Marine organisms as a therapeutic source against herpes simplex virus infection

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European Journal of Pharmaceutical Sciences 44 (2011) 11–20

Contents lists available at ScienceDirect

European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier .com/ locate/e jps

Review

Marine organisms as a therapeutic source against herpes simplex virus infection

Thanh-Sang Vo a, Dai-Hung Ngo a, Quang Van Ta a, Se-Kwon Kim a,b,⇑a Department of Chemistry, Pukyong National University, Busan 608-737, Republic of Koreab Marine Bioprocess Research Center, Pukyong National University, Busan 608-737, Republic of Korea

a r t i c l e i n f o

Article history:Received 1 May 2011Accepted 6 July 2011Available online 12 July 2011

Keywords:Herpes simplex virusMarine organismsSulfated polysaccharidesAlgaeMarine invertebrates

0928-0987/$ - see front matter � 2011 Elsevier B.V. Adoi:10.1016/j.ejps.2011.07.005

⇑ Corresponding author at: Department of Chemistsity, Busan 608-737, Republic of Korea. Tel.: +82 5162

E-mail address: [email protected] (S.-K. Kim).

a b s t r a c t

Herpes simplex virus (HSV) is a member of the Herpesviridae family that causes general communicableinfections in human populations throughout the world, the most common being genital and orolabial dis-ease. The current treatments for HSV infections are nucleoside analogs such as acyclovir, valacyclovir andfamciclovir. Despite the safety and efficacy, extensive clinical use of these drugs has led to the emergenceof resistant viral strains, mainly in immunocompromised patients. To counteract these problems, alter-native anti-HSV agents from natural products have been reported. Recently, a great deal of interest hasbeen expressed regarding marine organisms such as algae, sponges, tunicates, echinoderms, mollusks,shrimp, bacteria, and fungus as promising anti-HSV agents. This contribution presents an overview ofpotential anti-HSV agents derived from marine organisms and their promising application in HSVtherapy.

� 2011 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112. Potential anti-herpes virus agents from marine organisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.1. Marine algae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.1.1. Red macroalgae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.1.2. Brown macroalgae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132.1.3. Green macroalgae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142.1.4. Microalgae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2.2. Marine invertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

2.2.1. Sponges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152.2.2. Tunicates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162.2.3. Echinoderms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162.2.4. Mollusks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162.2.5. Shrimps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.3. Marine bacteria and fungus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3. Prospect of marine antiviral drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

ll rights reserved.

ry, Pukyong National Univer-97097; fax: +82 516297099.

1. Introduction

Viral diseases are still the leading cause of death in humansworldwide (Kitazato et al., 2007). Meanwhile, Herpesviridae, a largefamily of several pathogenic viruses, are able to cause a variety ofinapparent, mild or severe human infections. Among more than130 different members, nine different human herpes viruses have

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12 T.-S. Vo et al. / European Journal of Pharmaceutical Sciences 44 (2011) 11–20

been described and divided into three subfamilies, such asalpha-, beta-, and gamma-herpesviridae, based on their biologicalcharacteristics (Roizmann et al., 1992). Notably, herpes simplex virus1 (HSV-1) and herpes simplex virus 2 (HSV-2), a subfamily ofalpha-herpesviridae, are the most widely studied human herpesviruses. HSV-1 is more frequently associated with oral–facialinfections and encephalitis, whereas HSV-2 usually causes genitalinfections, and can be transmitted from infected mothers to neo-nates. Both viruses establish long-term latent infections in sensoryneurons and lesions at or near point of entry into the body (Whitleyand Roizman, 2001; Esmann, 2001). HSV infections are among themost common diseases of humans, with an estimated 60–95% ofthe adult population being infected by at least one of them (Bradyand Bernstein, 2004). Moreover, HSV infections were reported to berecognized as a risk factor for human immunodeficiency virus (HIV)infection (Celum, 2004). Effective anti-herpes drugs, such as acyclo-vir, valacyclovir, penciclovir, famciclovir, trifluridine, cidofovir, andvidarabine are available for treatment. These drugs act as nucleosideinhibitors of DNA polymerase (Brady and Bernstein, 2004). Acycloviris the first selective antiviral agent introduced, and is the drug com-monly employed in the treatment of HSV infection (Furmanet al., 1981). However, the prolonged therapies with the availableanti-herpes drugs have resulted in some undesirable effects and alsoinduced the emergence of drug-resistant strains (Bacon et al., 2003;Morfin and Thouvenot, 2003). Resistance to acyclovir and relatednucleoside analogs can occur following mutation in either HSVthymidine kinase or DNA polymerase (Pielop et al., 2000). For thisreason, the search for new types of anti-herpes virus agents withhigh efficacy on resistant mutant viral strains is urgently needed.

The marine environment, which represents approximately halfof the global biodiversity, contains a rich source of structurally di-verse and biologically active metabolites (Faulkner, 2002; Bluntet al., 2010). Products from marine organisms show many interest-ing activities, such as anti-cancer, anti-diabetic, anti-fungal, anti-coagulant, anti-inflammatory, and other pharmacological activities(Gul and Hamann, 2005; Mayer and Hamann, 2005). In relation toantiviral properties, the marine environment is believed to be ableto provide novel leads against pathogenic viruses that are evolvingand developing resistance to existing pharmaceuticals (Vo andKim, 2010; Donia and Hamann, 2003; Yasuhara-Bell and Lu,2010). Thus, marine organisms are regarded as a promising sourcefor the production of therapeutic drugs against viral diseases (Che,1991). This paper focuses on anti-herpes virus therapeutic agentsderived from marine organisms and their potential medical appli-cation as novel functional ingredients in anti-herpes virus therapy.

