti-NDV effect (Abula & Mulati,
Mukherjee and colleagues used utilized oleum-DMF reagent to syn­ 2018). Godoi and et al. evaluated the activity of sulfated polysaccharide
thesize a range of sulfated polysaccharides from various natural sources from the Adenanthera pavonina (SPLSAp) seeds against poliovirus type 1
(Mukherjee et al., 2019). These compounds exhibited high level of anti- (PV-1) in HEp-2 cell cultures (Godoi et al., 2014). The SPLSAp exhibited
human cytomegalovirus (HCMV) and anti-HSV-1 activity, EC50 values of a significant antiviral activity (IC50 of 1.18 μg/mL), and low cytotoxicity
2.34–7.77 μg/mL, at a low degree of cytotoxicity. Polysaccharides iso­ (CC50 of 500 μg/mL). Bush sophora root polysaccharide (BSRPS) and its
lated from the leaf of Azadirachta indica and their chemically sulfated sulfate, sBSRPS significantly inhibited the protein translation and RNA
derivatives were analyzed with their anti-HSV efficacy. These sulfated synthesis of duck hepatitis A virus-1 (DHAV-1), and the activity of
compounds showed better inhibition effect compared to the nonsulfated sulfated modifier was stronger than the original one (Chen, Yang, et al.,
ones (Faccin-galhardi et al., 2019). The antiviral efficacy of sulfated 2018).
Codonopsis pilosula polysaccharides-1 (SCPPS-1) was evaluated on HSV-
1, turned out the survival rate of the sulfated polysaccharide was higher 3. Antiviral mechanisms of sulfated polysaccharides
than control, its preventive effect was equal to Acyclovir, while its
therapeutic effect was better (Wang et al., 2015). Abula and et al. Viral infections have always been a worldwide problem that threaten
studied on the anti-Newcastle disease virus (NDV) effects of Ferula human health. The adhesion of pathogenic organisms to host tissues is
the prerequisite for the initiation of the infection. Usually, lectins pre­
Table 2 sent on the viral surface bind to complementary carbohydrates on the
Comparison of different sulfation methods of polysaccharides. host cell surface (Sharon, 2006). After the adhesion, the virus can get
access to the cytoplasm through receptor-mediated endocytosis or
Method name Sulfating agent and Characteristics
conditions endocytosis-independent receptor-mediated entry (Grove & Marsh,
2011). Viral genome is released and translated into viral polymerase
Nagasawa Concentrated sulfuric Stable conditions, fewer side reactions
method acid, pyridine and low toxicity of chemical reagents;
proteins. Viral RNA and structural protein are replicated, transcribed, or
Ice water bath polysaccharides degradation and synthesized in the cytoplasm, then translated in the host ribosome. The
carbonization by sulfuric acid. viral RNA and proteins are assembled to form a mature virion, then
Wolfrom Chlorosulfonic acid, The most common approach with high released from host cells for further infection (Fig. 3). The antiviral ac­
method pyridine, DMF DS value and yields; sensitive to
tivity of sulfated polysaccharides may be achieved by inhibiting one or
Ice water bath moisture, strong acid and violent
chemical reaction, difficult to control. more steps of viral infection. They can interfere with different stages of
SO3•pyridine Sulfur trioxide, Simple and convenient operation; the virus life cycle by directly interacting with virus particles, inhibiting
method pyridine reagents are more expensive, only the adsorption of the virus, hindering its binding to cell receptors, pre­
Ice water bath suitable for small-scale applications in venting the penetration of the virus into host cells, and activating
the lab.
intracellular signaling pathways. Moreover, it can enhance the host's

3
W. Lu et al.
Fig. 3. The process of viral infection and the antiviral phase of sulfated polysaccharides.
immune response and induce immune factors to accelerate virus clear­
ance (Chen et al., 2020; Chen & Huang, 2018; Wu et al., 2016).
