Next Article in Journal
Sequential Scheduling Method for FJSP with Multi-Objective under Mixed Work Calendars
Next Article in Special Issue
Ultrasound-Assisted Extraction of GAC Peel: An Optimization of Extraction Conditions for Recovering Carotenoids and Antioxidant Capacity
Previous Article in Journal
Transport and Deposition of Large Aspect Ratio Prolate and Oblate Spheroidal Nanoparticles in Cross Flow
Previous Article in Special Issue
Green Synthesized Silver Nanoparticles of Myrtus communis L (AgMC) Extract Inhibits Cancer Hallmarks via Targeting Aldose Reductase (AR) and Associated Signaling Network
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Processes
Volume 7
Issue 12
10.3390/pr7120887
processes-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Marine Algae: A Potential Resource of Anti-HSV Molecules

by
Mohamad Fawzi Mahomoodally
1,
Devina Lobine
1,
Kannan R. R. Rengasamy
2,
Shanmugaraj Gowrishankar
3,
Devesh Tewari
4,
Gokhan Zengin
5,
Doo Hwan Kim
2 and
Iyyakkannu Sivanesan
2,*
1
Department of Health Sciences, Faculty of Science, University of Mauritius, Réduit 80837, Mauritius
2
Department of Bioresources and Food Science, Konkuk University, Seoul 05029, Korea
3
Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630 003, India
4
Department of Pharmacognosy, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
5
Department of Biology, Science Faculty, Selcuk University, Campus, Konya 42250, Turkey
*
Author to whom correspondence should be addressed.
Processes 2019, 7(12), 887; https://doi.org/10.3390/pr7120887
Submission received: 29 September 2019 / Revised: 1 November 2019 / Accepted: 25 November 2019 / Published: 29 November 2019
(This article belongs to the Special Issue Production and Biomedical Applications of Bioactive Compounds)
Browse Figures
Versions Notes

Abstract

:
Herpes simplex viruses (HSVs) are common human pathogens belonging to the subfamily alpha-herpesvirinae that trigger severe infections in neonates and immunocompromised patients. After primary infection, the HSVs establish a lifelong latent infection in the vegetative neural ganglia of their hosts. HSV infections contribute to substantial disease burden in humans as well as in newborns. Despite a fair number of drugs being available for the treatment of HSV infections, new, effective, and safe antiviral agents, exerting different mechanisms of action, are urgently required, mainly due to the increasing number of resistant strains. Accumulating pieces of evidence have suggested that structurally diverse compounds from marine algae possess promising anti-HSV potentials. Several studies have documented a variety of algal polysaccharides possessing anti-HSV activity, including carrageenan and fucan. This review aimed to compile previous anti-HSV studies on marine algae–derived compounds, especially sulfated polysaccharides, along with their mode of action, toward their development as novel natural anti-HSV agents for future investigations.

1. Introduction

Viral infections count as the most predominant cause of death in humans worldwide [1]. Among the different deadly viruses, Herpesviridae, belonging to a large family, is responsible for a wide range of mild to severe infections in humans. Out of 130 members of the Herpesviridae family, eight human herpesviruses have been considered, based on their biological properties toward host range, genetic make-up, and mode of replication, into three subfamilies, namely alpha-, beta-, and gamma-herpesvirinae [2,3,4].
The most notable herpes viruses belonging to alpha-herpesvirinae are herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2), which have been widely studied. Although HSV-1 and HSV-2 are closely related, they differ at antigenic and biological levels [5]. Typically, HSV-1 is associated frequently with orofacial infections and encephalitis, while HSV-2 is associated with genital infections that can be transmitted from infected mother to fetus. These viruses can establish persistent, long-term, latent infections in sensory neurons and cause lesions at the entry point of the human body [6,7]. These characteristic features of latency enhance the pathogenicity of HSV and enable it to be used for therapeutic purposes.
Owing to the seriousness of infection caused by the pathogen, it has been considered as the most common microbial infection in humans. Approximately 3.7 billion people worldwide, under the age of 50 years (67%), have been estimated to be a victim of HSV-1, while approximately 417 million aged between 15 and 49 years (11%) are estimated to suffer from HSV-2 infection [8]. Paradoxically, HSV infection has been considered a menace in human immunodeficiency virus (HIV) infection.
The word “herpes” is derived from the Greek word “herpein,” meaning “to creep,” referring to recurring, lytic, and latent infections [9]. HSV-1 infection is not limited to mucous membranes or skin; it also affects eyes (herpetic keratitis), genital areas, and the central nervous system (meningitis and encephalitis) [10,11]. The viruses are the causative agents of different disease conditions like cold sores, chickenpox, mononucleosis, and warts, and can develop recurring and latent infections in both animals and humans [12]. HSV-1 and HSV-2 of alpha-herpesvirinae subfamily are responsible for the pathology of genital and/or oral herpes, herpes labialis (cold sores), and herpes genitalis, whereas varicella-zoster virus (VZV) of the same subfamily is responsible for chickenpox and shingles pathology. The β-herpesvirinae subfamily consists of Cytomegalovirus (CMV) and Roseolovirus B, which are associated with the pathology of retinitis, an infectious mononucleosis-like syndrome, and Roseola infantum or exanthem subitem. Kaposi’s sarcoma-associated herpesvirus (KSHV), of γ-herpesvirinae subfamily, is involved in the pathology of Castleman’s disease, Kaposi’s sarcoma, and primary effusion lymphoma, while Epstein–Barr virus (EBV) of γ-herpesvirinae subfamily is linked with the pathology of central nervous system, Burkitt’s lymphoma, infectious mononucleosis, post-transplant lymphoproliferative syndrome (PTLD), and nasopharyngeal carcinoma [9].
Human herpesviruses have a highly structured icosahedral-shaped nucleocapsid of 100 nm diameter, which encapsulates a linear double-stranded DNA of 120–230 kb, with approximately 80 reported genes. The capsid comprises of a dense matrix with an outer trilaminar lipid envelope upholding the viral proteins as well as host cell origins [13]. Various cellular proteins such as tubulin, actin, annexin, Hsp70, and Hsp90 are present in the herpes virus; however, their role is still unclear [14]. The viral life cycle is divided into different phases, like cellular invasion, viral transport, replication, maturation, assembly, and release [9].

2. Diseases, Symptoms, and Their Mode of Infection

Infections caused by HSV can be either primary or recurrent (reactivation) and are often contagious via infectious secretions. Clinical progression of the infection depends on several factors such as the age and immune level of the host, anatomic site of infection, and virulence type of virus. Primary infections by HSV have been observed with systemic signs, prolonged symptoms being accompanied by a higher rate of complications. In contrast, recurrent infections are usually weaker and smaller. The diseases caused by HSV are acute herpetic gingivostomatitis, acute herpetic pharyngotonsillitis, herpes labialis, herpetic whitlow, herpes gladiatorum, eczema herpeticum, and genital herpes [15,16,17]. Details of the disease, symptoms, and their mode of infections are given in Table 1.

3. Pathogenesis of HSV

Infectivity of HSV ranges from the host epithelial cells, fibroblasts, and lymphocytes to neuronal cells. Thus, HSV is termed a “broad cell tropic” [5]. The pathogenesis of HSV-1 is massive, since it causes primary infection in the non-keratinized mucosa as well as keratinized regions, such as gingiva, hard plate, and dorsum of the tongue [24]. Soon after the establishment of primary infection, the virus moves up to sensory nerve axons to cause chronic latent infection in trigeminal ganglia. Later, the latent viruses are reactivated by several triggering factors and cause recurrent lesions at the site of primary infection (Figure 1) [25].
Generally, HSV is more specific to sensory neurons and triggers an infection in the external layers of the skin and mucosa [26]. Hence, repeated infections are predominantly found in keratinized surfaces of mucosal membranes and skin [24].
The primary cause and ubiquitous pathogen for genital herpes is HSV-2. In the last couple of decades, an association of HSV-2 with HIV has also been observed, and HSV-2 infection was found to be associated with a threefold elevated risk of sexually acquired HIV [27]. A frequent, recurrent, and painful genital lesion, along with psychological stress, is observed in immunocompetent people with HSV-2 infections.

4. Establishment of Primary Infection

Primary infection is usually asymptomatic and is mostly seen in children and teenagers [28]. Susceptibility of individuals to HSV infection is altered by the polymorphism in genes coding for human leukocyte antigen (HLA) class-I with killer immunoglobulin-like receptors (KIR) and FcγRIIIA (CD16A) molecules, which are critical in regulating the effector functions of cytotoxic T and NK lymphocytes [29]. The low frequency of HLA class-I and B18 allele was found to be common amongst patients with herpes. However, the B35 allele renders protection against HSV infection [30]. The severity of primary infection caused by HSV is determined chiefly by the host immune response and its potential to interact with the viral genes [31]. Initiation of primary HSV-1 infection is mainly caused by the virion host shutoff protein, followed by the devastation of natural killer cells, key HLA complex class-I and class-II molecules, complementary proteins, and antibodies produced by the host immune defense mechanisms [32].