2. Potential anti-herpes virus agents from marine organisms

2.1. Marine algae

Marine algae are a large and diverse group of simple, typicallyautotrophic organisms, ranging from unicellular to multicellularforms. Two major types of marine algae can be identified as mac-roalgae (seaweeds) and microalgae. Macroalgae occupy the littoralzone, which included red macroalgae, brown macroalgae, andgreen macroalgae, whereas microalgae are found in both benthicand littoral habitats and also throughout the ocean waters asphytoplankton. Phytoplankton comprises organisms such as dia-toms, dinoflagellates, green and yellow-brown flagellates, andblue-green algae (Gamal, 2010). Marine algae are one of the mostimportant producers of biomass in the marine environment. Theyproduce a wide variety of chemically active metabolites in theirsurroundings as an aid to protect themselves against other settlingorganisms (Bhadury and Wright, 2004). So far, it was evidencedthat marine algae are potential anti-herpes virus agents (Deig,1974; Richards et al., 1978). Up to now, numerous studies have

confirmed the anti-HSV activity of algae that increase the interestin algae as a source of antiviral compounds.

2.1.1. Red macroalgaeThe importance of red macroalgae as a source of novel anti-HSV

agents has been recognized and reported by many researchers.According to Serkedjieva (2000), the water extract of Polysiphoniadenudate exhibited selective inhibition on the reproduction ofHSV-1 and HSV-2 at their effective concentration 50% (EC50) rangeof 8.7–47.7 mg/ml. The inhibition affected adsorption as well asintracellular stages of viral replication. Likewise, anti-HSV activi-ties of Symphyocladia latiuscula were evidenced by Park et al.(2005). A MeOH extract of S. latiuscula and its fractions was effec-tive against acyclovir and phosphonoacetic acid-resistant HSV-1(APr HSV-1), thymidine kinase deficient HSV-1 (TK HSV-1), andwild type HSV-1 in vitro without cytotoxicity. Specially, the majorcomponent of CH2Cl2-soluble fraction, 2,3,6-tribromo-4,5-dihydr-oxybenzyl methyl ether (TDB), inhibited wild type HSV-1, as wellas (APr HSV-1) and (TK HSV-1) with their inhibitory concentration50% (IC50) values of 5.48, 4.81, and 23.3 lg/ml, respectively. More-over, the oral administrations of TDB significantly delayed thedevelopment of skin lesions and suppressed virus yields in HSV-1-infected mice. In another study, Persian Gulf Gracilaria salicorniawas elucidated for its capability against HSV-2 (Zandi et al.,2007b). The antiviral activity of water extract from G. salicornia dis-played not only before attachment and entry of virus to the Verocells, but also on post attachment stages of virus replication. Re-cently, various marine red macroalgae from Morocco also havebeen evaluated for their potential against HSV-1 replicationin vitro (Rhimou et al., 2010). It was revealed that the aqueous ex-tracts of Asparagopsis armata, Ceramium rubrum, Gelidium pulchel-lum, Gelidium spinulosum, Halopitys incurvus, Hypnea musciformis,Plocamium cartilagineum, Boergeseniella thuyoides, Pterosiphoniacomplanata, and Sphaerococcus coronopifolius were capable ofinhibiting the replication of HSV-1 at an EC50 range of 2.5–75.9 lg/ml without any cytotoxic effect. Accordingly, the extractsof marine red macroalgae can be a rich source of potential antiviralcomponents. Interestingly, it has known that marine red macroal-gae contain significant quantities of sulfated polysaccharides thatmay be responsible for anti-HSV properties (McCandless andCraigie, 1979; Damonte et al., 2004).

Indeed, numerous sulfated polysaccharides from red macroal-gae have been determined to possess significant inhibition onherpes virus. Xylomannan, a sulphated polysaccharide from Notho-genia fastigiata, was found to inhibit efficiently the replication ofHSV-1 and HSV-2 under various experimental conditions (Damonteet al., 1994; Pujol et al., 1995). Furthermore, the xylomannansulfate of Scinaia hatei, which contained a backbone of a-(1?3)-linkedD-mannopyranosyl residues substituted at position 2, 4, and 6positions with single stubs of b-D-xylopyranosyl residues, exhib-ited potent antiviral activity against reference strains, syncytialformation, and TK acyclovir resistant strains of HSV-1 and HSV-2at IC50 range of 0.5–4.6 lg/ml (Mandal et al., 2008). Additionally,the sulfated xylomannan from Sebdenia polydactyla was indentifiedto have a similar backbone, but it differed from N. fastigiata xylo-mannan in the position of xylopyranosyl residues and from S. hateipolymer in the location of sulfate group (Ghosh et al., 2009). Thus,its activity against HSV-1 exhibited a different effect that showedmore strong inhibition than the known sulfated xylomannanwith IC50 range of 0.35–2.8 lg/ml. The appreciable inhibitionproduced by sulfated xylomannan was similar to that of standardanti-herpetic polysulfates, such as heparin and dextran sulfate.Notably, the inhibitions of in vitro HSV replication by thesexylomannans were observed at concentrations, which did not haveany effect on cell viability. These sulfated xylomannans represent apotential candidate for further clinical studies.

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Table 1Anti-HSV activity of sulfated galactans from red macroalgae.

Species Galactans Activity IC50a/EC50

b Ref.

Bostrychia montagnei BCW and BHW HSV-1 (strain F)HSV-1 (strain Field)HSV-1 (strain B2006)HSV-2 (strain G)

IC50: 12.9–20.5 lg/ml1.2–3.3 lg/ml1.5–1.9 lg/ml11.2–20.7 lg/ml

Duarte et al. (2001)

Gracilaria corticata WE2NGF HSV-1 (strain F)HSV-2 (strain G)

IC50: 0.19 lg/ml0.24 lg/ml

Mazumder et al. (2002)

Schizymenia binderi HSV-1 (strain F)HSV-1 (strain Field)HSV-1 (strain B2006)HSV-2 (strain G)

EC50: 0.76 lg/ml0.21 lg/ml0.18 lg/ml0.63 lg/ml

Matsuhiro et al. (2005)

Callophyllis variegate F1–F3 HSV-1 (strain F)HSV-2 (strain G)

IC50: 0.16–1.55 lg/ml0.21–2.19 lg/ml

Rodríguez et al. (2005)

Cryptopleura ramosa SG (2.8 kDa) HSV-1 and HSV-2 IC50: 1.6–4.2 lg/ml Carlucci et al. (1997b)Pterocludia cupillacea S1 HSV-1 and HSV-2 IC50: 3.2–12.0 lg/ml Pujol et al. (1996)Gymnogongrus torulosus DL-galactan HSV-2 IC50: 0.6–16 lg/ml Pujol et al. (2002)

a 50% inhibitory concentration.b 50% effective concentration.