3.1. Direct inactivation effects on virus
Sulfated polysaccharide can directly act on the surface of the viral
particle due to the negative charge it carries, thereby inhibiting the in­
fectious ability of the virus, or killing the virus so it loses infectious
ability. Marine sulfated polysaccharides could bind to the spike glyco­
protein to prevent SARS-CoV-2 host cell entry (Song et al., 2020). Wang
and et al. compared anti-NDV effect of four sulfated polysaccharides
from Chinese angelica and four sulfated polysaccharides from Lycium
barbarum by MTT method (Wang et al., 2011). The virus inhibitory rates
in mixed adding polysaccharides with NDV were significantly higher
than those of the control group, indicating the sulfated polysaccharides
could directly kill the virus. Iota-carrageenan, a high molecular weight
sulfated polysaccharide derived from the red seaweed, is an approved
antiviral drug used for respiratory tract infections (Morokutti-kurz &
Prieschl-grassauer, 2017). Experimental results showed that iota-
carrageenan could bind and inactivate virus particles in rapid and effi­
cient way. Carrageenan of Gigartina atropurpurea, sulfated fucoidan of
Undaria pinnatifida and Splachnidium rugosum can directly inactivate
HSV-2 at low concentrations, and their virus-killing activity enhanced
with their increasing molecular weight (Harden et al., 2009). Sulfated
chitooligo-saccharides can block viral entry and virus-cell fusion,
exhibiting remarkable inhibitory activities on HIV-1-induced syncytia
formation, lytic effect, and p24 antigen production (Artan et al., 2010).
Sulfated alginate polysaccharides from Laminaria angustata can inhibit
HSV-1 at low concentrations, and interfere with the infection process by
binding to glycoproteins on the viral envelope which recognize host cell
surface receptors (Saha et al., 2012).
3.2. Blocking the adsorption and invasion of virus
Viruses must be adsorbed and penetrated into target cells to initiate
4
Carbohydrate Polymers 272 (2021) 118526
infection. The heparin-like sulfated proteoglycan on the cell surface is
the initial receptor for the viral infection process. Natural and synthetic
sulfated polysaccharides have strong polyanionic properties and can
interact with the viruses or host cell surface protein by electrostatic
interaction to prevent the adsorption to the cell and block the binding
sites where the virus binds to the host cell receptor (Chen & Huang,
2018). The negatively charged sulfate groups in sulfated poly­
saccharides can interact with the positively charged amino acids in the
HIV surface glycoprotein gp120 at the V3 loop domain from the C-ter­
minus, then block the HIV-1 entry into CD4 cells. As the structure is
similar to the negatively charged glycosaminoglycan (GAG) on the cell
surface, sulfated polysaccharides can prevent the combination of virus
and target cell in a way of competitive inhibition to form a non-
infectious sulfated polysaccharide-virus complex; at the same time, it
can directly bind to T cell surface receptors, hindering the virus
adsorption to CD1 cells (Battulga et al., 2018; Liu et al., 2005). Asco­
phyllan, sulfated fucan polysaccharide isolated from Ascophyllum
nodosum, significantly inhibited the early step of HIV-1, HBV and HCV
infection, while it did not affect the late step (Ueno et al., 2019).
Fucoidan could directly interact with the envelope glycoprotein on the
dengue virus DEN2 surface. Its spatial conformation analysis revealed
that the surface protein of DEN2 has a similar structure to the heparin
binding site, and fucoidan was thought to inhibit virus binding to the
cells in a competitive manner (Hidari et al., 2008). 3,6-O-sulfated chi­
tosan possessed broad anti-HPV activities by directly targeting viral
capsid protein and host PI3K/Akt/mTOR pathway to inhibit cell auto­
phagy (Gao et al., 2018). The sulfate derivative of Cyathula officinalis
polysaccharide showed significant antiviral effects by interfering with
the HSV-2 adsorption process. The sulfate polysaccharide played as a
structural analog of cell surface receptor-heparan sulfate, competitively
bound with adsorption-related proteins, thereby preventing viruses
from entering target cells (Liu et al., 2004).