5. Involvement of Virion Host Shutoff Protein in Causing Infection

Virion host shutoff (Vhs) is a protein involved primarily in provoking the cellular gene expression of the host after the initial attack. It is one of the vital members involved in virulence, pathogenesis, and multiplication of HSV. Vhs, being a part of the tegument, is secreted mainly during the early and immediate-early phase of infection. It exhibits endoribonuclease activity by encoding the gene UL41, and hence, it has the potential to degrade all types RNA. Nevertheless, it degrades only the mRNA inside the host [33,34]. Cellular degradation of mRNA enhances the viral competition for translation and thus promotes the succession of viral infection. Meanwhile, by stabilizing the gE/gI complex, Vhs eventually stabilizes the viral mRNA that plays a crucial role in cell-to-cell spread [35]. Reduction of innate and adaptive immune response proteins by Vhs demonstrated the blockage of synthesis of type-I interferon, dendritic cells, and proinflammatory cytokines and chemokines [36,37,38] (Figure 2).

6. Immune Evading Strategies of HSV

To evade the host immune system and cause persistent primary infection, HSV adopts a multitude of strategies directed toward overcoming all mucosal barriers [39]. Usually, the mechanism of evasion targets the immune components like complementary proteins, major histocompatibility complex (MHC) class-I or class-II molecules, killer cells, and antibodies [40]. Glycoproteins that are found to be embedded in the outer lipid envelope mediate the attachment of HSV to the host cell receptors, blending of viral and host cell membranes, envelopment, and occurrence of the virus as newly formed nucleocapsids bud from host cell nuclei [41]. However, these glycoproteins are majorly targeted by humoral and cellular immune responses [42]. Instead, the glycoproteins bind with C3b, gE, and IgG Fc domain, and block the complement activation and antibody-mediated cellular cytotoxicity. Additionally, the regulation of ICP0 by HSV demonstrated higher resistance of the virus against immune attack by the interferon system of the host [43].

7. State of Viral Latency and Reactivation

In a viral infection, latency is characterized by the silent persistence of pathogen inside the body, existing in non-replicating and non-pathogenic mode [44]. Once it is exposed to certain triggering factors, it becomes active to cause infection or recurrence. Commonly, the sites of latency differ across herpes virus types. The type of virus and its specific latency site is shown in Table 2.
After establishing a primary infection, HSV-1 penetrates the nerve terminals of sensory neurons located at the periphery and reaches trigeminal nerve ganglion through the retrograde axon. It passes through the neuronal cell and blends the plasma membrane with an external envelope by exploiting the pH-dependent endocytic pathway [48]. The capsid proteins are essential for such site-specific fusion of viral particles with the infected cells. Later, the viral particle establishes latency inside neuronal cells by down-regulating the α-gene expression and DNA replication [49].
Upon favorable conditions, the HSV at the latent stage becomes active through activating factors such as sun exposure, stress, and trauma. The triggered HSV in the dorsal root ganglion establishes its recurrent infection by passing through the sensor nerves present in the junction of the epidermal-dermal layer. This recurrent infection is asymptomatic, which persists with no systemic sign. Most often, the mucocutaneous junction of lips is recurrently infected, which appears as cold sores, commonly known as recurrent herpes labialis [50].

8. Role of Keratin in Primary Recurrent Lesions

Unlike the other parts of human body, the oral cavity possesses a large number of keratinized and unkeratinized cells. These keratinized cells cover themselves by secreting keratin. Such types of cells are found abundantly in the mucocutaneous junction of the lip and tongue (especially on the hard palate, gingiva, and dorsum) [24]. In general, HSV causes primary lesions on unkeratinized tissues, such as labial and buccal mucosa. However, it can also cause lesions on keratinized tissues [51]. The keratin layer found on the surface of the cell wall reduces permeability of the cell for viral penetration. Hence, primary and recurrent lesions are more predominant in non-keratinized cells. Interestingly, in recurrent lesions, the HSV is already present in the ganglion, and hence, the need for viral penetration in such cases is not required, and keratin plays a protecting role for virus against immune response [24].

9. Anti-HSV Molecules from Marine Algae

Among the different marine resources, marine algae are considered to be one of the prominent primary producers in marine food webs, being rich in essential nutrients and bioactive molecules. Marine algae are functionally and morphologically diverse chlorophyll-containing organisms, composed of one cell or grouped into colonies, or as multi-cellular organisms, sometimes collaborating as simple tissues. These unicellular or multi-cellular organisms are classified into two major groups according to their size—macroalgae and microalgae [52,53].
Macroalgae are commonly known as seaweeds and are grouped into three major categories according to their pigmentation—green seaweeds (Chlorophyta), brown seaweeds (Phaeophyta), and red seaweeds (Rhodophyta) [54]. The pigment characteristics of macroalgae are related to their sea habitat, since not all of them need the same amount of light to perform photosynthesis. Therefore, green macroalgae, which can absorb a large amount of light energy, are distributed in coastal regions, while red and brown macroalgae occur at greater depths, where penetration of sunlight is limited. The microalgae consist of a wide range of autotrophic organisms, with the majority existing as small cells of approximately 3–20 µm [53].
Over the past decades, marine algae have stimulated significant economic interest as agar, fertilizer, food, source of iodine, and potash [55]. Amongst the marine natural products available in the market, approximately 9% of biomedical compounds have been isolated from algae. The marine organisms produce a myriad of bioactive compounds, including polysaccharides, chlorophyll, acetogenins, fatty acids, vitamins, xanthophylls, amino acids, and halogenated compounds [56,57].
The marine source is one of the most potent resources for antiviral compounds. Gerber et al. [58] first confirmed the possible anti-viral effect of an algal polysaccharide, obtained from Gelidium cartilagineum (Linnaeus) Gaillon, against influenza B virus and mumps. Polysaccharides obtained from various algae are being rigorously studied for structure exploration and biological effects, for a long time. Sulfated polysaccharides possess a variety of therapeutic activities, namely anticoagulant effect, antiviral effects on the immune system, and antitumor activity (Table 3) [59]. Different pharmacological activities of these high molecular weight sulfated polysaccharides are evaluated through their chemical structure, which includes molecular weight, degree of sulfation, conformation, dynamic stereochemistry, and constituent sugars. Despite the known HIV inhibitory activity of sulfated polysaccharides [60,61,62], application of cellulose sulfate has shown no protection in women with HIV [63].
The interaction between negatively charged molecules of the polysaccharides, including different sulfated polysaccharides with the positive charge present either in viruses or their cell surfaces, exhibits the preventive effect in the permeation of virus into the host cell [64,65].

9.1. Green Algae

A sulfated polysaccharide consisting of a huge quantity of L-rhamnose accompanied by a small amount of D-glucose was isolated from Monostroma nitidum Wittrock (family: Ulvophyceae) and referred to as rhamnansulfate [66]. Various studies have revealed that different rhamnan-types of sulfated polysaccharides exhibit strong antiviral activities against several enveloped viruses, like HSVs and HIV. These include rhamnansulfate from Monostroma latissimum Wittrock (Chlorophyta) and sodium spirulan obtained from Spirulina platensis (Gomont) Geitler (Cyanophyta) [67,68]. Additionally, few sulfated polysaccharides derived from seaweeds have been observed to cause nitric oxide (NO) production [69,70]. On the contrary, in some cases, rhamnansulfate was found to not induce NO production when evaluated in RAW264.7 cell lines [66]. Sulfated polysaccharides also act as heparan sulfate mimetics, thus targeting the attachments of the viruses and preventing their adherence to cells [60].
Several green algae have grown along the coastlines of India, and one of the predominant species is Scinaia hatei Børgesen, which contains sulfated xylomannan [71]. Various chemically altered structures, mainly polysaccharides, have been studied from this alga, by different researchers, for their antiviral activities. Ray et al. assessed the antiviral activity of sulfated xylomannan obtained from S. hatei and demonstrated potent antiviral efficacy of the chemically engineered sulfated xylomannan with limited degree of cytotoxicity. They observed that the compounds with higher sulfate content and lesser substitution of xylose with a greater molecular mass depicted more anti-HSV effect [72]. Anti-HSV effect of seven chemically altered polysaccharides, obtained from Enteromorpha compressa (Linnaeus) Nees, has been evaluated; out of these seven compounds, one derivative, namely SU1F1, which was a 22% (w/w) sulfated heteroglycuronan, exhibited acceptable inhibitory effect on the virus through a wide-ranging mechanism of action [73]. Sulfated polysaccharide fraction isolated from Caulerpa racemosa (Forsskål) J. Agardh was considered to be a selective inhibitor of thymidine kinase (TK) acyclovir-resistant HSV-1 and HSV-2 strains in Vero cells and reference strains with EC50 of approximately 2.2–4.2 µg/mL [60]. Further study on this green alga has shown the presence of a sulfoquinovosyldiacylglycerol compound, which was potent against standard and clinical HSV-2 strains at IC50 of 15.6 µg/mL [74].