T.-S. Vo et al. / European Journal of Pharmaceutical Sciences 44 (2011) 11–20 13

Similar to xylomannan, galactan sulfates derived from red mac-roalgae also manifest favorable inhibitions on herpes virus (Table1). These galactans were found to be highly selective antiviral sub-stances against the replication of the different strains of herpesviruses. Remarkably, Gymnogongrus griffithsiae and Cryptonemiacrenulata have known to represent an interesting source ofgalactans with selective and potent antiviral action against refer-ence strains, syncytial variants, and acyclovir-resistant strains ofHSV-1 and HSV-2 at IC50 values in the range 0.5–5.6 lg/ml (Talaric-o et al., 2004). The active galactans which extracted from C. crenu-lata exhibited a more effective antiviral action higher than thereference compounds heparin and dextran sulfate, whereas G. grif-fithsiae has no so notorious. Further, the crude galactan of C. crenu-lata showed a significant protective effect in vivo against HSV-2vaginal infection in a murine model, suggesting the potential useof this low cost product, easy to obtain in large quantities, for pro-phylaxis of virus infection. In addition, the strong anti-herpeticactivity of galactan sulfate obtained from Grateloupia indica hasbeen shown in recent study (Chattopadhyay et al., 2007). The iso-lated galactan exhibited potent anti-HSV effect on referencestrains, syncytial variants, and TK ACV resistant strains at low va-lue of IC50 (0.12–1.06 lg/ml), mainly affecting virus adsorption tothe host cells. The inhibition of in vitro HSV replication was ob-served at concentrations which do not have any effect on the cellviability.

The natural carrageenans, agaran, and xylan isolated from thered seaweed have recently identified as potent and selective inhib-itors of HSV-1 and HSV-2 (Table 2). Carrageenans isolated fromMeristiella gelidium were found to be among the most potent sul-fated polysaccharides obtained from red seaweeds according totheir inhibitory activity against herpes virus. The most active frac-tion obtained from M. gelidium showed a selectivity index againstHSV-2 of 25,000, a value high enough to regard this carrageenan

Table 2The effectiveness of carrageenans, agaran, and xylan from red macroalgae a

Species Components

Gigartina skottsbergii k-Carrageenans and l/m-carrageenanj/i-carrageenans

Stenogramme interrupta a/i-Carrageenank/n-carrageenan

Meristiella gelidium i/j/m-CarrageenanAcanthophora spicifera Agaran sulfateScinaia hatei Xylan

a 50% inhibitory concentration.

as a potential agent to be evaluated for the treatment of genitalHSV-2 infection (De S-F-Tischer et al., 2006). Additionally, the inhi-bition of in vivo HSV by carrageenan has been investigated in mod-el of murine infection (Carlucci et al., 2004; Pujol et al., 2006).Among them, the k-carrageenan extracted from the red seaweedGigartina skottsbergii revealed 100% protection against HSV-2mortality and replication in a very strict model of murineinfection at a high dose of virus. Furthermore, virus or neutralizingantibodies against HSV-2 was not detected in serum ofk-carrageenan-treated animals until 3 weeks after infection. Theseevidences warrant the availability of k-carrageenan to protect thewhole infectable surface of the mouse vagina.

In another sense, glycolipids from red alga Osmundaria obtusi-loba were recognized as an antiviral agent against acyclovir-sensi-ble and acyclovir-resistant HSV-1 (Mattos et al., 2011). Atmaximum non-toxic concentration, methanol (100 lg/ml) andacetone (50 lg/ml) fractions inhibited acyclovir-sensible HSV-1with percentages of 99.5% and 82.2%, respectively, and acyclovir-resistant HSV-1 with percentages of 99.9% and 99.7%, respectively.The antiviral activity of this alga was indentified to be due to gly-colipids of sulfoglycolipids and glycosyldiacylglycerols.

2.1.2. Brown macroalgaeBesides of red macroalgae, brown macroalgae also provide use-

ful additional therapy for treating several enveloped viruses infec-tions. During last years, screening assays of the antiviral agentsfrom marine organisms have lead to the identification of severalbrown macroalgae such as Sargassum patens, Surgassium latifolium,Cystoseira myrica, and Sargassum horneri with potent inhibitory ef-fects against HSV (Zhu et al., 2004, 2006; Asker et al., 2007; Zandiet al., 2007a; Hoshino et al., 1998). Meanwhile, fucoidans, a com-plex sulfated polysaccharide found mainly in brown macroalgae,have been reported in many papers for their anti-HSV activities.

gainst HSV.

IC50a Ref.

