key: cord-0738730-v2aefxsk
authors: Sharma, Nivya; Modak, Chandrima; Singh, Pankaj Kumar; Kumar, Rahul; Khatri, Dharmender; Singh, Shashi Bala
title: Underscoring the immense potential of chitosan in fighting a wide spectrum of viruses: A plausible molecule against SARS-CoV-2?
date: 2021-02-16
journal: Int J Biol Macromol
DOI: 10.1016/j.ijbiomac.2021.02.090
sha: 75b497bc3bb3462fd7e41e1c244628fa688063e4
doc_id: 738730
cord_uid: v2aefxsk

Chitosan is a deacetylated polycationic polysaccharide derived from chitin. It is structurally constituted of N-acetyl-D-glucosamine and β-(1-4)-linked D-glucosamine where acetyl groups are randomly distributed across the polymer. The parameters of deacetylation and depolymerization process greatly influence various physico-chemical properties of chitosan and thus, offer a great degree of manipulation to synthesize chitosan of interest for various industrial and biomedical applications. Chitosan and its various derivatives have been a potential molecule of investigation in the area of anti-microbials especially anti-fungal, anti-bacterial and antiviral. The current review predominantly highlights and discusses about the antiviral activities of chitosan and its various substituted derivatives against a wide spectrum of human, animal, plants and bacteriophage viruses. The extrinsic and intrinsic factors that affect antiviral efficacy of chitosan have also been talked about. With the rapid unfolding of COVID-19 pandemic across the globe, we look for chitosan as a plausible potent antiviral molecule for fighting this disease. Through this review, we present enough literature data supporting role of chitosan against different strains of SARS viruses and also chitosan targeting CD147 receptors, a novel route for invasion of SARS-CoV-2 into host cells. We speculate the possibility of using chitosan as potential molecule against SARS-CoV-2 virus.

As antibiotic resistance and zoonotic disease outbreaks are getting pervasive as documented over the past 30 years, these diminutive pathogens are accounting for almost 70 % of the infectious diseases with a scale of public health (1, 2) . According to the WHO 2014 global report on antimicrobial resistance, it has been highlighted how tuberculosis and gonorrheatreatment with current antibiotics have been anabsolute failure due to anti-microbial resistance and is becoming a great concern worldwide(3).As a countermeasure,current drug development needs to regularly focus on discovery and research for other alternative antimicrobial agents. Marine polysaccharides are one of themost explored molecules for various therapeuticsand biomedical applications. They have been in studies and are in use for decades now because they exhibit strong antimicrobial activities against abroad spectrum of bacteria, viruses and fungi(4)e.g. fucoidans extracted from brown algae found in themarine environment has shown anti-Human Immunodeficiency Virus-1 (anti-HIV-1) activity (5) .

Out of numerous marine studied polysaccharides, chitosan has gained significant attention as a potent anti-microbial agent. Chitosan is a randomly deacetylated copolymer of β-(1-4)-linked dglucosamine and N-acetyl-d-glucosamine (Figure 1) , derived from chitin which is the second most ubiquitous polysaccharide after cellulose and is present in theexoskeleton of various crustaceans, insects, and microfibrils of fungi (6) . Chitosanshows potent antifungal activities against deadly fungal strains like candida strains which contribute to a multitude of infections in humans, animals and bacterium species. Additionally, chitosan exhibitsantibacterial action against E-coli(gram-negative) and Staphylococcus aureus (gram-positive) (7) ,and numerous other pathogenic bacterial strains (8) likeBacillus megaterium, Salmonella stimulation of nitric oxide production in dog peripheral blood in-vitro suggesting stimulation of immune response (12, 13) . Inhibition of Chlamydia trachomatis bacteria by chitosan in-vitro in HeLa cells line was reported (10) .In line with applications for therapeutics and biomedical uses, chitosan possessesproperties of low allergenicity, biodegradability (14) , non-toxicity (6) , is economical to synthesize, andflexible to chemical modifications as has been documented over the years (8, (15) (16) (17) .