9.2. Red Algae

The significance of red algae, as a potential novel source of anti-HSV agents, is well-known [75,76,77]. Serkedjieva [78] reported that the Polysiphonia denudata (Dillwyn) Greville ex Harvey aquatic extract from the Bulgarian Black Sea coast demonstrated selective inhibition of HSV-1 and HSV-2 reproduction with IC50 ranging between 8.7 and 47.7 mg/mL. This inhibition was effective against intracellular viral replication and adsorption. Similarly, the anti-HSV effect of Persian Gulf Gracilaria salicornia (C. Agardh) E. Y. Dawson was demonstrated by Zandi et al. [79]. G. salicornia aqueous extract exhibited antiviral effect against HSV-2, not only prior to virus attachment and entry into Vero cells, but also on viral replication and post-attachment stages. In a study carried out by Rhimou et al. [80], the aqueous extracts of Ceramium rubrum C. Agardh, Pterosiphonia complanata (Clemente) Falkenberg, Asparagopsis armata Harvey, Gelidium spinulosum (C. Agardh) J. Agardh, Halopitys incurvus (Hudson) Batters, Gelidium pulchellum (Turner) Kützing, Hypnea musciformis (Wulfen) J. V. Lamouroux, Boergeseniella thuyoides (Harvey) Kylin, Plocamium cartilagineum (Linnaeus) P.S. Dixon, and Sphaerococcus coronopifolius Stackhouse were demonstrated to be effective at constraining HSV-1 replication at an EC50 of 2.5–75.9 µg/mL, deprived of any cytotoxic effect.
Indeed, numerous polysaccharides from red algae possess substantial antiviral activity against several animal viruses [64,81,82,83]. Reports are available for polysulfates, either naturally-occurring or chemically produced against a broad assortment of viruses, together with HSV-1, HSV-3, HIV, respiratory syncytial virus, influenza, and human cytomegalovirus [59,62,84]. An in-vitro and in-vivo study was performed by Huheihel et al. [85] in order to explore antiviral potency of a cell wall polysaccharide obtained from Porphyridium species. Results revealed the extracted polysaccharide to expressively inhibit infection of Vero cells caused by herpes simplex virus when evaluated in newborn rabbits and rats. This sulfated polysaccharide consisted of xylose, glucose, and galactose [86]. Although the exact mechanism of their anti-herpes activity is not yet clear, they are believed to exert inhibitory effect at an initial stage of the infection cycle, involving virus penetration into the host cell or virus adsorption onto cell, mainly due to interaction of the polysaccharide with the virus [85,87].
Acyclovir, along with some of its recently licensed nucleoside analogues (usually targets viral DNA synthesis), is still the drug of choice for systemic or topical delivery against herpes virus [6,88]. Many polysaccharides, with sulfated galactans representing the chief matrix polysaccharides, are present in red seaweed. The potent anti-HSV-2 effect was also recorded from a galactan preparation obtained from Cryptonemia crenulata (J. Agardh) J. Agardh in an in vivo murine model of HSV [59]. Alkali-extracted xylan (with a molecular weight of 12 kDa) from a red algae Scinaia hatei showed potent anti-HSV activity with a prominent effect on viral entry [89]. Another polysaccharide fraction obtained from the alga Lithothamnion muelleri inhibited HSV-1 and HSV-2 mainly due to viral adsorption inhibition and virus entry prevention into host cells [90]. Carrageenans are anionic sulfated polysaccharides classified into three groups, based on the existence of 3, 6-anhydrogalactopyranose and allocation of sulfate groups on the main structures, namely λ-, κ-, and ι-carrageenan (Figure 3). Carrageenans isolated from Meristiella gelidium had also been reported for their anti-HSV potentials [91]. Recently, the work done by Boulho et al. [92] demonstrated that iota-carrageenan fraction of Solieria chordalis (C. Agardh) J. Agardh is potent against HSV-1 (EC50 3.2 to 54.4 µg/mL) without cytotoxicity in that range of concentration.
Apart from carbohydrates, some proteins like griffithsin, which are lectin derivatives from red algae of Griffithsia genus, are among the most potent inhibitors of viral entry discovered [93]. Several reports of griffithsin are also available for anti-HSV activity. An in vitro study revealed griffithsin to demonstrate an IC50 at nanomolar range, and exhibit mild to moderate HSV-2 blocking effect [94,95]. The anti-HSV-2 effect of griffithsin is also reported in in vivo murine models [95]. The HSV-2 blocking effect was due to its interaction with glycoprotein D, which is involved in HSV-2 entry [94].

9.3. Brown Algae

Brown algae of the Dictyotaceae family are representative of over 40 species and are known to produce various secondary metabolites, especially of Diterpenes category. These are mainly divided into groups such as dolabellanes, extended sesquiterpenes, and xenicanes, based on the first formal cyclization of the geranyl-geraniol precursor. [96]. This family is among the most abundant seaweeds of prominent marine habitats like the Indian and Atlantic oceans [97,98,99]. Fifteen metabolites isolated from Dictyota linearis (Ag.) Grev. and 19 from Dictyota dichotoma (Huds.) Lam. did not show considerable effect against HSV-I and poliomyelitis virus I [96]. In another study by Garrido et al., dolabellane diterpene dolabelladienetriol and one diacetoxy-derivative obtained from Dictyota pfaffii Schnetter (Phaeophyceae) [100] were evaluated for sub-chronic toxicities and their anti-HSV effect [101]. Their study revealed that dolabelladienetriol exhibits anti-HIV activity with low toxicity; thus, it was concluded as a possible molecule for drug development against herpes infection [101]. Vallim et al. [97] had reported dolastane diterpenes 4-hydroxy-9,14-dihydroxydolasta-1(15), 7-diene (1) and 4,7,14-trihydroxydolasta-1(15), 8-diene (2), from Canistrocarpus cervicornis (Kützing) De Paula and De Clerck to repress HSV-1 infection in Vero cells (Figure 4).
Fucoidans or fucan sulfates, predominantly found in brown macroalgae, possess anti-HSV activities [102,103,104]. A general structural feature of fucoidans is the presence of a sufficient quantity of α-l-fucose residues and sulfate ester groups, along with a small quantity of other residues of monosaccharides including xylose, mannose, galactose, rhamnose, and glucuronic acid (Figure 5) [105]. In 2015, Thuy et al. extracted fucoidan fractions from Sargassum polycystum C. Agardh, Sargassum mcclurei Setchell, and Turbinara ornata (Turner) J. Agardh and estimated their selective antiviral activities against HSV-1. The extracted fucoidans were equally potent against HSV-1 with IC50 from 0.33 to 0.7 µg/mL, although they exhibited no cytotoxicity. Fucoidan isolated from Undaria pinnatifida (Harvey) Suringar has displayed activity against HSV-1 by directly inhibiting replication of the virus and/or stimulating innate and adaptive immune defenses [103]. Fucoidans isolated from different brown macroalgae such as Sargassum horneri (Turner) C. Agardh, Cystoseira indica (Thivy and Doshi) Mairh, Adenocystis utricularis (Bory) Skottsberg, Stoechospermum marginatum (C. Agardh) Kützing, and Sargassum tenerrimum J. Agardh have been continually found to exhibit anti-HSV activity [106,107,108,109,110]. Chattopadhyay et al. isolated polysaccharide fractions from Grateloupia indica Børgesen, which have shown anti-HSV activity (IC50 0.12–1.06 µg/mL), mainly owing to the inhibition of virus adsorption to host cell [111].
Alginates are the main acidic polysaccharides of the cell wall widely distributed in brown algae. They are linear anionic polysaccharides, composed of the main backbone of poly-d-glucuronic acid (G blocks) and poly-d-mannuronic acid (M blocks), together with alternate d-guluronic acid and d-mannuronic acid (GM blocks) (Figure 6) [56]. Peng et al. [112] had reported the polysaccharides from cultivated Sargassum naozhouense possess strong antiviral activity against HSV-1 strain F in-vitro with EC50 value of 8.29 μg/mL. Fourier Transform infrared spectroscopy (FT-IR) spectroscopy analysis revealed the polysaccharides from the studied S. naozhouense to possibly be alginates and fucoidan. A fraction of polysaccharide xylogalactofucan and alginic acid were separated from Sphacelaria indica Reinke and evaluated for anti-HSV activity. The compound showed potent anti-HSV effect, and the authors demonstrated sulfate content of the polysaccharides to be responsible for the anti-HSV effect [112].
A sulfated xylogalactofucan, along with alginic acid fractions, was extracted from Laminaria angustata Kjellman and evaluated for anti-HSV activity. The HSV-1 inhibitory effect was found to be enhanced upon the introduction of sulfate groups, and the effect was due to the direct interaction of polysaccharide with virus particles [113]. Various fractions of sulfated polysaccharides were obtained from Dictyota dichotoma, out of which, the ones rich in galactofucan showed moderate inhibitory effect against HSV-1, and some others, like xylomannan-rich fractions, showed activity against HSV-1 [114].