<1 lg/ml1.6–4.1 lg/ml

Carlucci et al. (1997a)

1.90–9.33 lg/ml0.65–2.88 lg/ml

Cáceres et al. (2000)

0.04–0.06 lg/ml De S-F-Tischer et al. (2006)0.6–1.8 lg/ml Duarte et al. (2004)0.22–1.37 lg/ml Mandal et al. (2010)

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14 T.-S. Vo et al. / European Journal of Pharmaceutical Sciences 44 (2011) 11–20

In 1999, Feldman and colleagues isolated fucoidan fractions (Ee, Ec,and Ea) from Leathesia difformis and determined their selectiveantiviral abilities against HSV-1 and HSV-2 (Feldman et al.,1999). Fucoidan Ea was shown to be the most active agent, withIC50 value in the range 0.5–1.9 lg/ml. Continually, fucoidans werefound in different marine brown macroalgae due to their anti-HSVproperty, including Adenocystis utricularis, S. horneri, Cystoseira indi-ca, Stoechospermum marginatum, and Sargassum tenerrimum (Ponceet al., 2003; Preeprame et al., 2001; Mandal et al., 2007; Adhikariet al., 2006; Sinha et al., 2010). Noticeably, Undaria pinnatifitida,the most commonly eaten brown seaweed in Japan, containssulphated polyanions and other components with appreciableanti-HSV effect. Galactofucan, the major component of an aqueousextract of Undaria pinnatifida, was evaluated for antiviral activityagainst 32 clinical strains of HSV, including 12 ACV-resistantstrains (four HSV-1 and eight HSV-2) and 20 ACV-susceptiblestrains (10 HSV-1 and 10 HSV-2). The median IC50 of galactofucanfor the 14 strains of HSV-1 and 18 strains of HSV-2 was 32 and0.5 lg/ml, respectively. It was indicated that galactofucan is signif-icantly more active against clinical strains of HSV-2 than HSV-1.The mode of action of the galactofucan was shown to be the inhi-bition of viral binding and entry into the host cell (Thompson andDragar, 2004). In addition, a fucoidan from sporophyll of U. pinnati-fida (Mekabu) was examined for its antiviral activity. The IC50 valuefor HSV-1 and HSV-2 were 2.5 and 2.6, respectively, under condi-tions in which the fucoidan was added at the same time as viralinfection (Lee et al., 2004a). In the in vivo conditions, ingestion offucoidan from U. pinnatifida was associated with increased healingrates in patients with active infections (Cooper et al., 2002). More-over, oral administration of the fucoidan from U. pinnatifida couldprotect mice from infection with HSV-1 as judged from the survivalrate and lesion scores (Hayashi et al., 2008). Substantially, naturalkiller and cytotoxic T lymphocytes activity in HSV-1-infected micewas enhanced by oral administration of the fucoidan. The produc-tion of neutralizing antibodies in the mice inoculated with HSV-1was significantly promoted during the oral administration of thefucoidan for 3 weeks. According to these results, fucoidan from U.pinnatifida was suggested as a topical microbicide for the preven-tion of transmission of HSV through direct inhibition of viral repli-cation and stimulation of both innate and adaptive immunedefense functions.

In recent years, anti-HSV activity of brown macroalgae wasknown due to their diterpene components. Two compounds ofditerpenes, 8,10,18-trihydroxy-2,6-dolabelladiene (1) and (6R)-6-hydroxydichotoma-4,14-diene-1,17-dial (2), were isolated fromDictyota pfaffii and Dictyota menstrualis (Abrantes et al., 2009). Itwas observed that compounds 1 and 2 inhibited HSV-1 replicationin a dose-dependent manner at EC50 values of 5.10 and 5.90 lM,respectively. Moreover, compound 1 could sustain its anti-herpeticactivity even when added to HSV-1-infected cells at 6 h after infec-tion, while compound 2 sustained its activity for up to 3 h afterinfection. Moreover, these compounds were fount to decrease thecontents of some HSV-1 early proteins, such as UL-8, RL-1, UL-12,UL-30, and UL-9. Similarly, the dolastane diterpenes 4-hydroxy-9,14-dihydroxydolasta-1(15),7-diene and 4,7,14-trihydroxydolasta1(15),8-diene isolated from Canistrocarpus cervicornis alsoexposed the suppressive effect on replication of HSV-1 (Vallimet al., 2010). These results suggested that the structures of brownmacroalgae diterpenes might be promising for future antiviraldesign.

In an investigation of El-Baroty et al. (2011), they revealed thatglycolipid achieved from brow alga Dilophys fasciola possessednoticeable effective against HSV-1. At concentration range of 25–100 lg/ml, glycolipid of D. fasciola caused remarkably inhibition%of HSV-1 with various degrees (78.5–100%). The IC50 value was10 lg/ml, compared to that 55 lg/ml for acyclovir. A suggestion

for active mechanism of glycolipid might involve in the bindingof the virus glycoprotein to algal glycolipid and cause an irrevers-ible denaturation that blocks the viral infectivity. In general, manyof natural lipid classes have been shown to have high virucidalactivity and are being developed as microbicidal ingredient in drugformulas to kill viruses (Hilmarsson et al., 2006).

2.1.3. Green macroalgaeAs expected, green macroalgae also emerge as novel antiviral

agents. Herein, Lee et al. (2004b) have estimated anti-HSV-1 activ-ity of natural sulfated polysaccharides from ten green macroalgae(Enteromorpha compressa, Monostroma nitidum, Caulerpa brachypus,Caulerpa okamurai, Caulerpa scapelliformis, Chaetomorpha crassa,Chaetomorpha spiralis, Codium adhaerens, Codium fragille, and Codi-um latum). Except for one from E. compressa, other sulfated poly-saccharides displayed strong anti-HSV-1 activities with IC50

range of 0.38–8.5 lg/ml, while having low cytotoxicities with50% inhibitory concentrations of >2900 lg/ml. In the delineationof the drug-sensitive phase, the polysaccharides of SX4 and SP4from C. brachypus, and SP11 from C. latum showed potentanti-HSV-1 activities with IC50 values of 6.0, 7.5, and 6.9 lg/ml,respectively, even when added to the medium 8 h post-infection.Subsequently, a polysaccharide from M. nitidum, rhamnan sulfate,was found to be effective against HSV-2 via blockade of virusadsorption and penetration steps onto host cell surface (Leeet al., 2010). Thus, it was indicated that some sulfated polysaccha-rides from green macroalgae not only inhibited the early stages ofHSV replication, such as virus binding to and penetration into hostcells, but also interfered with late steps of virus replication. Like-wise, sulfated polysaccharide fraction isolated from the hot waterextract of the green alga Caulerpa racemosa was regarded as aselective inhibitor of reference strains and TK� acyclovir-resistantstrains of HSV-1 and HSV-2 in Vero cells, with EC50 values in therange of 2.2–4.2 lg/ml (Ghosh et al., 2004). Further, this green algawas indentified to consist of a sulfoquinovosyldiacylglycerol com-pound which showed antiviral effect against both standard andclinical strains of HSV-2 at IC50 value of 15.6 lg/ml (Wang et al.,2007).