W. Lu et al. Carbohydrate Polymers 272 (2021) 118526

3.3. Inhibiting transcription and replication of virus
The sulfated polysaccharides chain has the same binding site as
certain enzymes of the RNA template primer, resulting in their
competitive inhibitory effects (Allard et al., 1998). On the other hand,
sulfated polysaccharides can directly interfere with viral replication-
related enzymes, as well as inhibit the transcription and replication by
acting on relevant intracellular targets. Ulvan (1068.2 kDa) and its
degraded fragment ulvan-F1 (38.5 kDa) from Ulva pertusa showed po­
tency of inhibiting the infection and replication of VSV (Chi et al., 2020).
The sulfated polysaccharide derived from Bush sophora root offered
stronger antiviral properties on inhibition of DHAV-1 protein translation
and RNA synthesis. Furthermore, the modifier dropped the protein
translation via suppressing DHAV-1 internal ribosome entry site activity
and dropped the DHAV-1 synthesis via suppressing cellular heat shock
protein 70 expression (Chen, Yang, et al., 2018). The sulfated derivatives
of Angelica polysaccharides were used to study the effect on murine
leukemia virus in vivo. Six sulfated derivatives were obtained with the
degree of sulfation of 0.68–1.91. They inhibited viral replication at doses
of 10 and 30 mg/kg (26% and 30% inhibition, respectively) (Yang et al.,
2012).
3.4. Blocking viral release from host cell membrane
Sulfated polysaccharides can block the viral release from infected
cells by modification of membrane plasticity or anchoring the progeny
virions to the cell and, consequently, constrain virus spread. Iota-
carrageenan and its N-sulfonated derivatives showed strong antiviral
activities against human metapneumovirus (hMPV), a kind of respira­
tory infections RNA virus, by blocking virus release from the cellular
membrane and inhibiting virus infectivity (Ciejka et al., 2019). A
fucoidan (KW) derived from brown algae Kjellmaniella crassifolia effec­
tively blocked IAV infection in vitro with low toxicity. KW could bind to
viral neuraminidase (NA) protein which promote the release process of
progeny virus from host cells, and inhibit the activity of NA to block the
viral release. KW also interfered with the activation of EGFR, NF-κB, and
Akt protein, suggesting that KW may also inhibit cellular EGFR pathway
which promote the invasion of IAV into host cells (Wang et al., 2017).
3.5. Enhancing antiviral immunomodulatory activity
mortality, indicating that sulfated modification could enhance the
adjuvanticity of lentinan and improve the immune effect of ND vaccine
(Guo et al., 2009). An found out that sulfated modification can signifi­
cantly improve the activity of Polygonum taipaishanease polysaccharide
against Transmissible gastroenteritis virus (TGEV), and also inhibit the
abilities of porcine endogenous Shigella and E. coli (An, 2016). The
Lymphocyte Immune factor IL-2 and TNF-α secretion activity was also
significantly enhanced in vitro. Moreover, structural modification such
as the phosphorylation would also enhance the antiviral, anti-
inflammatory and antitumor activity, especially the immune regu­
lating function of polysaccharides, which could provide theoretical basis
for the antiviral drug design and development in the future.
4. Potential structure-activity relationship of antiviral
polysaccharides
As more bioactivities of sulfated polysaccharides were reported, in-
depth studies on the structure-activity relationship of sulfated poly­
saccharides have a widespread and profound impact on polysaccharides
development and application. The structural diversity and complexity of
sulfated polysaccharides are crucial challenges for the study of their
structure-activity relationship (Fig. 4). The bulky acidic sulfate substit­
uent that dominate the physical characteristics of polyanions can
equally dominate the effects of such macromolecules in biological sys­
tems. The antiviral activity of sulfated polysaccharides determined by a
combination of structural features of the distribution of sulfate groups,
degree of sulfation in the carbohydrate backbone and molecular weight
of the macromolecule are undoubtedly important, but other factors such
as molecular construction and stereochemistry are also involved
(Harden et al., 2009).