10. Concluding Remarks and Future Prospects

Herpesviruses are accountable for causing various diseases in humans. With increasing seroprevalence rates, treatment of HSV infections remains a challenge, irrespective of the availability of various drugs with outstanding intrinsic antiviral activities. The present treatment for HSV infections is fairly safe and efficient. Nevertheless, long-term treatment with these drugs is frequently linked with toxicities and drug resistance, especially in immune-compromised patients, which restrict their utility and ultimate druggability. Hence, there is an apparent need to develop new antiviral drugs [5]. Since several new compounds are presently in clinical development, it would be useful if these compounds are screened not only for their antiviral properties but also for their potential use in combination with existing antivirals as multidrug regimens.
Algae constitute the richest source of well-known and novel biologically active compounds. All anti-HSV compounds, especially the sulfated polysaccharides summarized in this review, appear to be promising and potential leads for novel therapies in HSV infections. However, the number of species screened for anti-HSV so far is comparatively small, and there are numerous polysaccharides and bioactive compounds with antiviral properties that remain untapped. Although marine algae form a repertoire of an array of chemicals with noteworthy diversity, it is difficult to obtain high quantity preferred compounds. In this context, combinatorial genetic and metabolic engineering remain a solution for the large-scale commercial production of bioactive compounds of interest. Besides, aquaculture, chemical synthesis, and fermentation processes also present as options for large-scale production of a desired compound with anti-HSV properties [124].

Author Contributions

Conceptualization, M.F.M., D.L., and K.R.R.R.; writing—original draft preparation, M.F.M., D.L., K.R.R.R., S.G., D.T., G.Z., and I.S.; writing—review and editing, M.F.M., D.L., K.R.R.R., S.G., D.T., G.Z., D.H.K., and I.S.; funding acquisition, I.S.