In concurrent to SARS-CoV-2 outbreak, this review explores and highlight similarity between the binding affinity of spike glycoprotein to Angiotensin-converting enzyme receptor-2(ACE 2) as a primary cell entry receptor for bothSevere acute respiratory syndrome Coronavirus (SARS-CoV) andSevere acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) (18, 19) . Although studies are underway to completely comprehend the pathophysiology of SARS-CoV-2, yet inhibition of spike protein -ACE 2 receptors binding and cell fusionhas been looked upon as potential approaches to treat SARS-CoV-2 infectionas directed by various computational modeling and molecular dynamic studies (20) (21) (22) ,and for this intervention, chitosan and its derivatives stand as a promising candidates as they are reported to bind with the spike protein subunits in in-vitro studies done on LLC-MK2 cell line and also in molecular modeling studies as discussed later in this review. Also,chitosan targeting a potential receptor molecule, CD147

having a crucial role in SARS-CoV-2 invasion has been discussed in this review. With a dearth of drug candidates to fight this new variant of coronavirus, we believe that this review will provide some new insights in this field and will underscore the antiviral potential of compounds derived from the marine ecosystem. 

A gamut of factors mayaccount for theanti-microbial efficacy of chitosan against abroad spectrum of microbes i.e. synthesis process (enzymatic, hydrolysis, etc.), conditions such as temperature, pH, degree of deacetylation (DD), degree of substitution (DS), molecular weight, deproteinization, concentration, and source of native chitin from which it is derived (9, 15, 23, 24) .DD directly affecting solubility of chitosan in aqueous medium and its untimely effects on antiviral activity will be elaborated and discussed later in this review (25, 26) .

Extensive studies have been conducted to determine acorrelation between antimicrobial activity and overall charge on chitosan. Chitosan as a native molecule has limited activity as an antiviral agent over a wide range of viruses, but substitution at theamino group and hydroxyl group can significantly alter its efficacy against various viral strains. Likewise, reports of sulfated chitosan have been shown to possess better antiviral property against HIV-1 and have provided better results in comparison to other derivatives due to similarity with heparin structure discussed in detail later in this review. Chitosan oligomers which are derived by hydrolysis of chitosan havealso been reported for the wide-ranging antimicrobial actions by cell death or receptor binding inhibition. Moreover, themechanism of action along with physico-chemical propertiesof chitosan derivatives differs,and areimpacted by side-chain substitutions in concordance to chitosan itself (27) as mentioned in the review.

The direct inhibition mechanism of chitosan against plant virus replication has been rolled out throughoutvarious reports and findings. Also, support for chitosan inducing systemic resistance has been eminent (11 (Figure 2 )(28).

The efficacy of chitosan to induce resistance in cucumber plant against Cucumber mosaic virus was evaluated. Chitosan was used as astandalone target molecule and in combination with glycine betaine. The results of the study indicated significant upregulation of defense genes, as demonstrated by gene expression analysis along with enhanced phytohormones, enzymatic and non-enzymatic antioxidants, and osmoprotectant protective mechanisms (Figure 2) . Conversely, the amount of oxidative stress indicator, malondialdehyde, and stress hormones, abscisic acid significantly declined. Furthermore, treatment with acombination of Chitosan and glycine betaine showed asuperior effectthan individual chitosan in terms of decreasing the infection by 90% and 84.21% respectively vs. thecontrol group which was 95% affected. Also, a significant decline of disease severity to 2.88% and 6.22% respectively vs. thecontrol group at 70% was observed along with uplifting of protective mechanisms of the host plant (29) . Chitosan caused an increase in intercellular proteolytic enzymes like RNases and proteases in pre-treated tobacco leaves leading to the fragmentation of the virions (Figure 2) . The study also underscored that the thinning of virions is caused by partial untwining of viral capsid subunits lowering the proteolysis of viral proteins exposed on the surface obstructing the binding capacity of virions and there was no evident toxicity recorded in this study (30) . Chitosan binding to plant cell surface receptors and stimulation of systemic resistance was also suggested to act asacause and effect relationship. A research group concluded that chitosan binds to plant cell surface receptors and stimulates a defense response leading to the elicitation of systemic resistance. The mechanism of action was suggested to be through nitric oxide signaling via the production of asecond messenger, phosphatidic acid-induced through phospholipase C in a coordinated effort with diacylglycerol kinase (31, 32) . To underline themechanism of chitosan induced viral infection resistance against Tobacco Necrosis Virus (TNV),it wassuggested that chitosan induced apoptosis by acalcium-dependent mechanism which was directly time-dependent, triggering host defense system by acting as pathogen-associated molecular pattern molecule (PAMP) and activating the phospholipase-lipoxygenase pathway responsible forReactive Oxygen Species (ROS) production. Calcium-dependent pathway, cause activation of callose synthase (leading to callose deposition which constraints cell to cell virus transport), Mitogenactivated protein kinases activation (MAPK), increase ROS and Nitric Oxide (NO) production J o u r n a l P r e -p r o o f which leads to a hypersensitive reaction at areas of attempted pathogen infection and activates hormonal signaling cascades (Figure 2) . Although many of these aforementioned mechanisms garnered support from high-impact studies yet some of them still face the fire of controversy (11, 33) . Abscisic acid has alsobeen noted to attribute as a major factor of plant-pathogen resistance mechanism as it was documented to elicit the accumulation of callose sites in palisade mesophyll of tobacco leaves. Since callose is part of systemic permeability in plasmodesmata and abscisic acid is essential for callose accumulation, the presence of chitosan not only help in eliciting the concentration of abscisic acid but also helps in forming a uniform network of callose sites which decreases the virus lesions sites in chitosan treated leaves affecting the viral spread from cell to cell (Figure 2 ) (34) . Studies were also done to underscore the host immunomodulatory response at gene level induced by chitosan-N after inoculating papaya leaf with papaya leaf-distortion mosaic virus. The gene ontology analysis of differentially expressed genes demonstrated the potential of chitosan in upregulating plant disease resistance genes linked with pathways like starch and sucrose metabolism, phenylpropane biosynthesis and plant hormone signal transduction (35) . Altogether, these studies reflect that Chitosan promotes the inductionof systemic resistance in plants by altering various signaling pathways.