4.1. Degree of substitution
The polyanionic properties of sulfated polysaccharides are closely
related to the distribution of sulfate groups (Ghosh et al., 2009; Lahrsen
et al., 2019). The higher degree of substitution (DS) proves that the
polysaccharide binds more sulfated groups. The presence of sulfated
groups can improve the solution properties and structurally increase the

In accordance with the pathogenesis of the disease, the pathogenetic

therapy of virus infections should provide not only a direct effect on the
virus, or the adsorption and penetration process to the cell, but it should
also activate innate immunity, strengthen the antioxidant defense sys­
tem, induce the production of immune cytokines, and indirectly exert
antiviral effects (Besednova et al., 2016). A large number of pharma­
cological experiments have proved that, sulfated polysaccharides are
effective immune regulators which maintain homeostasis by regulating
macrophages, natural killer cells (NK cells), T/B lymphocytes, and other
immune cells. They could also promote the cytokines release and the
generation of antibodies, activate the complement systems, and accel­
erate the process of viral elimination (Huang et al., 2019; Sozzani et al.,
2010). The effect of polysaccharide from Polygonatum sibiricum and its
sulfated derivative (OS1,2,3) on NK cell activation and cytotoxicity was
investigated using NK-92 cells by determining the levels of cytotoxicity
and the gene expressions of INF-γ, granzyme-B, perforin, NKG2D, and
FasL. OS1,2,3 markedly promoted the activation and cytotoxicity of NK
cells by enhancing IFN-γ and perforin secretion, while increasing the
expression of the activating receptor (Yelithao et al., 2019). Chitosan
(Dimassi et al., 2018) could augment antigen-specific immune responses
by increasing the induction of T cells, and neutralize antibodies without
affecting lung histopathology in RSV-infected mice (Muralidharan et al.,
2019). Sulfated lentinan could significantly enhance serum antibody
titer and promote lymphocyte proliferation in vaccinated chickens Fig. 4. Structure features that may influence the antiviral activity of sulfated
which were challenged with NDV, with reduced morbidity and polysaccharides.

5
W. Lu et al.
negative charge distribution, which promote the antiviral potential of
polysaccharides (Wang et al., 2018). DS value could be affected by the
ratio of sulfation reagents, esterification temperature and reaction time.
It is well documented that the activity of sulfated polysaccharides had a
positive correlation with DS, that is, the higher DS, the better antiviral
potency. Sulfated Angelica polysaccharide (APS) with different DS
(0.68–1.91) had certain antiviral potency on murine leukemia virus
after sulfated modification, APS-1 with DS of 1.91 significantly induced
the antiviral activities in a dose dependent manner, indicating the
higher DS showed better efficacy (Yang et al., 2012). However, the
highest DS is not accompanied by the highest antiviral efficacy. The
antiviral activity of sulfated polysaccharides increases with the DS
within an optimal scope. There is cumulative evidence that the ideal DS
should be within the scope of 1.5–2.0 (Alban et al., 2002; Wang & Guan,
2000). Sulfated κ-carrageenan oligosaccharides had good inhibitory
actions on IAV replication in vitro and in vivo, the most active oligosac­
charide had a DS of 0.8–1.0 and a molecular weight of 1–3 kDa. DS and
molecular weight of sulfated polysaccharides might be the most
important factors which influence their bioactivities (Wang et al., 2012).
Furthermore, the antiviral activity of sulfated polysaccharides is also
closely related to the host immunomodulatory system. Study had shown
that the sulfated Lycium barbarum polysaccharides (LBPS) with higher
DS of 1.5 and 1.9 had stronger effect on lymphocyte proliferation,
indicating that sulfated modification could enhance the cellular immu­
nity, and there was certain relativity with the DS of sulfated poly­
saccharides (Wang et al., 2011).