Funding

This article was supported by the KU Research Professor Program of Konkuk University.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kitazato, K.; Wang, Y.; Kobayashi, N. Viral infectious disease and natural products with antiviral activity. Drug Discov. Ther. 2007, 1, 14–22. [Google Scholar]
  2. Roback, J.D.; Su, L.; Zimring, J.C.; Hillyer, C.D. Transfusion-transmitted cytomegalovirus: Lessons from a murine model. Transfus. Med. Rev. 2007, 21, 26–36. [Google Scholar] [CrossRef]
  3. Luecke, S.; Paludan, S.R. Innate recognition of alphaherpesvirus DNA. Adv. Virus Res. 2015, 92, 63–100. [Google Scholar] [CrossRef]
  4. Sehrawat, S.; Kumar, D.; Rouse, B.T. Herpesviruses: Harmonious Pathogens but Relevant Cofactors in Other Diseases? Front. Cell Infect. Microbiol. 2018, 8, 177. [Google Scholar] [CrossRef]
  5. Vadlapudi, A.; Vadlapatla, R.; Mitra, A. Update on emerging antivirals for the management of herpes simplex virus infections: A patenting perspective. Recent Pat. Anti-Infect. Drug Discov. 2013, 8, 55–67. [Google Scholar]
  6. Whitley, R.J.; Roizman, B. Herpes simplex virus infections. Lancet 2001, 357, 1513–1518. [Google Scholar] [CrossRef]
  7. Esmann, J. The many challenges of facial herpes simplex virus infection. J. Antimicrob. Chemother. 2001, 47, 17–27. [Google Scholar] [CrossRef]
  8. WHO. Herpes Simplex Virus. Available online: https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus (accessed on 24 June 2019).
  9. Chattopadhyay, D.; Mukhopadhyay, A.; Ojha, D.; Sadhukhan, P.; Dutta, S. Immuno-metabolic changes in herpes virus infection. Cytokine 2018, 112, 52–62. [Google Scholar] [CrossRef] [PubMed]
  10. Cardozo, F.; Larsen, I.; Carballo, E.; Jose, G.; Stern, R.; Brummel, R.; Camelini, C.; Rossi, M.; Simões, C.; Brandt, C. In vivo anti-HSV activity of a sulfated derivative of Agaricus brasiliensis mycelial polysaccharide. Antimicrob. Agents Chemother. 2013, 57, 2541–2549. [Google Scholar] [CrossRef] [PubMed]
  11. Wilhelmus, K.R. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst. Rev. 2015, 1, CD002898. [Google Scholar] [CrossRef] [PubMed]
  12. Gupta, R.; Warren, T.; Wald, A. Genital herpes. Lancet 2007, 370, 2127–2137. [Google Scholar] [CrossRef]
  13. Mettenleiter, T.C.; Klupp, B.G.; Granzow, H. Herpesvirus assembly: A tale of two membranes. Curr. Opin. Microbiol. 2006, 9, 423–429. [Google Scholar] [CrossRef] [PubMed]
  14. Ren, X.; Xue, C.; Kong, Q.; Zhang, C.; Bi, Y.; Cao, Y. Proteomic analysis of purified Newcastle disease virus particles. Proteome Sci. 2012, 10, 32. [Google Scholar] [CrossRef] [PubMed]
  15. Whitley, R.; Kimberlin, D.W.; Cg, P. Pathogenesis and Disease. In Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis; Arvin, A.C.-F.G., Mocarski, E., Eds.; Cambridge University Press: Cambridge, UK, 2007. [Google Scholar]
  16. Koelle, D.M.; Corey, L. Herpes simplex: Insights on pathogenesis and possible vaccines. Annu. Rev. Med. 2008, 59, 381–395. [Google Scholar] [CrossRef] [PubMed]
  17. Kumar, S.P.; Chandy, M.L.; Shanavas, M.; Khan, S.; Suresh, K.V. Pathogenesis and life cycle of herpes simplex virus infection-stages of primary, latency and recurrence. J. Oral Maxillofac. Surg. Med. Pathol. 2016, 28, 350–353. [Google Scholar] [CrossRef]
  18. George, A.K.; Anil, S. Acute herpetic gingivostomatitis associated with herpes simplex virus 2: Report of a case. J. Int. Oral Health: Jioh 2014, 6, 99. [Google Scholar]
  19. Rosain, J.; Froissart, A.; Estrangin, E.; Rozenberg, F. Severe acute pharyngotonsillitis due to herpes simplex virus type 2 in a young woman. J. Clin. Virol. 2015, 63, 63–65. [Google Scholar] [CrossRef]
  20. Spruance, S.L.; Overall, J.C., Jr.; Kern, E.R.; Krueger, G.G.; Pliam, V.; Miller, W. The natural history of recurrent herpes simplex labialis: Implications for antiviral therapy. N. Engl. J. Med. 1977, 297, 69–75. [Google Scholar] [CrossRef]
  21. Kopriva, F. Recurrent herpetic whitlow in an immune competent girl without vesicular lesions. Eur. J. Pediatrics 2002, 161, 120–121. [Google Scholar] [CrossRef]
  22. Wei, E.Y.; Coghlin, D.T. Beyond Folliculitis: Recognizing rerpes gladiatorum in adolescent athletes. J. Pediatrics 2017, 190, 283. [Google Scholar] [CrossRef]
  23. Harindra, V.; Paffett, M.C. Recurrent eczema herpeticum: An underrecognised condition. Sex. Transm. Infect. 2001, 77, 76. [Google Scholar] [CrossRef]
  24. Friedman, H.M. Keratin, a dual role in herpes simplex virus pathogenesis. J. Clin. Virol. 2006, 35, 103–105. [Google Scholar] [CrossRef] [PubMed]
  25. Raborn, G.W.; Grace, M.G. Recurrent herpes simplex labialis: Selected therapeutic options. J. Can. Dent. Assoc. 2003, 69, 498–504. [Google Scholar] [PubMed]
  26. Cabrera, J.R.; Borbolla, A. Herpes simplex virus and neurotrophic factors. J. Hum. Virol. Retrovirol. 2015, 2, 00027. [Google Scholar]
  27. Freeman, E.E.; Weiss, H.A.; Glynn, J.R.; Cross, P.L.; Whitworth, J.A.; Hayes, R.J. Herpes simplex virus 2 infection increases HIV acquisition in men and women: Systematic review and meta-analysis of longitudinal studies. AIDS 2006, 20, 73–83. [Google Scholar] [CrossRef]
  28. James, S.; Whitley, R. Treatment of herpes simplex virus infections in pediatric patients: Current status and future needs. Clin. Pharm. Ther. 2010, 88, 720–724. [Google Scholar] [CrossRef]
  29. Moraru, M.; Cisneros, E.; Gómez-Lozano, N.; de Pablo, R.; Portero, F.; Cañizares, M.; Vaquero, M.; Roustán, G.; Millán, I.; López-Botet, M. Host genetic factors in susceptibility to herpes simplex type 1 virus infection: Contribution of polymorphic genes at the interface of innate and adaptive immunity. J. Immunol. 2012, 188, 1103434. [Google Scholar] [CrossRef]
  30. Gallina, G.; Cumbo, V.; Messina, P.; Modica, M.; Caruso, C. MHC-linked genetic factors (HLA-B35) influencing recurrent circumoral herpetic lesions. Dis. Markers 1987, 5, 191–197. [Google Scholar]
  31. Pasieka, T.J.; Lu, B.; Crosby, S.D.; Wylie, K.M.; Morrison, L.A.; Alexander, D.E.; Menachery, V.D.; Leib, D.A. Herpes simplex virus virion host shutoff attenuates establishment of the antiviral state. J. Virol. 2008, 82, 5527–5535. [Google Scholar] [CrossRef]
  32. Fakioglu, E.; Wilson, S.S.; Mesquita, P.M.; Hazrati, E.; Cheshenko, N.; Blaho, J.A.; Herold, B.C. Herpes simplex virus downregulates secretory leukocyte protease inhibitor: A novel immune evasion mechanism. J. Virol. 2008, 82, 9337–9344. [Google Scholar] [CrossRef]
  33. Oroskar, A.A.; Read, G.S. Control of mRNA stability by the virion host shutoff function of herpes simplex virus. J. Virol. 1989, 63, 1897–1906. [Google Scholar]
  34. Kwong, A.D.; Frenkel, N. Herpes simplex virus-infected cells contain a function (s) that destabilizes both host and viral mRNAs. Proc. Natl. Acad. Sci. USA 1987, 84, 1926–1930. [Google Scholar] [CrossRef] [PubMed]
  35. Kalamvoki, M.; Qu, J.; Roizman, B. Translocation and colocalization of ICP4 and ICP0 in cells infected with herpes simplex virus 1 mutants lacking glycoprotein E, glycoprotein I, or the virion host shutoff product of the UL41 gene. J. Virol. 2008, 82, 1701–1713. [Google Scholar] [CrossRef] [PubMed]
  36. Duerst, R.J.; Morrison, L.A. Herpes simplex virus 2 virion host shutoff protein interferes with type I interferon production and responsiveness. Virology 2004, 322, 158–167. [Google Scholar] [CrossRef]
  37. Suzutani, T.; Nagamine, M.; Shibaki, T.; Ogasawara, M.; Yoshida, I.; Daikoku, T.; Nishiyama, Y.; Azuma, M. The role of the UL41 gene of herpes simplex virus type 1 in evasion of non-specific host defence mechanisms during primary infection. J. Gen. Virol. 2000, 81, 1763–1771. [Google Scholar] [CrossRef] [PubMed]
  38. Murphy, J.A.; Duerst, R.J.; Smith, T.J.; Morrison, L.A. Herpes simplex virus type 2 virion host shutoff protein regulates alpha/beta interferon but not adaptive immune responses during primary infection in vivo. J. Virol. 2003, 77, 9337–9345. [Google Scholar] [CrossRef] [PubMed]
  39. Rolinski, J.; Hus, I. Immunological aspects of acute and recurrent herpes simplex keratitis. J. Immunol. Res. 2014, 2014, 513560. [Google Scholar] [CrossRef]
  40. Hook, L.M.; Lubinski, J.M.; Jiang, M.; Pangburn, M.K.; Friedman, H.M. Herpes simplex virus type 1 and 2 glycoprotein C prevents complement-mediated neutralization induced by natural immunoglobulin M antibody. J. Virol. 2006, 80, 4038–4046. [Google Scholar] [CrossRef] [Green Version]
  41. Morrison, L.A.; Knipe, D.M. Immunization with replication-defective mutants of herpes simplex virus type 1: Sites of immune intervention in pathogenesis of challenge virus infection. J. Virol. 1994, 68, 689–696. [Google Scholar]
  42. Riley, L.E. Herpes Simplex Virus. Semin. Perinatol. 1998, 22, 284–292. [Google Scholar]
  43. Leib, D. Counteraction of Interferon-Induced Antiviral Responses by Herpes Simplex Viruses. In Viral Proteins Counteracting Host Defenses; Springer: Berlin, Germany, 2002; pp. 171–185. [Google Scholar]