2.1.4. MicroalgaeIn fact, microalgae are attracting to enormous attention, and the

topics have been discussed by a number of researchers. Microalgaehave been recognized to provide chemical and pharmacologicalnovelty and diversity, and they are considered as the actual pro-ducers of some highly bioactive compounds found in marine re-sources (Shimizu, 1996). Among the different compounds withhighly biological activities, microalgae present attraction due toantiviral profile. According to Hayashi and co-workers, the waterextract of Spirulina platensis was shown to inhibit the replicationin vitro of HSV-1 in HeLa cells within the concentration range of0.08–50 mg/ml (Hayashi et al., 1993). Addition of the S. platensisextract (1 mg/ml) at 3 h before infection causes blockade ofvirus-specific protein synthesis at 50% effective inhibition dose(ED50) value of 0.173 mg/ml without affecting host cell proteinsynthesis. Moreover, it was observed that food containing the S.platensis extract effectively prolonged the survival time of infectedhamsters at doses of 100 and 500 mg/kg per day. Subsequently,Hayashi et al. isolated from S. platensis a novel sulfated polysaccha-ride, calcium spirulan (Ca-SP), which inhibits the replicationin vitro of several enveloped viruses including HSV-1, human cyto-megalovirus, measles virus, mumps virus, influenza A virus, andHIV-1 virus. The anti-HSV-1 activity of Ca-SP was determined tobe fivefold higher than that of dextran sulfate (Hayashi et al.,1996a,b). In a similar trend, other bioactive components from S.platensis were explored due to anti-HSV activity. As expected, apolysaccharide with rhamnose as the main sugar component and

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T.-S. Vo et al. / European Journal of Pharmaceutical Sciences 44 (2011) 11–20 15

a glycolipid sulphoquinovosyl diacylglycerol were found to be ac-tive against HSV-1 at IC50 values of 21.32 and 6.8 lg/ml, respec-tively (Chirasuwan et al., 2007, 2009). While S. platensis wasefficient for anti-HSV-1, Spirulina maxima exposed inhibitory activ-ity against HSV-2. A hot water extract of S. maxima showed appre-ciable suppression HSV-2 infection at the initial events ofadsorption and penetration (ED50, 0.069 mg/ml) (Hernández-Coronaet al., 2002).

Recently, many other microalgae have been discovered withprotective effect against HSV infection and replication (Table 3).Among them, blue-green alga Aphanothece sacrum and red micro-alga Porphyridium sp. exhibited appreciable inhibitions in bothin vitro and in vivo model. Specially, cyanovirin-N, a proteinproduced from blue-green alga Nostoc ellipsosporum, was demon-strated to block HSV-1 entry into cells and inhibited membrane fu-sion mediated by HSV glycoproteins (Tiwari et al., 2009). Thiscompound was suggested as a stronger potential for antiviral ther-apy against HSV-1.

2.2. Marine invertebrates

Due to natural selection, a range of antiviral agents may developin marine invertebrates to protect them from viral infection. Theinnate defenses available to marine invertebrates can include sec-ondary metabolites, bioactive peptides, and proteins, thus servingas models for development of new drugs for treating human dis-eases. Indeed, several marine invertebrates that produce importantantiviral compounds have been reported so far, including sponges,tunicates, echinoderms, and mollusks.

2.2.1. SpongesMarine sponges have been considered as a gold mine during the

past 50 years due to the diversity of their secondary metabolites.More than 5300 different natural compounds have been discov-ered from sponges and their associated microorganisms, and hun-dred new compounds are being added every year (Faulkner, 2002).Therefore, sponges have the potential to provide future drugsagainst important diseases, such as cancer, microbial diseases, ma-laria, and inflammations (Sipkema et al., 2005). In relation to HSVinfections, the exploration of the marine sponges represents apromising strategy in the search for active compounds. Many pa-pers showed the results of the screening of marine sponges for

Table 3Marine microalgae-derived anti-HSV agents.

Species Components Activity

Green microalga: Dunaliellaprimolecta

Pheophorbide-like compounds Inhibit HSV-1 duinvasion in Vero

Green microalga: Chlorellavulgaris

Water and ethanol extracts Inhibit 70% of HScellsInhibit HSV-1 re

Blue-green alga:Aphanothece sacrum

Sulphated polysaccharide(ASWPH)

Anti-HSV-2

Blue-green alga: Nostocellipsosporum

A sugar binding antiviral protein(cyanovirin-N)

In vitro block HS

Red microalga:Porphyridium sp.

Cell-wall sulphatedpolysaccharide

Inhibit HSV-1 anpreventing adsorcellsInhibiting the proparticles inside t

Red microalga:Porphyridium sp.

Cell-wall sulphatedpolysaccharide

Prevented the apdevelopment ofinfection in rats

Diatom: Haslea ostrearia A water-soluble fraction Inhibit HSV-1 repDiatom: Navicula directa Naviculan Anti-HSV-1

Anti-HSV-2

a 50% inhibitory concentration.b 50% effective concentration.

anti-HSV activity, and several active compounds have been iso-lated and characterized (Table 4). For the first time, two nucleo-sides of spongothymidine and spongouridine were isolated fromthe Caribbean sponge Cryptotethya crypta (Bergmann and Burke,1955). Spongothymidine was found selective against HSV-l andHSV-2 (ID50, 0.25–0.5 lg/ml) (Aswell et al., 1977; Miller et al.,1977). Otherwise, spongouridine has been used as a starting mate-rial for the synthesis of marine adenine arabinoside (Vidarabine orAra-A) to improve its anti-HSV activity (Utagawa et al., 1980;Privat de Garilhe and de Rudder, 1964; Schwartz et al., 1976).The evidence that adenine arabinoside is rapidly converted intoadenine arabinoside triphosphate, which inhibits viral DNA poly-merase and DNA synthesis of herpes in infected cells. Hence, itwas licensed as the first antiviral nucleoside for the treatment ofsystematic herpes virus infection and one of the three marine-de-rived drugs currently approved by Food and Drug Administrationin the United States (Mayer et al., 2010).

In addition, Perry et al. (1988) isolated mycalamide A and Bfrom New Zealand sponge of the genus Mycale and investigatedin vitro antiviral activity of these compounds. It was observed thatmycalamide A inhibited HSV-1 at 0.005 lg/disk. Meanwhile,mycalamide B showed greater antiviral activity than mycalamideA, with a minimum dose of inhibition of 0.001–0.002 lg/disk(Perry et al., 1990). In another study, Burres and Clement (1989)have discovered that these compounds inhibited the protein syn-thesis and translation of RNA into protein in a cell-free lysate ofrabbit reticulocytes. Moreover, the inhibition of protein synthesiswas also described via the binding of mycalamide A to the E siteof the large ribosomal subunit of Haloarcula marismortui (Gurelet al., 2009). Thus, antiviral activity of mycalamide A and B wassuggested to be due to protein synthesis inhibition. Subsequently,ptilomycalin A, a new class of marine polycyclic guanidine alka-loids possessing potent antiviral and antibiotic activities, has beendetermined on the basis of NMR analyses of its trifluoroacetylderivative. This alkaloid was isolated from the Caribbean spongePtilocaulis spiculifer and red Hemimycale sp., have shown efficientagainst HSV-1 at a concentration of 0.2 lg/ml (Kashman et al.,1989).

Recently, marine sponges collected along the Brazilian coasthave been evaluated for novel antiviral drug leads. Among 27 dif-ferent marine sponges, the aqueous extracts of Cliona sp., Agelassp., and Tethya sp. presented the most promising results against

IC50a/EC50

b Ref.

ring adsorption andcells

Completely inhibit at 5 lg/ml Ohta et al. (1998)

V-1 infection in Vero

plication in Vero cell

At 75 lg/mlIC50: 61.0–80.2 lg/ml

Santoyo et al. (2010)

IC50: 0.32–1.2 lg/ml Ogura et al. (2010)

V-1 entry Tiwari et al. (2009)

d HSV-2 infection byption into the host

duction of new viralhe host cells

IC50: 1 lg/ml Huleihel et al. (2001)

pearance andsymptoms of HSV-1and rabbits

Against HSV-1 infectionat 100 lg/ml

Huheihel et al. (2002)

lication in Vero cells EC50: 14 lg/ml Bergé et al. (1999)IC50: 8.7–14.0 lg/mlIC50: 3.4–7.4 lg/ml

Lee et al. (2006)

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Table 4Anti-HSV substances from marine sponges.

Species Substances Class Ref.

Cryptotethya crypta Spongothymidine and ara-A Nucleoside Bergmann and Burke (1955)Mycale sp. Mycalamide A–B Nucleosides Perry et al. (1988, 1990)Ptilocaulis spiculifer and red Hemimycale sp. Ptilomycalin A Polycyclic guanidine alkaloids Kashman et al. (1989)Aaptos aaptos 4-Methylaaptamine Alkaloid Coutinho et al. (2002) and Souza et al. (2007)Halicortex sp. Dragmacidin F Alkaloid Cutignano et al. (2000)Pachypellina sp. 8-Hydroxymanzamine A Alkaloid Ichiba et al. (1994)Hamigera tarangaensis Hamigeran B Phenolic macrolides Wellington et al. (2000)

16 T.-S. Vo et al. / European Journal of Pharmaceutical Sciences 44 (2011) 11–20

HSV-1 (da Silva et al., 2006). The importance of marine sponges asa source of novel alkaloids, in particular those with antiviral activ-ity, has been recognized. The alkaloid 4-methylaaptamine fromBrazil sponge Aaptos sp. was confirmed to inhibit HSV-1 replicationat an EC50 of 2.4 lM, which is more potent than acyclovir (8.6 lM)(Coutinho et al., 2002; Souza et al., 2007). Further,4-methylaaptamine sustained anti-herpetic activity even whenadded to HSV-1-infected Vero cells at 4 h after infection, suggest-ing the inhibition of initial events during HSV-1 replication. Inaddition, it was observed that 4-methylaaptamine impaired HSV-1 penetration without affecting viral adsorption and suppressedthe expression of an HSV-1 immediate-early protein ICP27, thuspreventing viral replication. Likewise, dragmacidin F, a novel anti-viral alkaloid from the Mediterranean sponge Halicortex sp., wasreported to be able to delay syncytia formation by HIV-2 at IC50

value of 0.91 lM. However, it weakly protected HSV-1-infectedcells from HSV-induced destruction (95.8 lM) (Cutignano et al.,2000). In addition, the first antiviral effect of alkaloid 8-hydroxy-manzamine A from the sponge Pachypellina sp. (from ManadoBay, Sulawesi, Indonesia) has been reported. This compound hasexhibited an appreciable inhibition against HSV-2 with a minimaleffective concentration of 0.05 lg/ml (Ichiba et al., 1994). Besides,an early screening by Wellington et al. (2000) revealed that hamig-eran B among seven new compounds from Hamigera tarangaensisshowed 100% in vitro inhibition against both the herpes and polioviruses. Overall, several of compounds from marine sponges have agreat potential for anti-HSV drug development, such as 4-meth-ylaaptamine, manzamines and hamigeran B. However, antiviralcompounds from marine sponges do not give protection againstviruses, but they may result in drugs to treat already infectedindividuals.