4.2. Sulfation pattern
After sulfation of polysaccharides, the sulfated hydroxyl groups
showed changes in steric hindrance and electrostatic repulsion; more­
over, the flexion and extension of the polysaccharide chain and the
water solubility increased, resulting in the alteration of biological ac­
tivities. The anticoagulant activity and cytotoxicity of sulfated de­
rivatives of agarose and carrageenan were investigated in order to find
out the structure-activity relationship of these polysaccharides (Liang
et al., 2014). The substitution position demonstrated the biggest impact
on both the anticoagulant activity and the cell proliferation compared to
substitution degree. Moreover, the secondary structures of glycans also
play a key role in their biological activities. The sulfation pattern of
polysaccharides from Nemalion helminthoides was investigated based on
their antiviral activity against HSV-1/-2 and DENV-2. From methylation
analysis, C-2 and C-6 sulfation would be preferentially occurred first,
and the abundant sulfation on C-2 seemed to be a decisive factor for the
change in the antiviral activity. Thus, the structures exhibiting sulfation
pattern in C-2 and C-6 could effectively simulate the structure of cellular
heparan sulfate, receptor or co-receptor of a wide spectrum of virus like
HSV and DENV (Recalde et al., 2012). Furthermore, studies have
showed that some natural polysaccharides had no antiviral activity or
the activity was quite weak, but exhibited antiviral activity after sulfa­
tion (Teng et al., 2019). Sulfated polysaccharide from Codonopsis pilosula
had strong anti-HSV-1 effect in comparison with the nonsulfated poly­
saccharide. The spatial conformation change may occupy binding sites
of the host cell receptors to prevent the virus absorption, also, it may
affect the functions of some key enzymes in the virus replication (Wang
et al., 2015). On the contrary, the sulfated polysaccharides will reduce
or lose their antiviral activity after the sulfate groups are removed.
Compared with 6-O-sulfated chitosan, O-2 and/or O-3 selective-
sulfation increased the inhibitory rate of HIV replication, and
completely inhibited the infection to T lymphocytes at 0.28 μg/mL. The
results revealed that the selective sulfation pattern afford potent anti­
retroviral agents showing a much higher inhibitory effect on the HIV
infection (Nishimura et al., 1998).
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Carbohydrate Polymers 272 (2021) 118526
4.3. Molecular weight of polysaccharides
The antiviral activity of the polysaccharide requires some minimal
density of the charge, which is created by sulfate and carboxyl ions, as
well as the optimal length of the polymer chain. In general, the higher
the molecular weight, the better the activity. The anti-HIV activity of
dextran sulfate enhanced with the increase of its relative molecular
weight. The activity reached the maximum at 100,000, and maintained
potency between 10,000 and 500,000 (Gou, 2012; Zhuge et al., 2002).
Mohsen and colleagues obtained three groups of water-soluble sulfated
polysaccharides from brown algae Sargassum latifolium. The SP-III with a
higher molecular weight and DS elicited marked anti-HSV-1 and anti-
HAV activity contrary to other components with lower molecular
weight and DS (Mohsen et al., 2007). The interaction between sulfated
polysaccharides with potent anti-HIV activity was investigated using
SPR and DLS to elucidate their anti-HIV mechanism. Dextran and cur­
dlan sulfates exhibited strong interaction with poly-L-lysine and the
interaction strengthened with their increasing molecular weights and
DS, indicating that the anti-HIV activity could be induced by the elec­
trostatic interaction between the negatively charged sulfated poly­
saccharides and positively charged HIV gp120 (Battulga et al., 2018).
However, some low molecular weight sulfated polysaccharides also
have antiviral potential. For example, Artan and et al. found that
sulfated chitosan SCOS III with molecular weight of 3–5 kDa showed the
best inhibitory effect on HIV-1 replication, and can significantly inhibit
the syncytium formation, lysis effect and p24 antigen production
induced by HIV-1. The inhibition mechanism might be related to the
better absorption of sulfated polysaccharides with lower molecular
weight (Artan et al., 2010). Although sulfated polysaccharides showed
potent antiviral activities, the high molecular weight and/or over­
sulfated polysaccharides may also give side effects as platelet aggrega­
tion, strong allergic-type reactions which should be taken into
consideration for the further research of these polymers (Fonseca et al.,
2010; Guerrini et al., 2008). Therefore, further experiments should be
conducted to figure out how the molecular weight of polysaccharides
interfere with the antiviral activity.
4.4. Molecular composition and configuration
Besides the molecular weight, molecular composition and configu­
ration also affect the antiviral activity of sulfated polysaccharides. The
monosaccharide composition of the sugar chain and the type of glyco­
sidic bond directly determine the potential of the activity. The type of
branched chain, polymerization degree, their distribution and DS on the
sugar chain determine the strength of the activity (Thuy et al., 2015).
Rabanal and et al. extracted a series of sulfated polysaccharides with
different monosaccharide compositions from brown algae Dictyota
dichotoma. The sulfated galactofucans/fucogalactans seemed to be
responsible of the inhibitory effect of HSV-1 and CVB3 activities, indi­
cating that galacto-fucoside played a critical role in antiviral activity of
sulfated polysaccharides, and the hydrophobicity of the methyl group on
C-6 of fucose might be responsible for this effect (Rabanal et al., 2014).
In addition, structural modification based on sulfated polysaccharides/
oligosaccharides (such as adding hydrophobic functional groups or
changing its spatial arrangement) is of great significance to improve
their antiviral activities. The anti-CVB3 activity of sulfated poly­
saccharides extracted from Pteridium chinense was significantly
enhanced after selenization. The selenium polysaccharides may inhibit
viral infections by preventing the adsorption of viruses (Men et al.,
2009). Said and et al. screened 37 sulfated oligosaccharide-lipophilic
conjugates for antiviral and virucidal activity of HIV, found that these
conjugates were more likely to interact with the viral lipid shell and
competitively blocked infection through a higher binding affinity for cell
surface HS binding site of gp120, and showed potency as virucidals
against both HIV-1 and HSV-2 as well. The lipophilic tails on the con­
jugates may play an important role on reducing host protein binding
W. Lu et al.
(Said et al., 2010). The advanced structure of polysaccharides, such as
chain flexibility and spatial conformation, has a greater impact on
polysaccharide activity than the primary structure. Hendricks and et al.
generated heparan sulfate octasaccharide (HS-octa) decoy liposomes
which significantly inhibited RSV, HSV, and hPIV3 (human para­
influenza virus 3) infectivity in vitro to a greater extent than either full-
length heparin or HS-octa alone. The degree of inhibition correlated
with the density of HS-octa displayed on the liposome surface. Thus, the
molecular modification of decoy liposomes may introduce promising
therapeutic antiviral agent and illustrate the utility of the liposome
delivery platform (Hendricks et al., 2015). In recent years, using GAGs
as a drug delivery system which is able to target the viruses, to load
antiviral drugs and to control their release over time represents becomes
an interesting antiviral strategy. Heparin nanoassemblies formed by the
auto-association of O-palmitoyl heparin with α-cyclodextrin in water
exerted strong antiviral activity against HSV-1, HSV-2, HPV-16 and RSV
infections. The crystal-like arrangement of the nanoassemblies with
higher level of sulfation exerted stronger antiviral activity, indicating
the polysaccharide configuration may be important in the development
of antiviral agents (Lembo et al., 2014).