The physico-chemical properties of chitosan such as 1)molecular structure, molecular mass, DD,2)Degree of polymerization (DP),achieved by depolymerizationmethods such as enzymatic or chemical hydrolysis concentration, 3) plant variety, and in some cases virus type as discussed abovefor mechanism of action(11), significantly impacts viral resistance, as the receptor structure and function differ in different plant varieties with varying affinity to chitosan 

The impact of physico-chemical properties of Chitosan on coliphages T2, T4, and T7 inactivation was studied by synthesizing its various derivatives differing in terms of the DP, the net charge, and the number of amino groups. Different phage strains showed different inactivation abilities in the presence of chitosan fragments, but it varied in a dose-dependent fashion except forthe T2 page. Virulence of T2 Phage relied on the degree of polymerization, but no specific pattern was observed. With the same degree of polymerization, unmodified chitosan showed more activity than deaminated derivatives. Also, a model based on adecrease in antiphage activity with a decrease in amino groups was observed. Conversely, anionic derivatives with a net negative charge showed a reduction of activity. Electronic microscopy pictures of T2 phage after treatment with chitosan fragments reflected distinct structure alterations in terms of J o u r n a l P r e -p r o o f the absence of long-tail fibers, contracted tail sheaths, and deformed basal plate (43) . Inhibition of phage virulence was reported at low DP due to absorption of chitosan in the bacterial cell wall whereas, in contrast, inhibition of phage infection at higher DP was due to decrease of phage bacteria replication. It was also concluded that inhibition of phage reproduction and inhibition of phage infection remainedindependent of the degree of deamination but were dependent on the concentration of chitosan (44) . An inverse relationship between the DP and concentration was noted for inhibition of phage infection i.e. lower DP and higher concentration had the best results whereas, in contrast, degree of deamination was not related to the inhibition property. Overall, low DP, high concentration, and deamination provided the best yield for Phage infection inhibitions, but it was speculated that inhibition was caused due to theantibacterial property of chitosan (45) . 

A comprehensive study enlisting antiviral activities by chitosan on various types of viruses cited some interesting reports to decipher the possible mechanism of chitosan antiviral activity.

Adecrease in the yield ofsuch infectious gene containing phages was observed and chitosan J o u r n a l P r e -p r o o f binding to smaller peptide fragments in anagar medium was suggested. Oligomer reported better inhibition for phage infections unlike anionic sulfate substituted groups which were ineffective against phage infection in contradictionwith other viruses (50) . Positive charge on chitosan amino groups was cited to be a major contributor for the overallcationic property of chitosan and was suggested to be responsible for inactivation of phage infection and it was valid for plant viruses too (51, 52) .Three major mechanisms were cited to be responsible for chitosan antiviral efficiency against phage infections. 1) Cell death of phage bacteria 2) decrease in thevirulence of daughter bacteriophages 3) inhibition of reproduction of virulent phage viruses. It was concluded that the bactericidal effect was not a contributor to the inhibition of the phage infection mechanism. It was cited that chitosan has transpiredthemorphological damageinvirions in support of the second suggested mechanism, but it is still not ostensiblewhich stage of replication chitosan affects in phage infection (10).