2.2.2. TunicatesTunicates provide a rich source of biologically active com-

pounds with potentially useful medicinal properties. Over 50 sec-ondary metabolites isolated so far from tunicates and a numberof them are bioactive peptides. Eudistomins, which contain substi-tuted oxathiazepine or oxathiazepinotetrahydro-b-carboline ringsystem, displayed high antiviral activity against HSV-1. These com-pounds were isolated from the colonial caribbean tunicate Eudis-toma olivaceum (Rinehart et al., 1984; Kobayashi et al., 1984).Besides, didemnins, a new class of cyclic depsipeptides obtainedfrom tunicate Trididemnum solidum, exhibited suppression ongrowth of a variety of RNA and DNA viruses in vitro, and protectmice from HSV-2 infection (Rinehart et al., 1988, 1983).

2.2.3. EchinodermsEchinoderms are considered as an animal without any value,

but they have a series of pharmaceutical functions due to its sec-ondary metabolites with several biological activities. Previousstudies showed that secondary metabolites from echinodermsexhibited antiviral activity. Polyhydroxy steroids and saponinsfrom China starfish Asterina pectinifera have antiviral activity

against HSV-1 at the minimal inhibitory concentration (MIC) rangeof 0.05–0.2 lM (Peng et al., 2010). Additionally, sulfated polyhydr-oxysteroids were isolated from the ophiuroid Astrotoma agassiziiand proved to be active against the replication of HSV-2 withIC50 values of 18.4 and 24.3 lg/ml, respectively (Comin et al.,1999). On the other hand, two new trisulfated triterpene glyco-sides, liouvillosides A and B, obtained from the Antarctic seacucumber Staurocucumis liouvillei displayed virucidal effect onHSV-1 at concentrations below 10 lg/ml (Maier et al., 2001).

2.2.4. MollusksLike all invertebrates, mollusks can protect themselves against

previous infection via innate immunity (Hooper et al., 2007). Theirenormous success indicates compensation for the lack of adaptiveimmunity with effective innate defenses. Therefore, molluscs rep-resent a great resource for discovery of antiviral compounds. Forinstance, paolin, a substance isolated from oysters and clams tis-sues showed antiviral activity against herpes virus (Li et al.,1965; Prescott et al., 1966). Also, Olicard et al. (2005a,b) describeda peptide from oyster Crassostrea gigas hydrolysate and demon-strated the antiviral activity of C. gigas acellular hemolymphagainst in vitro HSV growth. Likewise, Carriel-Gomes et al. (2006)showed the prominent inhibition of HSV-1 replication by cellularfraction obtained from oyster Crassostrea rhizophorae, particularlyin post-infection treatment assay. In another sense, five other mar-ine mollusks of economic importance in Brittany were screened forantiviral activity, including three farmed bivalve molluscs (Cerasto-derma edule, Ruditapes philippinarum, and Ostrea edulis) and twogastropods (Buccinum undatum and Crepidula fornicate) (Deferet al., 2009). The evidence that potent anti-HSV-1 activity couldbe detected in all investigated mollusk species and the most activefraction was attributed to C. edule acidic extract. In the most recentstudy, antiviral activity of abalone Haliotis laevigata against HSV-1has been assessed by adding hemolymph or lipophilic extract atdifferent times during the plaque assay (Dang et al., 2011). It wasshowed that hemolymph could inhibit viral infection at an earlystage. Conversely, the antiviral effect of the lipophilic extract isefficient when added one hour after infection, suggesting that itmay act at an intracellular stage of infection. Thus, abalone hasbeen suggested to contain two antiviral compounds with differentmodes of action against viral infection.

2.2.5. ShrimpsAntimicrobial peptides (AMPs), which are widely distributed in

all living organisms, play important role in the innate immune sys-tem and function as a first line of defense against invading micro-organisms (Brown and Hancock, 2006). Although AMPs have beenmainly focused in numerous studies due to antibacterial and anti-fungal activities, some of these molecules have also been shown tobe effective against viral pathogens (Carriel-Gomes et al., 2007).Anti-lipopolysaccharide factors (ALFs) and Penaeidin-3, whichhave isolated from shrimp Penaeus monodon and Litopenaeus van-namei, respectively, presented significant activity against HSV-1

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T.-S. Vo et al. / European Journal of Pharmaceutical Sciences 44 (2011) 11–20 17

in the simultaneous treatment. ALFs and Penaeidin-3 inhibitedover 72% and 85% of the viral replication at 100 lM, respectively.Despite the fact that antiviral activity of these peptides was activeat concentrations too close to their 50% cytotoxic concentration(CC50), but the further modifications on peptide structures is prom-ising to increase the selectivity with infectious HSV.

2.3. Marine bacteria and fungus

Almost all forms of life in the marine environment, such as al-gae, sponges, corals, ascidians have been investigated for their nat-ural products content (Faulkner, 2000a,b). Meanwhile, marinemicroorganisms have received very little attention due to the diffi-culty in the search of metabolites (Jha and Zi-rong, 2004). How-ever, when interests have turned to marine microorganisms,bacteria and fungus have recognized as a likely source of pharma-cological agents (Debbab et al., 2010; Penesyan et al., 2010; Bugniand Ireland, 2004). According to the investigation of Yasuhara-Bellet al. (2010), it is clear that marine bacteria possibly act against abroad-spectrum of viruses. In the relation to HSV-1, the bacterialextracts of 162 M(4) and 367 M(1) highly blocked viral attachmentonto Vero cells (P90%). While bacterial extracts of 298 M(2) mod-erately inhibited viral attachment (P50%), it exhibited the mostinhibition on viral replication. At 72 h post-infection, this extractstill showed signs of significant viral inhibition. Whereas, other vir-al extracts, such as 162 M(4), 185 M(4), 397(1), and 495 M(1)showed signs of viral inhibition against HSV-1 within 24 h post-infection. These results are not sufficient to suggest the applicationof these extracts as treatments of established viral infection. In-stead, these extracts may be employed in prophylaxis to preventinfection and spread of infection, due to the high inhibitory levelin the viral attachment.

Currently, there have been only a few compounds derived frommarine bacteria with antiviral activity. Macrolactin A have beenisolated from deep-sea bacterium and determined to possess pro-tective effect against viral replication. Macrolactin A includes 24-membered ring lactones, related glucose b-pyranosides and openchain acids. This compound shows significant inhibition of HSV-1(strain LL) and HSV-2 (strain G) with IC50 values of 5.0 and8.3 lg/ml, respectively (Gustafson et al., 1989). Notably, manymarine bacteria produce exopolysaccharides (EPS) as a strategyfor growth, adherence to solid surfaces and survival in adverse con-ditions (Arena et al., 2006, 2009). These compounds are known tointerfere with the adsorption and penetration of viruses into hostcells, as well as inhibit various retroviral reverse transcriptases.EPS-1 and EPS-2, two new exopolysaccharides, were achieved fromBacillus licheniformis and Geobacillus thermodenitrificans, respec-tively. These bacteria isolated from a shallow marine hot springof the Vulcano Island, Italy. It has proved that both EPS-1 andEPS-2 were able to inhibit HSV-2 replication through up-regulatingthe expression of proinflammatory cytokines or triggering polari-zation in favor of the Th1 subset (Arena et al., 2006, 2009).

In addition to marine bacteria, the group of marine fungus rep-resents an important source for the discovery of novel naturalproducts (Cueto et al., 2006; Li et al., 2006). In the search fornew antiviral compounds from marine microorganisms, a seriesof novel linear peptides, Halovirs A–E, were isolated from the mar-ine fungus Scytidium species. These compounds exposed antiviralactivity against HSV-1 and HSV-2 with ED50 range of 1.1–3.5 lM.Halovir A was determined to equally inhibit replication of HSV-1and HSV-2 with an ED50 value of 280 nM in a standard plaquereduction assay. It was presumed that halovirs render HSV non-infectious by possible membrane destabilization (Rowley et al.,2003). In a further study, they explored structure–activity relation-ships of halovirs and demonstrated their antiviral activity due to anNa-acyl chain of at least 14 carbons and an Aib-Pro dipeptide (Row-

ley et al., 2004). Balticols A–F are other marine fungus-derivedantiviral compounds that were isolated from the AcOEt extract ofthe culture broth of fungal strain 222 belonging to the Ascomycota.This fungus has found on driftwood collected at the coast of theGreifswalder Bodden, Baltic Sea, Germany. The isolated com-pounds exhibited inhibitory activity against HSV-1. The most po-tent antiviral activity has observed for balticol E and balticol Dwith IC50 values of 0.01 and 0.1 lg/ml, respectively (Shushniet al., 2009).

3. Prospect of marine antiviral drugs

Recently, there are few drugs licensed for the treatment of HSVinfections. Meanwhile, drug resistance is an important clinicalproblem that may lead to ineffective therapy. Therefore, the devel-opment of new antiviral agents with diverse kinds of antiviral ac-tions is always required. It is clear that marine environment storesnumerous undiscovered organisms with their unique metabolites,thus numbers of novel drugs will be discovered that viruses havenot yet developed resistance to. Otherwise, various derivatives ofa common class of compound are being produced by multipleorganisms. A virus that has developed resistance to a particulardrug may not be resistant to other naturally occurring derivatives,which have the potential to possess similar antiviral activities.

It is true that the development of marine antiviral drugs stillfaces several challenges, such as toxic side effects and large-scaleproduction. For instance, sponge-derived compounds were shownto exhibit strong HSV inhibition but have toxic effect, which causesdamage to the host. However, biochemical technologies can be ap-plied for the manipulation of naturally occurring compounds, suchas removal or modification of toxic groups present in these com-pounds to produce novel derivatives that are reduced cytotoxici-ties and increased specificities. Furthermore, the antiviral activityof potential compounds can be improved through knowledge ofthe structure–activity relationship, mechanism of action, drugmetabolism, and combinatorial chemistry studies.

Another obstacle for drug development is due to the large-scaleproduction. Although marine natural products are potentialsources of a wide range of chemicals with remarkable diversity,but it is not easy to isolate a large yield of desired compounds.Likely, the combinatorial genetic and metabolic engineering willbe the future solution for commercial production of these com-pounds. In addition, the aquaculture, chemical synthesis, and fer-mentation processes are also expected to gain the large-scaleproduction.

4. Conclusion

The infections with HSV can lead to a variety of skin and muco-sal diseases. Despite intensive research, no prophylactic HSV vac-cine has proven to be effective because the viruses establishlatency and reactivations occur in the presence of humoral andcell-mediated immunity. The suggested options for treatment ofHSV infections include oral acyclovir, valacyclovir, and famciclovir.However, the further discovery of new drugs as well as the adapta-tion of current drugs is very necessary for the war against viralinfection and drug-resistant viruses. As expected, a large numberof anti-HSV components from marine origin have been identifiedbased on the specific assay system or screening approach. Theextensive studies of marine natural products with anti-HSV activ-ity will contribute to the development of novel antiviral agents.Thus, it is believed that the marine organisms play a vital role inthe pharmaceutical industry to develop novel drugs against herpessimplex virus.

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18 T.-S. Vo et al. / European Journal of Pharmaceutical Sciences 44 (2011) 11–20

Acknowledgements

This study was supported by a Grant from Marine BioprocessResearch Center of the Marine Bio 21 Project funded by the Minis-try of Land, Transport and Maritime, Republic of Korea.

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