  44. Arduino, P.G.; Porter, S.R. Herpes Simplex Virus Type 1 infection: Overview on relevant clinico-pathological features. J. Oral Pathol. Med. 2008, 37, 107–121. [Google Scholar] [CrossRef]
  45. Grinde, B. Herpesviruses: Latency and reactivation–viral strategies and host response. J. Oral Microbiol. 2013, 5, 22766. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Thellman, N.M.; Triezenberg, S.J. Herpes simplex virus establishment, maintenance, and reactivation: In vitro modeling of latency. Pathogens 2017, 6, 28. [Google Scholar] [CrossRef] [PubMed]
  47. Blyth, W.; Hill, T. Establishment, maintenance, and control of herpes simplex virus (HSV) latency. In Immunobiology of Herpes Simplex Virus Infection; CRC Press: Boca Raton, FL, USA, 1984; pp. 9–32. [Google Scholar]
  48. Nicola, A.V.; Hou, J.; Major, E.O.; Straus, S.E. Herpes simplex virus type 1 enters human epidermal keratinocytes, but not neurons, via a pH-dependent endocytic pathway. J. Virol. 2005, 79, 7609–7616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Rajendran, R. Shafer’s Textbook of Oral Pathology; Elsevier: Amsterdam, The Netherlands, 2009. [Google Scholar]
  50. Nikkels, A.F.; Pièrard, G.E. Treatment of mucocutaneous presentations of herpes simplex virus infections. Am. J. Clin. Dermatol. 2002, 3, 475–487. [Google Scholar] [CrossRef] [PubMed]
  51. Spruance, S. Pathogenesis of herpes simplex labialis: Excretion of virus in the oral cavity. J. Clin. Microbiol. 1984, 19, 675–679. [Google Scholar]
  52. El Gamal, A.A. Biological importance of marine algae. Saudi Pharm. J. 2010, 18, 1–25. [Google Scholar] [CrossRef] [Green Version]
  53. Lordan, S.; Ross, R.P.; Stanton, C. Marine bioactives as functional food ingredients: Potential to reduce the incidence of chronic diseases. Mar. Drugs 2011, 9, 1056–1100. [Google Scholar] [CrossRef] [Green Version]
  54. Belghit, I.; Rasinger, J.D.; Heesch, S.; Biancarosa, I.; Liland, N.; Torstensen, B.; Waagbø, R.; Lock, E.-J.; Bruckner, C.G. In-depth metabolic profiling of marine macroalgae confirms strong biochemical differences between brown, red and green algae. Algal Res. 2017, 26, 240–249. [Google Scholar] [CrossRef]
  55. Yasuhara-Bell, J.; Lu, Y. Marine compounds and their antiviral activities. Antivir. Res. 2010, 86, 231–240. [Google Scholar] [CrossRef]
  56. Ahmadi, A.; Zorofchian Moghadamtousi, S.; Abubakar, S.; Zandi, K. Antiviral Potential of Algae Polysaccharides Isolated from Marine Sources: A Review. Biomed. Res. Int. 2015, 2015, 825203. [Google Scholar] [CrossRef] [Green Version]
  57. Zhao, C.; Yang, C.; Liu, B.; Lin, L.; Sarker, S.D.; Nahar, L.; Yu, H.; Cao, H.; Xiao, J. Bioactive compounds from marine macroalgae and their hypoglycemic benefits. Trends Food Sci. Technol. 2018, 72, 1–12. [Google Scholar] [CrossRef]
  58. Gerber, P.; Dutcher, J.D.; Adams, E.V.; Sherman, J.H. Protective effect of seaweed extracts for chicken embryos infected with influenza B or mumps virus. Proc. Soc. Exp. Biol. Med. 1958, 99, 590–593. [Google Scholar] [CrossRef] [PubMed]
  59. Talarico, L.B.; Zibetti, R.G.; Faria, P.C.; Scolaro, L.A.; Duarte, M.E.; Noseda, M.D.; Pujol, C.A.; Damonte, E.B. Anti-herpes simplex virus activity of sulfated galactans from the red seaweeds Gymnogongrus griffithsiae and Cryptonemia crenulata. Int. J. Biol. Macromol. 2004, 34, 63–71. [Google Scholar] [CrossRef] [PubMed]
  60. Ghosh, T.; Chattopadhyay, K.; Marschall, M.; Karmakar, P.; Mandal, P.; Ray, B. Focus on antivirally active sulfated polysaccharides: From structure–activity analysis to clinical evaluation. Glycobiology 2008, 19, 2–15. [Google Scholar] [CrossRef] [PubMed]
  61. Vaheri, A. Heparin and related polyonic substances as virus inhibitors. Acta Pathol. Microbiol. Scand. 1964, 171, 1–98. [Google Scholar]
  62. Witvrouw, M.; De Clercq, E. Sulfated polysaccharides extracted from sea algae as potential antiviral drugs. Gen. Pharm. Vasc. Syst. 1997, 29, 497–511. [Google Scholar] [CrossRef]
  63. Cohen, J. Microbicide Fails to Protect against HIV; American Association for the Advancement of Science: Washington, DC, USA, 2008. [Google Scholar]
  64. Ehresmann, D.; Deig, E.; Hatch, M. Antiviral properties of algal polysaccharides and related compounds. Mar. Algae Pharm. Sci. 1979, 11, 293–302. [Google Scholar]
  65. Hatch, M.; Ehresmann, D.; Deig, E.; Vedros, N. Further-studies on chemical compoisition and an initial in vivo evaluation of antiviral material in extracts of macroscopic marine-algae. J. Phycol. 1977, 13, 28. [Google Scholar]
  66. Lee, J.-B.; Koizumi, S.; Hayashi, K.; Hayashi, T. Structure of rhamnan sulfate from the green alga Monostroma nitidum and its anti-herpetic effect. Carbohydr. Polym. 2010, 81, 572–577. [Google Scholar] [CrossRef]
  67. Hayashi, T.; Hayashi, K.; Maeda, M.; Kojima, I. Calcium spirulan, an inhibitor of enveloped virus replication, from a blue-green alga Spirulina platensis. J. Nat. Prod. 1996, 59, 83–87. [Google Scholar] [CrossRef]
  68. Lee, J.-B.; Hayashi, K.; Hayashi, T.; Sankawa, U.; Maeda, M. Antiviral activities against HSV-1, HCMV, and HIV-1 of rhamnan sulfate from Monostroma latissimum. Planta Med. 1999, 65, 439–441. [Google Scholar] [CrossRef] [PubMed]
  69. Leiro, J.M.; Castro, R.; Arranz, J.A.; Lamas, J. Immunomodulating activities of acidic sulphated polysaccharides obtained from the seaweed Ulva rigida C. Agardh. Int. Immunopharmacol. 2007, 7, 879–888. [Google Scholar] [CrossRef] [PubMed]
  70. Nakamura, T.; Suzuki, H.; Wada, Y.; Kodama, T.; Doi, T. Fucoidan induces nitric oxide production via p38 mitogen-activated protein kinase and NF-κB-dependent signaling pathways through macrophage scavenger receptors. Biochem. Biophys. Res. Commun. 2006, 343, 286–294. [Google Scholar] [CrossRef] [PubMed]
  71. Mandal, P.; Pujol, C.A.; Carlucci, M.J.; Chattopadhyay, K.; Damonte, E.B.; Ray, B. Anti-herpetic activity of a sulfated xylomannan from Scinaia hatei. Phytochemistry 2008, 69, 2193–2199. [Google Scholar] [CrossRef]
  72. Ray, S.; Pujol, C.A.; Damonte, E.B.; Ray, B. Additionally sulfated xylomannan sulfates from Scinaia hatei and their antiviral activities. Carbohydr. Polym. 2015, 131, 315–321. [Google Scholar] [CrossRef]
  73. Lopes, N.; Ray, S.; Espada, S.F.; Bomfim, W.A.; Ray, B.; Faccin-Galhardi, L.C.; Linhares, R.E.C.; Nozawa, C. Green seaweed Enteromorpha compressa (Chlorophyta, Ulvaceae) derived sulphated polysaccharides inhibit herpes simplex virus. Int. J. Biol. Macromol. 2017, 102, 605–612. [Google Scholar] [CrossRef]
  74. Wang, H.; Li, Y.-L.; Shen, W.-Z.; Rui, W.; Ma, X.-J.; Cen, Y.-Z. Antiviral activity of a sulfoquinovosyldiacylglycerol (SQDG) compound isolated from the green alga Caulerpa racemosa. Bot. Mar. 2007, 50, 185–190. [Google Scholar] [CrossRef]
  75. Carlucci, M.J.; Pujol, C.A.; Ciancia, M.; Noseda, M.D.; Matulewicz, M.C.; Damonte, E.B.; Cerezo, A.S. Antiherpetic and anticoagulant properties of carrageenans from the red seaweed Gigartina skottsbergii and their cyclized derivatives: Correlation between structure and biological activity. Int. J. Biol. Macromol. 1997, 20, 97–105. [Google Scholar] [CrossRef]
  76. Rodríguez, M.C.; Merino, E.R.; Pujol, C.A.; Damonte, E.B.; Cerezo, A.S.; Matulewicz, M.C. Galactans from cystocarpic plants of the red seaweed Callophyllis variegata (Kallymeniaceae, Gigartinales). Carbohydr. Res. 2005, 340, 2742–2751. [Google Scholar] [CrossRef]
  77. Kulshreshtha, G.; Burlot, A.S.; Marty, C.; Critchley, A.; Hafting, J.; Bedoux, G.; Bourgougnon, N.; Prithiviraj, B. Enzyme-assisted extraction of bioactive material from Chondrus crispus and Codium fragile and its effect on herpes simplex virus (HSV-1). Mar. Drugs 2015, 13, 558–580. [Google Scholar] [CrossRef] [Green Version]
  78. Serkedjieva, J. Antiherpes virus effect of the red marine alga Polysiphonia denudata. Z. Nat. C 2000, 55, 830–835. [Google Scholar] [CrossRef] [PubMed]
  79. Zandi, K.; Salimi, M.; Sartavi, K. In vitro antiviral activity of the red marine alga from Persian gulf, Gracilaria salicornia against herpes simplex virus type 2. J. Biol. Sci. 2007, 7, 1274–1277. [Google Scholar]
  80. Rhimou, B.; Hassane, R.; Nathalie, B. Antiviral activity of the extracts of Rhodophyceae from Morocco. Afr. J. Biotechnol. 2010, 9, 7968–7975. [Google Scholar]
  81. Gonzalez, M.; Alarcón, B.; Carrasco, L. Polysaccharides as antiviral agents: Antiviral activity of carrageenan. Antimicrob. Agents Chemother. 1987, 31, 1388–1393. [Google Scholar] [CrossRef] [Green Version]
  82. Nakashima, H.; Kido, Y.; Kobayashi, N.; Motoki, Y.; Neushul, M.; Yamamoto, N. Purification and characterization of an avian myeloblastosis and human immunodeficiency virus reverse transcriptase inhibitor, sulfated polysaccharides extracted from sea algae. Antimicrob. Agents Chemother. 1987, 31, 1524–1528. [Google Scholar] [CrossRef] [Green Version]
  83. Neushul, M. Antiviral carbohydrates from marine red algae. In Thirteenth International Seaweed Symposium; Springer: Berlin, Germany, 1990; pp. 99–104. [Google Scholar]