The virulence of theSARS-CoV virus is primarily attributed to the ability of its spike protein to bind the ACE-2 receptors present in the human respiratory tract and initiate infection (21, 22, 53) .Cryo-electron microscopy images have revealed the structure of spike protein as a homotrimeric peptide with theS1 and theS2 subunits in each monomer. Cryoelectron microscopy performed for spike protein in its prefusion state at 3Å resolution put forward some insightful observations. It was noted that one of the three Receptor Binding Domains (RBDs) of S1 subunit of spike proteinstays in up-conformation (state of instability and receptor accessible position) which is coveted for receptor binding. As soon as the receptor binds to it, the entire receptor binding domain undergoes hinge like movement leading to augmented instabilityand turning all the three RBDs in to up-conformation.Follwing this, the whole S1 subunit out of sheer instability sheds apart leading to refolding of S2 subunit (54) . This stimulatesthe S2 subunit to acquire a stable state required for membrane fusion which subsequently results in virus introduction into the host cell (21, 22, 55) . The Receptor Binding Domain (RBD) of theS1 subunit comprises a core and a receptor-binding motif, the latterone being highly desired for specific recognition and strong binding to ACE2 receptor ( Figure   J o u r n a l P r e -p r o o f 3A) (56) . It has been observed that SARS-CoV and SARS-CoV-2 both use human ACE2 receptor as a port of entry to gain access to host cells ( Figure 3A) . However, the binding affinity of the spike protein's RBD of latter virus to hACE2 is more but the overall interaction of its spike protein with hACE2 is low compared to the former virus type. These results were generated from a protein pull-down assay, using cell surface- 

The exploration of other potential receptors for SARS-CoV-2 binding shows that the spread of They have suggested that theanti-HIV-1 activity of sulfonic groups at C-2 and C-3 is due to interaction with GP120 envelope glycoprotein as they have shown anticoagulant property whereas substitution atC-6 had non-specific ionic interaction with blood coagulating factors (88) .This argument of non-specific ionic interaction of sulfate substitution was supported bya 

Modification of low molecular weight chitosan oligomers (COS) with tripeptides like tryptophan 

However, the effect was weaker for WMQ-COS (93) .Polyelectrolyte nano-complexes of chitosan and hyaluronan stabilized with Zinc (II) were evaluated for their synergistic effect when they were loaded with a very potent anti-HIV-1 drug, Tenofovir. When internalized inside human peripheral blood mononuclear cells infected with HIV-1, these nanocarriers caused considerable reduction in viral infection by limiting capsid p24 protein production(94). proportional to the chitosan concentration (as survival rates started to dwindle with lower amounts of chitosan (30 μg or 10 μg)). They also observed asignificant reduction in virus load and augmented inflammatory markers and leukocyte infiltration in lung/trachea tissue. Notably, the protective immune responses lasted for ten days. However, changing the route to intraperitoneal protected only 10% of animals even at the highest dose of chitosan (100 μg).Comparatively, a low protective effect was recorded against PR8 strain ofinfluenza virus unlike H1N1 and H9N2 strains where full-fledged protection was seen (101) .

Although metal ions have higher affinity binding with proteins, the study done by Lin et al., showed that type of protein residue, position, and pH affects their binding affinity. Also, it was observed that nickel ions had thebest binding affinity to enterovirus-71 in the presence of chitosan as Ni 2+ has six available coordination bonds. Chitosan chelating with nickel ions provided a greater chelation potential to Ni 2+ with the exposed protein of enterovirus-71 and also provided more excellent stability of the bond formation between them concerningNi 2+ and protein binding (102) . highlighted that the pH of the medium had a bigger sayon virus infectivity than the type of solvent used to lower the pH of chitosan, except in the case with high molecular weight chitosan dissolved inhydrochloric and acetic acid and had activity against MS2 and FCV-F9 strains.

Moreover, chitosans were found to be the most potent antiviral agents against MS2, followed by FCV-F9 and phi X174 viral strains, while no activity was observed against MNV-1. Decrease in MS2 infectivity by chitosan reflected a directly proportionate dependence on molecular weight but the sensitivity of FCV-F9 and phi X174viruses was found to be molecular weight independent (110) .

Enterovirus is associated with wide-ranging human health syndromes. 

This review brings under light the immense potential hold by Chitosan as anti-microbial therapeutic and adjuvant for existing drugs given the challenges in antibiotics drug discovery especially antivirals. Chitosan, a cationic polysaccharide is obtained from Chitin, found 

The authors declare no conflict of interest

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This work was proposed by Nivya Sharma and ChandrimaModak and supported by National