4.5. Solution conformation
Solution conformation is one of the hot issues in the study of poly­
saccharide structure-activity relationship (Meng et al., 2020). The
conformation of polysaccharides is mainly associated with chain struc­
ture and intramolecular forces, including hydrogen bonding, dipole in­
teractions, hydrophobic forces and electrostatic forces. However,
external conditions (such as heat treatment, ultrasonic waves, pH, ions
or solvents) can change the conformation of polysaccharide in solution
(Yang et al., 2020). The macromolecules have specific chain confor­
mation in solution formed by the morphological characteristics,
including polysaccharide conformation and flexibility of sugar chain
(Antoniou et al., 2010; Xie et al., 2015). It has been reported that sul­
fation can change the conformation of polysaccharides in solution
(Wang et al., 2016). Sulfated polysaccharides of Artemisia sphaerocephala
showed more expanded conformation of random coil in aqueous solu­
tion, which was attributed to the breakup of rigid hydrogen bonds and
elastic contributions. And they exhibited enhanced DPPH, superoxide
and hydroxyl radical scavenging activities and chelating abilities in vitro.
In addition, the antioxidant activities of Ganoderma lucidum poly­
saccharide were associated with the conformational change. The intro­
duction of the sulfated groups made the polysaccharide more
outstretched, which improved its water-solubility, thus further
increased their antioxidant activity (Zhang et al., 2015). The change in
the solution comformation of sulfated Hypsizigus marmoreus has also
been reported. Compared with nonsulfated ones, the sulfated poly­
saccharides showed a lower molecular weight and considerably higher
radius of gyration, suggesting that the sulfated derivatives may become
more extended. In addition, the structural change in the solution com­
formation may also improve the anticancer and immonomodulatory
activity of the native polysaccharides by increasing the levels of NO, IL-1
and TNF-α (Bao et al., 2010).
5. Conclusions and future prospects
Polysaccharides, as one of the most abundant biomacromolecule in
nature, have been hot issues in the last several decades. Particularly,
sulfated polysaccharides have a variety of antiviral properties, due to
their ability to imitate patterns of sulfate substitution on GAGs present in
cell membranes (Ghosh et al., 2009). Sulfated polysaccharides have
multi-aspect and complicate antiviral mechanisms. They may directly
inhibit the infection by interfering with virus adsorption, invasion,
uncoating, transcription, replication, assembly and release steps in the
virus life circle. In addition, they may play an indirect role by enhancing
the immune responses to accelerate the viral clearance process.
7
Carbohydrate Polymers 272 (2021) 118526
The antiviral activity was affected by DS, substitution position, mo­
lecular weight, molecular structure characteristics and spatial confor­
mation of the active sulfated polysaccharides. Whether the different
structural features are related to their acting sites and target cells still
need to be explored. The specific mechanism of various polysaccharides
activity are also quite different, and the relationship between the
structure/conformation and activity has not been clarified in detail.
However, with the improvement of molecular modification methods and
instrumental analysis techniques, the structure and activity mechanism
of sulfated polysaccharides will surely be further elucidated. Further­
more, integrated traditional Chinese and Western veterinary medicine is
important and beneficial to research and develop more effective anti­
viral drugs. The immuno-enhancing ability of Astragalus polysaccharide
(APS) has been certified in many studies, but APS and its sulfate (sAPS)
exhibited anti-DHAV abilities in vitro while did not in vivo. And their
abilities of scavenging free radicals and alleviating the hepatic injuries
were weak. Thus, the syndrome differentiation based on an overall
analysis of the illness and the patient's condition should also be taken
into account on drug development of sulfated polysaccharides (Chen
et al., 2015).
The natural and artificially synthesized sulfated polysaccharides
derived from a variety of edible and medicinal organisms are broad-
spectrum, non-toxic, biodegradable and biocompatible, and have
promising prospects in application for novel and potent antiviral drugs
or combination drugs in the upcoming decades. Besides, sulfated
polysaccharide-based nanoassemblies, drug delivery systems and vac­
cine adjuvants will play important roles in antiviral field. Therefore, the
sulfated polysaccharides will have the chance to produce medically
relevant virucidal drugs with proper pharmacokinetics, pharmacody­
namics, hydrolytic stability, and free toxicological profile in the further
scientific and clinical antiviral research.
Acknowledgement
This work was supported by the Natural Science Foundation Program
of Shaanxi Province Department of Science and Technology (Program
No.: 2020JQ-986), China.
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