  84. Witvrouw, M.; Desmyter, J.; De Clercq, E. Antiviral Portrait Series: 4. Polysuifates as inhibitors of HIV and other enveloped viruses. Antivir. Chem. Chemother. 1994, 5, 345–359. [Google Scholar] [CrossRef]
  85. Huheihel, M.; Ishanu, V.; Tal, J.; Arad, S.M. Activity of Porphyridium sp. polysaccharide against herpes simplex viruses in vitro and in vivo. J. Biochem. Biophys. Methods 2002, 50, 189–200. [Google Scholar] [CrossRef]
  86. Geresh, S.; Arad, S. The extracellular polysaccharides of the red microalgae: Chemistry and rheology. Bioresour. Technol. 1991, 38, 195–201. [Google Scholar] [CrossRef]
  87. Baba, M.; Schols, D.; De Clercq, E.; Pauwels, R.; Nagy, M.; Györgyi-Edelényi, J.; Löw, M.; Görög, S. Novel sulfated polymers as highly potent and selective inhibitors of human immunodeficiency virus replication and giant cell formation. Antimicrob. Agents Chemother. 1990, 34, 134–138. [Google Scholar] [CrossRef] [Green Version]
  88. De Clercq, E.; Herdewijn, P. Strategies in the design of antiviral drugs. Pharm. Sci. Encycl. Drug Discov. Dev. Manuf. 2010. [Google Scholar] [CrossRef]
  89. Mandal, P.; Pujol, C.A.; Damonte, E.B.; Ghosh, T.; Ray, B. Xylans from Scinaia hatei: Structural features, sulfation and anti-HSV activity. Int. J. Biol. Macromol. 2010, 46, 173–178. [Google Scholar] [CrossRef] [PubMed]
  90. Malagoli, B.G.; Cardozo, F.T.; Gomes, J.H.S.; Ferraz, V.P.; Simões, C.M.; Braga, F.C. Chemical characterization and antiherpes activity of sulfated polysaccharides from Lithothamnion muelleri. Int. J. Biol. Macromol. 2014, 66, 332–337. [Google Scholar] [CrossRef] [PubMed]
  91. de SF-Tischer, P.C.; Talarico, L.B.; Noseda, M.D.; Guimarães, S.M.P.B.; Damonte, E.B.; Duarte, M.E.R. Chemical structure and antiviral activity of carrageenans from Meristiella gelidium against herpes simplex and dengue virus. Carbohydr. Polym. 2006, 63, 459–465. [Google Scholar] [CrossRef]
  92. Boulho, R.; Marty, C.; Freile-Pelegrín, Y.; Robledo, D.; Bourgougnon, N.; Bedoux, G. Antiherpetic (HSV-1) activity of carrageenans from the red seaweed Solieria chordalis (Rhodophyta, Gigartinales) extracted by microwave-assisted extraction (MAE). J. Appl. Phycol. 2017, 29, 2219–2228. [Google Scholar] [CrossRef]
  93. Lusvarghi, S.; Bewley, C.A. Griffithsin: An antiviral lectin with outstanding therapeutic potential. Viruses 2016, 8, 296. [Google Scholar] [CrossRef]
  94. Levendosky, K.; Mizenina, O.; Martinelli, E.; Jean-Pierre, N.; Kizima, L.; Rodriguez, A.; Kleinbeck, K.; Bonnaire, T.; Robbiani, M.; Zydowsky, T.M. Griffithsin and carrageenan combination to target HSV-2 and HPV. Antimicrob. Agents Chemother. 2015. [Google Scholar] [CrossRef] [Green Version]
  95. Nixon, B.; Stefanidou, M.; Mesquita, P.M.; Fakioglu, E.; Segarra, T.; Rohan, L.; Halford, W.; Palmer, K.E.; Herold, B.C. Griffithsin protects mice from genital herpes by preventing cell-to-cell spread. J. Virol. 2013, 87, 6257–6269. [Google Scholar] [CrossRef] [Green Version]
  96. Siamopoulou, P.; Bimplakis, A.; Iliopoulou, D.; Vagias, C.; Cos, P.; Berghe, D.V.; Roussis, V. Diterpenes from the brown algae Dictyota dichotoma and Dictyota linearis. Phytochemistry 2004, 65, 2025–2030. [Google Scholar] [CrossRef]
  97. Vallim, M.A.; Barbosa, J.E.; Negratilde, D.; De-Paula, J.C.; Galvatilde, V.A.G.; Teixeira, V.L.; de Palmer Paixatilde, I.C.N. In vitro antiviral activity of diterpenes isolated from the Brazilian brown alga Canistrocarpus cervicornis. J. Med. Plants Res. 2010, 4, 2379–2382. [Google Scholar]
  98. de Araujo, J.M.; Tappin, M.R.R.; da Rocha Fortes, R.; Lopes-Filho, E.A.P.; Salgueiro, F.; De Paula, J.C. Chemodiversity of the brown algae Canistrocarpus cervicornis (Dictyotaceae, Phaeophyceae) in tropical and subtropical populations along the southwestern Atlantic coast of Brazil. J. Appl. Phycol. 2018, 30, 611–618. [Google Scholar] [CrossRef]
  99. Mashjoor, S.; Yousefzadi, M.; Esmaeili, M.A.; Rafiee, R. Cytotoxicity and antimicrobial activity of marine macro algae (Dictyotaceae and Ulvaceae) from the Persian Gulf. Cytotechnology 2016, 68, 1717–1726. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Pardo-Vargas, A.; de Barcelos Oliveira, I.; Stephens, P.R.S.; Cirne-Santos, C.C.; de Palmer Paixão, I.C.N.; Ramos, F.A.; Jiménez, C.; Rodríguez, J.; Resende, J.A.L.C.; Teixeira, V.L. Dolabelladienols A–C, new diterpenes isolated from Brazilian brown alga Dictyota pfaffii. Mar. Drugs 2014, 12, 4247–4259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Garrido, V.; Barros, C.; Melchiades, V.A.; Fonseca, R.R.; Pinheiro, S.; Ocampo, P.; Teixeira, V.L.; Cavalcanti, D.N.; Giongo, V.; Ratcliffe, N.A. Subchronic toxicity and anti-HSV-1 activity in experimental animal of dolabelladienetriol from the seaweed, Dictyota pfaffii. Regul. Toxicol. Pharm. 2017, 86, 193–198. [Google Scholar] [CrossRef] [PubMed]
  102. Berteau, O.; Mulloy, B. Sulfated fucans, fresh perspectives: Structures, functions, and biological properties of sulfated fucans and an overview of enzymes active toward this class of polysaccharide. Glycobiology 2003, 13, 29–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Hayashi, K.; Nakano, T.; Hashimoto, M.; Kanekiyo, K.; Hayashi, T. Defensive effects of a fucoidan from brown alga Undaria pinnatifida against herpes simplex virus infection. Int. Immunopharmacol. 2008, 8, 109–116. [Google Scholar] [CrossRef]
  104. Hoshino, T.; Hayashi, T.; Hayashi, K.; Hamada, J.; Lee, J.-B.; Sankawa, U. An antivirally active sulfated polysaccharide from Sargassum horneri (TURNER) C. AGARDH. Biol. Pharm. Bull. 1998, 21, 730–734. [Google Scholar] [CrossRef] [Green Version]
  105. Cuong, H.D.; Thuy, T.T.T.; Huong, T.T.; Ly, B.M.; Van, T.T.T. Structure and hypolipidaemic activity of fucoidan extracted from brown seaweed Sargassum henslowianum. Nat. Prod. Res. 2015, 29, 411–415. [Google Scholar] [CrossRef]
  106. Ponce, N.M.; Pujol, C.A.; Damonte, E.B.; Flores, M.A.L.; Stortz, C.A. Fucoidans from the brown seaweed Adenocystis utricularis: Extraction methods, antiviral activity and structural studies. Carbohydr. Res. 2003, 338, 153–165. [Google Scholar] [CrossRef]
  107. Preeprame, S.; Hayashi, K.; Lee, J.-B.; Sankawa, U.; Hayashi, T. A novel antivirally active fucan sulfate derived from an edible brown alga, Sargassum horneri. Chem. Pharm. Bull. 2001, 49, 484–485. [Google Scholar] [CrossRef] [Green Version]
  108. Mandal, P.; Mateu, C.G.; Chattopadhyay, K.; Pujol, C.A.; Damonte, E.B.; Ray, B. Structural features and antiviral activity of sulphated fucans from the brown seaweed Cystoseira indica. Antivir. Chem. Chemother. 2007, 18, 153–162. [Google Scholar] [CrossRef] [Green Version]
  109. Adhikari, U.; Mateu, C.G.; Chattopadhyay, K.; Pujol, C.A.; Damonte, E.B.; Ray, B. Structure and antiviral activity of sulfated fucans from Stoechospermum marginatum. Phytochemistry 2006, 67, 2474–2482. [Google Scholar] [CrossRef] [PubMed]
  110. Sinha, S.; Astani, A.; Ghosh, T.; Schnitzler, P.; Ray, B. Polysaccharides from Sargassum tenerrimum: Structural features, chemical modification and anti-viral activity. Phytochemistry 2010, 71, 235–242. [Google Scholar] [CrossRef] [PubMed]
  111. Chattopadhyay, K.; Mateu, C.G.; Mandal, P.; Pujol, C.A.; Damonte, E.B.; Ray, B. Galactan sulfate of Grateloupia indica: Isolation, structural features and antiviral activity. Phytochemistry 2007, 68, 1428–1435. [Google Scholar] [CrossRef] [PubMed]
  112. Peng, Y.; Xie, E.; Zheng, K.; Fredimoses, M.; Yang, X.; Zhou, X.; Wang, Y.; Yang, B.; Lin, X.; Liu, J.; et al. Nutritional and chemical composition and antiviral activity of cultivated seaweed Sargassum naozhouense Tseng et Lu. Mar. Drugs 2013, 11, 20–32. [Google Scholar] [CrossRef] [Green Version]
  113. Bandyopadhyay, S.S.; Navid, M.H.; Ghosh, T.; Schnitzler, P.; Ray, B. Structural features and in vitro antiviral activities of sulfated polysaccharides from Sphacelaria indica. Phytochemistry 2011, 72, 276–283. [Google Scholar] [CrossRef]
  114. Saha, S.; Navid, M.H.; Bandyopadhyay, S.S.; Schnitzler, P.; Ray, B. Sulfated polysaccharides from I: Structural features and in vitro antiviral activities. Carbohydr. Polym. 2012, 87, 123–130. [Google Scholar] [CrossRef]
  115. Rabanal, M.; Ponce, N.M.; Navarro, D.A.; Gómez, R.M.; Stortz, C.A. The system of fucoidans from the brown seaweed Dictyota dichotoma: Chemical analysis and antiviral activity. Carbohydr. Polym. 2014, 101, 804–811. [Google Scholar] [CrossRef]
  116. Lee, J.-B.; Hayashi, K.; Maeda, M.; Hayashi, T. Antiherpetic activities of sulfated polysaccharides from green algae. Planta Med. 2004, 70, 813–817. [Google Scholar] [CrossRef]
  117. Ghosh, P.; Adhikari, U.; Ghosal, P.K.; Pujol, C.A.; Carlucci, M.a.J.; Damonte, E.B.; Ray, B. In vitro anti-herpetic activity of sulfated polysaccharide fractions from Caulerpa racemosa. Phytochemistry 2004, 65, 3151–3157. [Google Scholar] [CrossRef]
  118. Gomaa, H.H.; Elshoubaky, G.A. Antiviral activity of sulfated polysaccharides carrageenan from some marine seaweeds. Int. J. Curr. Pharm. Rev. Res. 2016, 7, 34–42. [Google Scholar]
  119. Duarte, M.; Noseda, D.; Noseda, M.; Tulio, S.; Pujol, C.; Damonte, E. Inhibitory effect of sulfated galactans from the marine alga Bostrychia montagnei on herpes simplex virus replication in vitro. Phytomedicine 2001, 8, 53–58. [Google Scholar] [CrossRef] [PubMed]
  120. Carlucci, M.J.; Scolaro, L.A.; Errea, M.I.; Matulewicz, M.C.; Damonte, E.B. Antiviral activity of natural sulphated galactans on herpes virus multiplication in cell culture. Planta Med. 1997, 63, 429–432. [Google Scholar] [CrossRef] [PubMed]
  121. Chattopadhyay, K.; Ghosh, T.; Pujol, C.A.; Carlucci, M.J.; Damonte, E.B.; Ray, B. Polysaccharides from Gracilaria corticata: Sulfation, chemical characterization and anti-HSV activities. Int. J. Biol. Macromol. 2008, 43, 346–351. [Google Scholar] [CrossRef] [PubMed]
  122. Pujol, C.; Estevez, J.; Carlucci, M.; Ciancia, M.; Cerezo, A.; Damonte, E. Novel DL-galactan hybrids from the red seaweed Gymnogongrus torulosus are potent inhibitors of herpes simplex virus and dengue virus. Antivir. Chem. Chemother. 2002, 13, 83–89. [Google Scholar] [CrossRef] [Green Version]
  123. Matsuhiro, B.; Conte, A.F.; Damonte, E.B.; Kolender, A.A.; Matulewicz, M.C.; Mejías, E.G.; Pujol, C.A.; Zúñiga, E.A. Structural analysis and antiviral activity of a sulfated galactan from the red seaweed Schizymenia binderi (Gigartinales, Rhodophyta). Carbohydr. Res. 2005, 340, 2392–2402. [Google Scholar] [CrossRef]
  124. Thompson, K.D.; Dragar, C. Antiviral activity of Undaria pinnatifida against herpes simplex virus. Phytother. Res. 2004, 18, 551–555. [Google Scholar] [CrossRef]
Processes 07 00887 g001 550
Figure 1. Model of herpes simplex virus (HSV) establishing infection in host. (a) HSV enters the sensory nerve terminals and is transferred to the dorsal root ganglion, which is situated within the epidermal-dermal junction. (b) In chronic cases, the virus which is already present inside the ganglion and reaches the tissues by penetrating through the sensory nerves.
Figure 1. Model of herpes simplex virus (HSV) establishing infection in host. (a) HSV enters the sensory nerve terminals and is transferred to the dorsal root ganglion, which is situated within the epidermal-dermal junction. (b) In chronic cases, the virus which is already present inside the ganglion and reaches the tissues by penetrating through the sensory nerves.
Processes 07 00887 g001
Processes 07 00887 g002 550
Figure 2. Schematic representation of the mechanism of virion host shutoff (Vhs) in establishing viral infection in host.
Figure 2. Schematic representation of the mechanism of virion host shutoff (Vhs) in establishing viral infection in host.
Processes 07 00887 g002
Processes 07 00887 g003 550
Figure 3. Chemical structure of carrageenan units, namely, kappa, lambda, and iota, isolated from red seaweeds.
Figure 3. Chemical structure of carrageenan units, namely, kappa, lambda, and iota, isolated from red seaweeds.
Processes 07 00887 g003
Processes 07 00887 g004 550
Figure 4. Dolastane diterpenes 1 and 2 isolated from C. cervicornis.
Figure 4. Dolastane diterpenes 1 and 2 isolated from C. cervicornis.
Processes 07 00887 g004
Processes 07 00887 g005 550
Figure 5. Chemical structure of fucoidan unit.
Figure 5. Chemical structure of fucoidan unit.
Processes 07 00887 g005
Processes 07 00887 g006 550
Figure 6. Chemical structure of alginate polysaccharide (GM blocks).
Figure 6. Chemical structure of alginate polysaccharide (GM blocks).
Processes 07 00887 g006
Table
Table 1. Details of the diseases caused by herpes simplex viruses (HSVs) with symptoms and mode of infections.
Table 1. Details of the diseases caused by herpes simplex viruses (HSVs) with symptoms and mode of infections.
DiseaseVirusSymptomsMode of InfectionAge GroupCourse of InfectionIncubation PeriodRef.
Acute herpetic gingivostomatitisHSV-1High body temperature (102–104 °F), lethargy, swollen erythematous, anorexia, friable gums, vesicular lesions (on the oral mucosa, tongue, lips and later rupture and coalesce, leaving ulcerated plaques) and regional lymphadenopathy.Through infected saliva.>0.6 to >5 years and in adult.5–7 days3–6 days[18]
Acute herpetic pharyngotonsillitisHSV-2Headache, fever, malaise, sore throat, ulcerative lesions on tonsils and pharynx showing grayish exudates.Through infected saliva and mucous.>0.6 to >5 years and in adult.5–7 days3–6 days[19]
Herpes labialisHSV-1Lesions with pain, burning, and tingling at a face, around the lips, erythematous papules.Through infected saliva and mucous.All age groups.0–14 days3–6 days[20]
Herpetic whitlowHSV-1 and HSV-2Infections and lesions in fingers associated with swelling, tenderness, and reddening of the infected finger. Occasionally with fever and swollen lymph nodes.Transmitted from primary orofacial and genital infected victims.
May also be transmitted from self or other infected victims.
Healthcare personnel’s, including dentists during oral examinations oral care with ungloved hands		Thumb-sucking children with primary HSV-1 oral infection
Adults aged 20 to 30 following contact with HSV-2-infected genitals.		10–14 days2–20 days[21]
Herpes gladiatorumHSV-1Infection of the face, arms, neck, and upper trunk.
Fever.
Swollen lymph glands.
The affected area suffers a tingling feeling. A bunch of clear, fluid-filled blisters surrounded by redness lesions which may or may not provoke painfully.		Typically seen in wrestlers and participants in some contact sports such as rugby. Infection is promoted by trauma to the skin sustained during matches.Males and females of all ages of athletes.<8 days7–10 days[22]
Eczema herpeticumHSV-1 or HSV-2Clusters of itchy and/or painful blisters with uncontrolled atopic dermatitis, which may end up in increased morbidity, and mortality, if it prolongs further.Through infected saliva and contact.Males and females of all ages but is more common in infants and children with atopic dermatitis.5 to 12 days7 to 10 days[23]
Table
Table 2. Types of virus and its specific site of latency.
Table 2. Types of virus and its specific site of latency.
Family of Herpes VirusName of the VirusSite of LatencyReferences
GammaherpesvirinaeEpstein-Barr Virus (EBV) or human herpesvirus 4 (HHV-4)Lymphocytes[45]
BetaherpesvirinaeMurine cytomegalovirusSalivary gland, spleen, and lymphocytes[46]
AlphaherpesvirinaeHerpes simplex virusNervous site, especially trigeminal ganglion[47]
Table
Table 3. Polysaccharide extracts from green, red, and brown algae with activity against HSV-1 and HSV-2.
Table 3. Polysaccharide extracts from green, red, and brown algae with activity against HSV-1 and HSV-2.
SpeciesExtracts/CompoundsActivity (IC50 = μg/mL)References
HSV-1HSV-2
Green Algae
Caulerpa brachypusSP-rhamnan type and galactan type1.9 (rhamnan type) & 0.65 (galactan type)-[115]
Caulerpa okamuraiSP-galactan type0.55-[115]
Caulerpa racemosaSP fractions4.23.0[116]
Caulerpa scapelliformisSP-galactan type1.6-
Chaetomorpha crassaSP-arabinoxylogalactan type0.85-[115]
Chaetomorpha spiralisSP-arabinoxylogalactan type1.9-[115]
Codium fragileSP-arabinan type0.86-[115]
Codium latumSP-arabinan type0.38-[115]
Enteromorpha compressasulphated heteroglycuronan28.2-[73]
Monostroma nitidumSP-rhamnan type0.4-[115]
Red Algae
Acanthophora specifiraCarrageenan80.5-[117]
Bostrychia montagneiSulfated galactan1311[118]
Callophyllis variegataSulfated galactan0.20,2[76]
Gigartina skottsbergiiLambda-type carrageenan0.60.4[119]
Grateloupia indicaSulfated galactan0.30.3[120]
Gymnogongrus torulosusDL-hybrid sulfated galactan 0.6[121]
Meristiella gelidiumMixture of iota/kappa/nu-carrageenans 2–0.04 [122]
Scinaia hateiSulfated xylomannan0.50.5[71]
Brown Algae
Adenocystis utricularisSulfated galactofucan0.30.5[106]
Cystoseira indicaSulfated fucan2.81.3[108]
Hydroclathrus clathratusCarrageenan100.5 [117]
Laminaria angustataXylogalactofucan0.2–25 [123]
Stoechospermum marginatumSulfated fucan3.60.5[109]
Undaria pinnatifidaGalactofucan sulfate320.5[103,114]

Share and Cite

MDPI and ACS Style

Mahomoodally, M.F.; Lobine, D.; Rengasamy, K.R.R.; Gowrishankar, S.; Tewari, D.; Zengin, G.; Kim, D.H.; Sivanesan, I. Marine Algae: A Potential Resource of Anti-HSV Molecules. Processes 2019, 7, 887. https://doi.org/10.3390/pr7120887

AMA Style

Mahomoodally MF, Lobine D, Rengasamy KRR, Gowrishankar S, Tewari D, Zengin G, Kim DH, Sivanesan I. Marine Algae: A Potential Resource of Anti-HSV Molecules. Processes. 2019; 7(12):887. https://doi.org/10.3390/pr7120887

Chicago/Turabian Style

Mahomoodally, Mohamad Fawzi, Devina Lobine, Kannan R. R. Rengasamy, Shanmugaraj Gowrishankar, Devesh Tewari, Gokhan Zengin, Doo Hwan Kim, and Iyyakkannu Sivanesan. 2019. "Marine Algae: A Potential Resource of Anti-HSV Molecules" Processes 7, no. 12: 887. https://doi.org/10.3390/pr7120887

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop