Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated.

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Kamýcká 129 6 Suchdol 165 21 Prague Czech Republic

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Molecular Biology and Pharmaceutical Biotechnology Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackého tř 1946 1 612 42 Brno Czech Republic

Department of Natural Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackého tř 1946 1 612 42 Brno Czech Republic

Division of Oncology Biomedical Center Martin Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Museum of Literature in Moravia Klášter 1 664 61 Rajhrad Czech Republic

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Parker F., Nye R.N. Studies on Filterable Viruses: II. Cultivation of Herpes Virus. Am J Pathol. 1925;1:337–340. PubMed PMC

Nahmias A.J., Dowdle W.R. Antigenic and biologic differences in herpesvirus hominis. Prog. Med. Virol. 1968;10:110–159. PubMed

Sanders J.E., Garcia S.E. Pediatric herpes simplex virus infections: An evidence-based approach to treatment. Pediatr. Emerg. Med. Pract. 2014;11:1–19. PubMed

Miller A.S., Bennett J.S. Challenges in the care of young infants with suspected neonatal herpes simplex virus. Hosp. Pediatr. 2015;5:106–108. doi: 10.1542/hpeds.2014-0095. PubMed DOI

Widener R.W., Whitley R.J. Herpes simplex virus. Handb. Clin. Neurol. 2014;123:251–263. PubMed

Akinyi B., Odhiambo C., Otieno F., Inzaule S., Oswago S., Kerubo E., Ndivo R., Zeh C. Prevalence, incidence and correlates of HSV-2 infection in an HIV incidence adolescent and adult cohort study in western Kenya. PLoS ONE. 2017;12:e017890. doi: 10.1371/journal.pone.0178907. PubMed DOI PMC

Memish Z.A., Almasri M., Chentoufi A.A., Al-Tawfiq J.A., Al-Shangiti A.M., Al-Kabbani K.M., Otaibi B., Assirri A., Yezli S. Seroprevalence of Herpes Simplex Virus Type 1 and Type 2 and Coinfection with HIV and Syphilis: The First National Seroprevalence Survey in Saudi Arabia. Sex. Trans. Dis. 2015;42:526–532. doi: 10.1097/OLQ.0000000000000336. PubMed DOI

Birkmann A., Zimmermann H. HSV antivirals - current and future treatment options. Curr. Opin. Virol. 2016;18:9–13. doi: 10.1016/j.coviro.2016.01.013. PubMed DOI

Kenny K., Leung W., Stephanson K., Ross S. Clinical practice in prevention of neonatal HSV infection: A survey of obstetrical care providers in Alberta. J. Obstet. Gynaecol. Can. 2013;35:131–137. doi: 10.1016/S1701-2163(15)31017-3. PubMed DOI

Johnston C., Koelle D.M., Wald A. Current status and prospects for development of an HSV vaccine. Vaccine. 2014;32:1553–1560. doi: 10.1016/j.vaccine.2013.08.066. PubMed DOI PMC

Zhu X.P., Muhammad Z.S., Wang J.G., Lin W., Guo S.K., Zhang W. HSV-2 vaccine: current status and insight into factors for developing an efficient vaccine. Viruses. 2014;6:371–390. doi: 10.3390/v6020371. PubMed DOI PMC

Hassan S.T.S., Šudomová M., Masarčíková R. Herpes simplex virus infection: an overview of the problem, pharmacologic therapy and dietary measures. Ceska Slov. Farm. 2017;66:95–102. PubMed

Knipe D.M., Cliffe A. Chromatin control of herpes simplex virus lytic and latent infection. Nat. Rev. Microbiol. 2008;6:211–221. doi: 10.1038/nrmicro1794. PubMed DOI

Roizman B., Whitley R.J. An inquiry into the molecular basis of HSV latency and reactivation. Annu. Rev. Microbiol. 2013;67:355–374. doi: 10.1146/annurev-micro-092412-155654. PubMed DOI

Cliffe A.R., Garber D.A., Knipe D.M. Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. J. Virol. 2009;83:8182–8190. doi: 10.1128/JVI.00712-09. PubMed DOI PMC

Cliffe A.R., Arbuckle J.H., Vogel J.L., Geden M.J., Rothbart S.B., Cusack C.L., Strahl B.D., Kristie T.M., Deshmukh M. Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch is Required for Herpes Simplex Virus Reactivation. Cell Host. Microbe. 2015;18:649–658. doi: 10.1016/j.chom.2015.11.007. PubMed DOI PMC

Johnston C., Corey L. Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding. Clin. Microbiol. Rev. 2016;29:149–161. doi: 10.1128/CMR.00043-15. PubMed DOI PMC

Xu X., Zhang Y., Li Q. Characteristics of herpes simplex virus infection and pathogenesis suggest a strategy for vaccine development. Rev. Med. Virol. 2019;29:2054. doi: 10.1002/rmv.2054. PubMed DOI PMC

Nicoll M.P., Proença J.T., Efstathiou S. The molecular basis of herpes simplex virus latency. FEMS Microbiol. Rev. 2012;36:684–705. doi: 10.1111/j.1574-6976.2011.00320.x. PubMed DOI PMC

Mancini M., Vidal S.M. Insights into the pathogenesis of herpes simplex encephalitis from mouse models. Mamm. Genome. 2018;29:425–445. doi: 10.1007/s00335-018-9772-5. PubMed DOI PMC

Egan K.P., Wu S., Wigdahl B., Jennings S.R. Immunological control of herpes simplex virus infections. J. Neurovirol. 2013;19:328–345. doi: 10.1007/s13365-013-0189-3. PubMed DOI PMC

Vlietinck A.J., De Bruyne T., Vanden Berghe D.A. Plant substances as antiviral agents. Curr. Org. Chem. 1997;1:307–344.

Cheng C.-L., Xu H.-X. Antiviral agents from traditional Chinese medicine against herpes simplex virus. J. Trad. Med. 2005;22:133–137.

Chattopadhyay D. Ethnomedicinal antivirals: scope and opportunity. In: Ahmad I., Aqil F., Owais M., editors. Modern Phytomedicine: Turning Medicinal Plants into Drugs. Wiley-VCH Verlag GmbH & Co; Weinheim, Germany: 2006. pp. 313–339.

Hassan S.T., Masarčíková R., Berchová K. Bioactive natural products with anti-herpes simplex virus properties. J. Pharm. Pharmacol. 2015;67:1325–1336. doi: 10.1111/jphp.12436. PubMed DOI

Savi L.A., Barardi C.R., Simões C.M. Evaluation of antiherpetic activity and genotoxic effects of tea catechin derivatives. J. Agric. Food Chem. 2006;54:2552–2557. doi: 10.1021/jf052940e. PubMed DOI

Lyu S.Y., Rhim J.Y., Park W.B. Antiherpetic activities of flavonoids against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro. Arch. Pharm. Res. 2005;28:1293–1301. doi: 10.1007/BF02978215. PubMed DOI

Lee S., Lee H.H., Shin Y.S., Kang H., Cho H. The anti-HSV-1 effect of quercetin is dependent on the suppression of TLR-3 in Raw 264.7 cells. Arch. Pharm. Res. 2017;40:623–630. doi: 10.1007/s12272-017-0898-x. PubMed DOI

Medini F., Megdiche W., Mshvildadze V., Pichette A., Legault J., St-Gelais A., Ksouri R. Antiviral-guided fractionation and isolation of phenolic compounds from Limonium densiflorum hydroalcoholic extract. C. R. Chim. 2016;19:726–732. doi: 10.1016/j.crci.2016.03.006. DOI

Pradhan P., Nguyen M.L. Herpes simplex virus virucidal activity of MST-312 and epigallocatechin gallate. Virus Res. 2018;2:93–98. doi: 10.1016/j.virusres.2018.03.015. PubMed DOI

Li J.J., Chen G.D., Fan H.X., Hu D., Zhou Z.Q., Lan K.H., Zhang H.P., Maeda H., Yao X.S., Gao H. Houttuynoid M, an Anti-HSV Active Houttuynoid from Houttuynia cordata Featuring a Bis-houttuynin Chain Tethered to a Flavonoid Core. J. Nat. Prod. 2017;80:3010–3013. doi: 10.1021/acs.jnatprod.7b00620. PubMed DOI

Li T., Liu L., Wu H., Chen S., Zhu Q., Gao H., Yu X., Wang Y., Su W., Yao X., et al. Anti-herpes simplex virus type 1 activity of Houttuynoid A, a flavonoid from Houttuynia cordata Thunb. Antiviral. Res. 2017;144:273–280. doi: 10.1016/j.antiviral.2017.06.010. PubMed DOI

Argenta D.F., Silva I.T., Bassani V.L., Koester L.S., Teixeira H.F., Simões C.M. Antiherpes evaluation of soybean isoflavonoids. Arch. Virol. 2015;160:2335–2342. doi: 10.1007/s00705-015-2514-z. PubMed DOI

Čulenová M., Sychrová A., Hassan S.T.S., Berchová-Bímová K., Svobodová P., Helclová A., Michnová H., Hošek J., Vasilev H., Suchý P., et al. Multiple In vitro biological effects of phenolic compounds from Morus alba root bark. J. Ethnopharmacol. 2019;248:112296. doi: 10.1016/j.jep.2019.112296. PubMed DOI

Fritz D., Venturi C.R., Cargnin S., Schripsema J., Roehe P.M., Montanha J.A., von Poser G.L. Herpes virus inhibitory substances from Hypericum connatum Lam., a plant used in southern Brazil to treat oral lesions. J. Ethnopharmacol. 2007;113:517–520. doi: 10.1016/j.jep.2007.07.013. PubMed DOI

Ojha D., Das R., Sobia P., Dwivedi V., Ghosh S., Samanta A., Chattopadhyay D. Pedilanthus tithymaloides Inhibits HSV Infection by Modulating NF-κB Signaling. PLoS ONE. 2015;10:e0139338. doi: 10.1371/journal.pone.0139338. PubMed DOI PMC

De Oliveira A., Prince D., Lo C.Y., Lee L.H., Chu T.C. Antiviral activity of theaflavin digallate against herpes simplex virus type 1. Antiviral. Res. 2015;118:56–67. doi: 10.1016/j.antiviral.2015.03.009. PubMed DOI PMC

Likhitwitayawuid K., Chaiwiriya S., Sritularak B., Lipipun V. Antiherpetic flavones from the heartwood of Artocarpus gomezianus. Chem. Biodivers. 2006;3:1138–1143. doi: 10.1002/cbdv.200690115. PubMed DOI

El-Toumy S.A., Saliba J.Y., El-Kashak W.A., Marty C., Bedoux G., Bourgougnon N. Antiviral effect of polyphenol rich plant extracts on herpes simplex virus type 1. Food Sci. Human Wellness. 2018;7:91–101. doi: 10.1016/j.fshw.2018.01.001. DOI

Li Y., Leung K.T., Yao F., Ooi L.S.M., Ooi V.E.C. Antiviral flavans from the leaves of Pithecellobium clypearia. J. Nat. Prod. 2006;69:833–835. doi: 10.1021/np050498o. PubMed DOI

Boff L., Silva I.T., Argenta D.F., Farias L.M., Alvarenga L.F., Pádua R.M., Braga F.C., Leite J.P., Kratz J.M., Simões C.M. Strychnos pseudoquina A. St. Hil.: a Brazilian medicinal plant with promising in vitro antiherpes activity. J. Appl. Microbiol. 2016;121:1519–1529. doi: 10.1111/jam.13279. PubMed DOI

Uozaki M., Yamasaki H., Katsuyama Y., Higuchi M., Higuti T., Koyama A.H. Antiviral effect of octyl gallate against DNA and RNA viruses. Antiviral Res. 2007;73:85–91. doi: 10.1016/j.antiviral.2006.07.010. PubMed DOI

Kesharwani A., Polachira S.K., Nair R., Mishra N.N., Gupta S.K. Anti-HSV-2 activity of Terminalia chebula Retz extract and its constituents, chebulagic and chebulinic acids. BMC Complement Altern. Med. 2017;17:110. doi: 10.1186/s12906-017-1620-8. PubMed DOI PMC

Lavoie S., Côte I., Pichette A., Gauthier C., Quellet M., Nagau-Lavoie F., Mshvildadze V., Legault J. Chemical composition and anti-herpes simplex virus type 1 (HSV-1) activity of extracts from Cornus canadensis. BMC Complement. Altern. Med. 2017;17:123. doi: 10.1186/s12906-017-1618-2. PubMed DOI PMC

Hassan S.T.S., Švajdlenka E., Berchová-Bímová K. Hibiscus sabdariffa L. and Its Bioactive Constituents Exhibit Antiviral Activity against HSV-2 and Anti-enzymatic Properties against Urease by an ESI-MS Based Assay. Molecules. 2017;22:722. doi: 10.3390/molecules22050722. PubMed DOI PMC

Hassan S.T.S., Šudomová M., Berchová-Bímová K., Šmejkal K., Echeverría J. Psoromic Acid, a Lichen-Derived Molecule, Inhibits the Replication of HSV-1 and HSV-2, and Inactivates HSV-1 DNA Polymerase: Shedding Light on Antiherpetic Properties. Molecules. 2019;24:2912. doi: 10.3390/molecules24162912. PubMed DOI PMC

Thongchuai B., Tragoolpua Y., Sangthong P., Trisuwan K. Antiviral carboxylic acids and naphthoquinones from the stems of Rhinacanthus nasutus. Tetrahedron Lett. 2015;56:5161–5163. doi: 10.1016/j.tetlet.2015.07.082. DOI

He Y.C., Lu Z.H., Shi P., Hao J.C., Zhao Z.J., Xie H.T., Mao P., Chen S.J. Anti-herpes simplex virus activities of bioactive extracts from Antrodia camphorata mycelia. Antivir. Ther. 2016;21:377–383. doi: 10.3851/IMP2988. PubMed DOI

Huang Z., Nong X., Ren Z., Wang J., Zhang X., Qi S. Anti-HSV-1, antioxidant and antifouling phenolic compounds from the deep-sea-derived fungus Aspergillus versicolor SCSIO 41502. Bioorg. Med. Chem. Lett. 2017;27:787–791. doi: 10.1016/j.bmcl.2017.01.032. PubMed DOI

Ma F., Shen W., Zhang X., Li M., Wang Y., Zou Y., Li Y., Wang H. Anti-HSV Activity of Kuwanon X from Mulberry Leaves with Genes Expression Inhibitory and HSV-1 Induced NF-κB Deactivated Properties. Biol. Pharm. Bull. 2016;39:1667–1674. doi: 10.1248/bpb.b16-00401. PubMed DOI

Cavalcanti J.F., de Araujo M.F., Gonçalves P.B., Romeiro N.C., Villela Romanos M.T., Curcino Vieira I.J., Braz-Filho R., de Carvalho M.G., Sanches M.N.G. Proposed anti-HSV compounds isolated from Simira species. Nat. Prod. Res. 2018;32:2720–2723. doi: 10.1080/14786419.2017.1375914. PubMed DOI

Flores D.J., Lee L.H., Adams S.D. Inhibition of Curcumin-Treated Herpes Simplex Virus 1 and 2 in Vero Cells. Adv. Microbiol. 2016;06:276–287. doi: 10.4236/aim.2016.64027. DOI

Rajtar B., Skalicka-Woźniak K., Świątek Ł., Stec A., Boguszewska A., Polz-Dacewicz M. Antiviral effect of compounds derived from Angelica archangelica L. on Herpes simplex virus-1 and Coxsackievirus B3 infections. Food Chem. Toxicol. 2017;109:1026–1031. PubMed

Benzekri R., Bouslama L., Papetti A., Hammami M., Smaoui A., Limam F. Anti HSV-2 activity of Peganum harmala (L.) and isolation of the active compound. Microb. Pathog. 2018;114:291–298. doi: 10.1016/j.micpath.2017.12.017. PubMed DOI

Hutterer C., Milbradt J., Hamilton S., Zaja M., Leban J., Henry C., Vitt D., Steingruber M., Sonntag E., Zeitträger I., et al. Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) exert a strong anti-herpesviral activity. Antiviral. Res. 2017;143:113–121. doi: 10.1016/j.antiviral.2017.04.003. PubMed DOI

Zalilawati M.R., Andriani Y., Shaari K., Bourgougnon N., Ali A.M., Muhammad T.S.T., Mohamad H. Induction of apoptosis and anti HSV-1 activity of 3-(Phenethylamino) demethyl(oxy)aaptamine from a Malaysian Aaptos aaptos. J. Chem. Pharm. Res. 2015;7:330–341.

Hassan S.T.S., Berchová-Bímová K., Šudomová M., Malaník M., Šmejkal K., Rengasamy K.R.R. In Vitro Study of Multi-Therapeutic Properties of Thymus bovei Benth. Essential Oil and Its Main Component for Promoting Their Use in Clinical Practice. J. Clin. Med. 2018;7:283. doi: 10.3390/jcm7090283. PubMed DOI PMC

Brezáni V., Leláková V., Hassan S.T.S., Berchová-Bímová K., Nový P., Klouček P., Maršík P., Dall’Acqua S., Hošek J., Šmejkal K. Anti-Infectivity against Herpes Simplex Virus and Selected Microbes and Anti-Inflammatory Activities of Compounds Isolated from Eucalyptus globulus Labill. Viruses. 2018;10:360. doi: 10.3390/v10070360. PubMed DOI PMC

Liao H.B., Huang G.H., Yu M.H., Lei C., Hou A.J. Five Pairs of Meroterpenoid Enantiomers from Rhododendron capitatum. J. Org. Chem. 2017;82:1632–1637. doi: 10.1021/acs.joc.6b02800. PubMed DOI

Cagno V., Sgorbini B., Sanna C., Cagliero C., Ballero M., Civra A., Donalisio M., Bicchi C., Lembo D., Rubiolo P. In vitro anti-herpes simplex virus-2 activity of Salvia desoleana Atzei & V. Picci essential oil. PLoS ONE. 2017;12:e0172322. PubMed PMC

Ghannadi A., Fattahian K., Shokoohinia Y., Behbahani M., Shahnoush A. Anti-Viral Evaluation of Sesquiterpene Coumarins from Ferula assa-foetida against HSV-1. Iran. J. Pharm. Res. 2014;13:523–530. PubMed PMC

Krawczyk E., Łuczak M., Kobus M., Bańka D., Daniewski W. Antiviral Activity of N-Benzoylphenylisoserinates of Lactarius Sesquiterpenoid Alcohols in vitro. Planta Med. 2003;69:552–554. PubMed

Rezeng C., Yuan D., Long J., Suonan D., Yang F., Li W., Tong L., Jiumei P. Alantolactone exhibited anti-herpes simplex virus 1 (HSV-1) action in vitro. Biosci. Trends. 2015;9:420–422. doi: 10.5582/bst.2015.01171. PubMed DOI

Tsai Y.C., Cheng Y.B., Lo I.W., Cheng H.H., Lin C.J., Hwang T.L., Kuo Y.C., Liou S.S., Huang Y.Z., Kuo Y.H., et al. Seven new sesquiterpenoids from the fruits of Schisandra sphenanthera. Chem. Biodivers. 2014;11:1053–1068. doi: 10.1002/cbdv.201300259. PubMed DOI

Rédei D., Kúsz N., Rafai T., Bogdanov A., Burián K., Csorba A., Mándi A., Kurtán T., Vasas A., Hohmann J. 14-Noreudesmanes and a phenylpropane heterodimer from sea buckthorn berry inhibit Herpes simplex type 2 virus replication. Tetrahedron. 2019;75:1364–1370. doi: 10.1016/j.tet.2019.01.050. DOI

Zhang L.B., Liao H.B., Zhu H.Y., Yu M.H., Lei C., Hou A.J. Antiviral clerodane diterpenoids from Dodonaea viscosa. Tetrahedron. 2016;72:8036–8041. doi: 10.1016/j.tet.2016.10.034. DOI

Soares A.R., Abrantes J.L., Lopes Souza T.M., Leite Fontes C.F., Pereira R.C., de Palmer Paixão Frugulhetti I.C., Teixeira V.L. In vitro antiviral effect of meroditerpenes isolated from the Brazilian seaweed Stypopodium zonale (Dictyotales) Planta Med. 2007;73:1221–1224. doi: 10.1055/s-2007-981589. PubMed DOI

Krawczyk E., Luczak M., Kniotek M., Nowaczyk M. Cytotoxic, antiviral (in-vitro and in-vivo), immunomodulatory activity and influence on mitotic divisions of three taxol derivatives: 10-Deacetyl-baccatin III, methyl (N-benzoyl-(2′R,3′S)-3′-phenylisoserinate) and N-benzoyl-(2′R,3′S)-3′-phenylisoserine. J. Pharm. Pharmacol. 2005;57:791–797. doi: 10.1211/0022357056235. PubMed DOI

Wiart C., Kumar K., Yusof M.Y., Hamimah H., Fauzi Z.M., Sulaiman M. Antiviral properties of ent-labdene diterpenes of Andrographis paniculata nees, inhibitors of herpes simplex virus type 1. Phytother. Res. 2005;19:1069–1070. doi: 10.1002/ptr.1765. PubMed DOI

Barbosa J.P., Pereira R.C., Abrantes J.L., Cirne dos Santos C.C., Rebello M.A., Frugulhetti I.C., Texeira V.L. In vitro antiviral diterpenes from the Brazilian brown alga Dictyota pfaffii. Planta Med. 2004;70:856–860. doi: 10.1055/s-2004-827235. PubMed DOI

Isaka M., Chinthanom P., Srichomthong K., Thummarukcharoen T. Lanostane triterpenoids from fruiting bodies of the bracket fungus Fomitopsis feei. Tetrahedron Lett. 2017;58:1758–1761. doi: 10.1016/j.tetlet.2017.03.066. DOI

Lv X.J., Li Y., Ma S.G., Qu J., Liu Y.B., Li Y.H., Zhang D., Li L., Yu S.S. Antiviral Triterpenes from the Twigs and Leaves of Lyonia ovalifolia. J. Nat. Prod. 2016;79:2824–2837. doi: 10.1021/acs.jnatprod.6b00585. PubMed DOI

Hassan S.T.S., Berchová-Bímová K., Petráš J., Hassan K.T.S. Cucurbitacin B interacts synergistically with antibiotics against Staphylococcus aureus clinical isolates and exhibits antiviral activity against HSV-1. S. Afr. J. Bot. 2017;108:90–94. doi: 10.1016/j.sajb.2016.10.001. DOI

Da Rosa Guimarães T., Quiroz C.G., Borges C.R., de Oliveira S.Q., de Almeida M.T., Bianco É.M., Moritz M.I., Carraro J.L., Palermo J.A., Cabrera G., et al. Anti HSV-1 activity of halistanol sulfate and halistanol sulfate C isolated from Brazilian marine sponge Petromica citrina (Demospongiae) Mar. Drugs. 2013;11:4176–4192. doi: 10.3390/md11114176. PubMed DOI PMC

Laconi S., Madeddu M.A., Pompei R. Autophagy activation and antiviral activity by a licorice triterpene. Phytother. Res. 2014;28:1890–1892. doi: 10.1002/ptr.5189. PubMed DOI

Ikeda T., Yokomizo K., Okawa M., Tsuchihashi R., Kinjo J., Nohara T., Uyeda M. Anti-herpes virus type 1 activity of oleanane-type triterpenoids. Biol. Pharm. Bull. 2005;28:1779–1781. doi: 10.1248/bpb.28.1779. PubMed DOI

Li Y., Jiang R., Ooi L.S., But P.P., Ooi V.E. Antiviral triterpenoids from the medicinal plant Schefflera heptaphylla. Phytother. Res. 2007;21:466–470. doi: 10.1002/ptr.1962. PubMed DOI

Mukherjee H., Ojha D., Bag P., Chandel H.S., Bhattacharyya S., Chatterjee T.K., Mukherjee P.K., Chakraborti S., Chattopadhyay D. Anti-herpes virus activities of Achyranthes aspera: an indian ethnomedicine, and its triterpene acid. Microbiol. Res. 2013;168:238–244. doi: 10.1016/j.micres.2012.11.002. PubMed DOI

Zhou M., Xu M., Ma X.X., Zheng K., Yang K., Yang C.R., Wang Y.F., Zhang Y.J. Antiviral triterpenoid saponins from the roots of Ilex asprella. Planta Med. 2012;78:1702–1705. doi: 10.1055/s-0032-1315209. PubMed DOI

Liu F., Wang Y.-N., Li Y., Ma S.-G., Qu J., Liu Y.-B., Niu C.-S., Tang Z.H., Li Y.-H., Li L., et al. Triterpenoids from the twigs and leaves of Rhododendron latoucheae by HPLC‒MS‒SPE‒NMR. Tetrahedron. 2019;75:296–307. doi: 10.1016/j.tet.2018.11.059. DOI

Sun Y.L., Wang J., Wang Y.F., Zhang X.Y., Nong X.H., Chen M.Y., Xu X., Qi S.H. Cytotoxic and Antiviral Tetramic Acid Derivatives from the Deep-Sea-Derived Fungus Trichobotrys effuse DFFSCS021. Tetrahedron. 2015;71:9328–9332. doi: 10.1016/j.tet.2015.10.010. DOI

Álvarez Á.L., Habtemariam S., Abdel Moneim A.E., Melón S., Dalton K.P., Parra F. A spiroketal-enol ether derivative from Tanacetum vulgare selectively inhibits HSV-1 and HSV-2 glycoprotein accumulation in Vero cells. Antiviral Res. 2015;119:8–18. doi: 10.1016/j.antiviral.2015.04.004. PubMed DOI

Pongmuangmul S., Phumiamorn S., Sanguansermsri P., Wongkattiya N., Fraser I.H., Sanguansermsri D. Anti-herpes simplex virus activities of monogalactosyl diglyceride and digalactosyl diglyceride from Clinacanthus nutans, a traditional Thai herbal medicine. Asian Pac. J. Trop. Biomed. 2016;6:192–197. doi: 10.1016/j.apjtb.2015.12.014. DOI

Ma F.W., Kong S.Y., Tan H.S., Wu R., Xia B., Zhou Y., Xu H.X. Structural characterization and antiviral effect of a novel polysaccharide PSP-2B from Prunellae spica. Carbohydr. Polym. 2016;152:699–709. doi: 10.1016/j.carbpol.2016.07.062. PubMed DOI

Jin F., Zhuo C., He Z., Wang H., Liu W., Zhang R., Wang Y. Anti-herpes simplex virus activity of polysaccharides from Eucheuma gelatinae. World J. Microbiol. Biotechnol. 2015;31:453–460. doi: 10.1007/s11274-015-1798-1. PubMed DOI

Sahera F.M., Mohsen M.S.A., El-Sayed O.H. Chemical structure and antiviral activity of sulfated polysaccharides from Surgassium latifolium; Proceedings of the Medical Research Day, Faculty of Medicine; Jazan University, Al Maarefah Rd, Jazan, Saudi Arabia. June 2011.

Zhu W., Chiu L.C., Ooi V.E., Chan P.K., Ang P.O., Jr. Antiviral property and mechanisms of a sulphated polysaccharide from the brown alga Sargassum patens against Herpes simplex virus type 1. Phytomedicine. 2006;13:695–701. doi: 10.1016/j.phymed.2005.11.003. PubMed DOI

Lee J.-B., Takeshita A., Hayashi K., Hayashi T. Structures and antiviral activities of polysaccharides from Sargassum trichophyllum. Carbohydr. Polym. 2001;86:995–999. doi: 10.1016/j.carbpol.2011.05.059. DOI

Bedoux G., Caamal-Fuentes E., Boulho R., Marty C., Bourgougnon N., Freile-Pelegrín Y., Robledo D. Antiviral and Cytotoxic Activities of Polysaccharides Extracted from Four Tropical Seaweed Species. Nat. Prod. Commun. 2017;12:807–811. doi: 10.1177/1934578X1701200602. DOI

Hardouin K., Bedoux G., Burlot A.-S., Donnay-Moreno C., Bergé J.-P., Nyvall-Collén P., Bourgougnon N. Enzyme-assisted extraction (EAE) for the production of antiviral and antioxidant extracts from the green seaweed Ulva armoricana (Ulvales, Ulvophyceae) Algal Res. 2016;16:233–239. doi: 10.1016/j.algal.2016.03.013. DOI

Vanderlei E., Eloy Y., de Araújo I., Quinderé A., Fontes B., Mendes G., Cavalcanti J., Romanos M., Benevides N. Structural features, molecular weight and anti-HSV activity of sulfated polysaccharides from three red seaweeds. J. Chem. Pharm. Res. 2016;8:164–170.

Bouhlal R., Haslin C., Chermann J.-C., Colliec-Jouault S., Sinquin C., Simon G., Cerantola S., Riadi H., Bourgougnon N. Antiviral Activities of Sulfated Polysaccharides Isolated from Sphaerococcus coronopifolius (Rhodophytha, Gigartinales) and Boergeseniella thuyoides (Rhodophyta, Ceramiales) Marine Drugs. 2011;9:1187–1209. doi: 10.3390/md9071187. PubMed DOI PMC

Saha S., Navidb M.H., Bandyopahyay S.S., Schitzlerb P., Ray B. Sulfated polysaccharides from Laminaria angustata: Structural features and in vitro antiviral activities. Carbohydr. Polym. 2012;87:123–130. doi: 10.1016/j.carbpol.2011.07.026. PubMed DOI

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. doi: 10.1016/j.ijbiomac.2017.04.043. PubMed DOI

Karmakar P., Pujol C.A., Damonte E.B., Ghosh T., Ray B. Polysaccharides from Padina tetrastromatica: Structural features, chemical modification and antiviral activity. Carbohydr. Polym. 2010;80:513–520. doi: 10.1016/j.carbpol.2009.12.014. DOI

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. doi: 10.1016/j.phytochem.2006.05.024. PubMed DOI

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. doi: 10.1177/095632020701800305. PubMed DOI

Lee J.B., Hayashi K., Hashimoto M., Nakano T., Hayashi T. Novel antiviral fucoidan from sporophyll of Undaria pinnatifida (Mekabu) Chem. Pharm. Bull. 2004;52:1091–1094. doi: 10.1248/cpb.52.1091. PubMed DOI

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. doi: 10.1016/j.phytochem.2007.02.008. PubMed DOI

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. doi: 10.1016/j.carres.2005.08.004. PubMed DOI

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. doi: 10.1016/S0141-8130(96)01145-2. PubMed DOI

Li Z., Liu J., Zhao Y. Possible mechanism underlying the antiherpetic activity of a proteoglycan isolated from the mycelia of Ganoderma lucidum in vitro. J. Biochem. Mol. Biol. 2005;38:34–40. doi: 10.5483/BMBRep.2005.38.1.034. PubMed DOI

Dong C.X., Hayashi K., Lee J.B., Hayashi T. Characterization of structures and antiviral effects of polysaccharides from Portulaca oleracea L. Chem. Pharm. Bull. 2010;58:507–510. doi: 10.1248/cpb.58.507. PubMed DOI

Lopes N., Faccin-Galhardi L.C., Espada S.F., Pacheco A.C., Ricardo N.M., Linhares R.E., Nozawa C. Sulfated polysaccharide of Caesalpinia ferrea inhibits herpes simplex virus and poliovirus. Int. J. Biol. Macromol. 2013;60:93–99. doi: 10.1016/j.ijbiomac.2013.05.015. PubMed DOI

Lee J.B., Tanikawa T., Hayashi K., Asagi M., Kasahara Y., Hayashi T. Characterization and biological effects of two polysaccharides isolated from Acanthopanax sciadophylloides. Carbohydr. Polym. 2015;116:159–166. doi: 10.1016/j.carbpol.2014.04.013. PubMed DOI

Kanekiyo K., Lee J.B., Hayashi K., Takenaka H., Hayakawa Y., Endo S., Hayashi T. Isolation of an antiviral polysaccharide, nostoflan, from a terrestrial cyanobacterium, Nostoc flagelliforme. J. Nat. Prod. 2005;68:1037–1041. doi: 10.1021/np050056c. PubMed DOI

Ghosh P., Adhikari U., Ghosal P.K., Pujol C.A., Carlucci M.J., Damonte E.B., Ray B. In vitro anti-herpetic activity of sulfated polysaccharide fractions from Caulerpa racemosa. Phytochemistry. 2004;65:3151–3157. doi: 10.1016/j.phytochem.2004.07.025. PubMed DOI

Cavicchioli V.Q., Carvalho O.V., Paiva J.C., Todorov S.D., Silva Júnior A., Nero L.A. Inhibition of herpes simplex virus 1 (HSV-1) and poliovirus (PV-1) by bacteriocins from Lactococcus lactis subsp. lactis and Enterococcus durans strains isolated from goat milk. Int. J. Antimicrob. Agents. 2018;51:33–37. PubMed

Quintana V.M., Torres N.I., Wachsman M.B., Sinko P.J., Castilla V., Chikindas M. Antiherpes simplex virus type 2 activity of the antimicrobial peptide subtilosin. J. Appl. Microbiol. 2014;117:1253–1259. doi: 10.1111/jam.12618. PubMed DOI PMC

Liang X., Nong X.H., Huang Z.H., Qi S.H. Antifungal and Antiviral Cyclic Peptides from the Deep-Sea-Derived Fungus Simplicillium obclavatum EIODSF 020. J. Agric. Food Chem. 2017;65:5114–5121. doi: 10.1021/acs.jafc.7b01238. PubMed DOI

Ma X., Nong X.-H., Ren Z., Wang J., Liang X., Wang L., Qi S.-H. Antiviral peptides from marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501. Tetrahedron Lett. 2017;58:1151–1155. doi: 10.1016/j.tetlet.2017.02.005. DOI

Gong M., Piraino F., Yan N., Zhang J., Xia M., Ma J., Cheng J., Liu X. Purification, partial characterization and molecular cloning of the novel antiviral protein RC28. Peptides. 2009;30:654–659. doi: 10.1016/j.peptides.2008.11.016. PubMed DOI

Vilas Boas L.C.P., de Lima L.M.P., Migliolo L., Mendes G.d.S., de Jesus M.G., Franco O.L., Silva P.A. Linear antimicrobial peptides with activity against herpes simplex virus 1 and Aichi virus. Biopolym. 2017;108:e22871. doi: 10.1002/bip.22871. PubMed DOI

El-Fakharany E.M., Uversky V.N., Redwan E.M. Comparative Analysis of the Antiviral Activity of Camel, Bovine, and Human Lactoperoxidases Against Herpes Simplex Virus Type 1. Appl. Biochem. Biotechnol. 2017;182:294–310. doi: 10.1007/s12010-016-2327-x. PubMed DOI

Levendosky K., Mizenina O., Martinelli E., Jean-Pierre N., Kizima L., Rodriguez A., Kleinbeck K., Bonnaire T., Robbiani M., Zydowsky T.M., et al. Griffithsin and carrageenan combination to target herpes simplex virus 2 and human papillomavirus. Antimicrob. Agents Chemother. 2015;59:7290–7298. doi: 10.1128/AAC.01816-15. PubMed DOI PMC

Albiol Matanic V.C., Castilla V. Antiviral activity of antimicrobial cationic peptides against Junin virus and herpes simplex virus. Int. J. Antimicrob. Agents. 2004;23:382–389. doi: 10.1016/j.ijantimicag.2003.07.022. PubMed DOI

Waxman L., Darke P.L. The herpesvirus proteases as targets for antiviral chemotherapy. Antivir. Chem. Chemother. 2000;11:1–22. doi: 10.1177/095632020001100101. PubMed DOI

Reardon J.E. Herpes simplex virus type 1 DNA polymerase. Mechanism-based affinity chromatography. J. Biol. Chem. 1990;265:7112–7115. PubMed

Valencia F., Veselenak R.L., Bourne N. In vivo evaluation of antiviral efficacy against genital herpes using mouse and guinea pig models. Methods Mol. Biol. 2013;1030:315–326. PubMed

Osada N., Kohara A., Yamaji T., Hirayama N., Kasai F., Sekizuka T., Kuroda M., Hanada K. The genome landscape of the african green monkey kidney-derived Vero cell line. DNA Res. 2014;21:673–683. doi: 10.1093/dnares/dsu029. PubMed DOI PMC

D’Aiuto L., Williamson K., Dimitrion P., McNulty J., Brown C.E., Dokuburra C.B., Nielsen A.J., Lin W.J., Piazza P., Schurdak M.E., et al. Comparison of three cell-based drug screening platforms for HSV-1 infection. Antiviral Res. 2017;142:136–140. doi: 10.1016/j.antiviral.2017.03.016. PubMed DOI PMC

Cotarelo M., Catalán P., Sánchez-Carrillo C., Menasalvas A., Cercenado E., Tenorio A., Bouza E. Cytopathic effect inhibition assay for determining the in-vitro susceptibility of herpes simplex virus to antiviral agents. J. Antimicrob. Chemother. 1999;44:705–708. doi: 10.1093/jac/44.5.705. PubMed DOI

Thi T.N., Deback C., Malet I., Bonnafous P., Ait-Arkoub Z., Agut H. Rapid determination of antiviral drug susceptibility of herpes simplex virus types 1 and 2 by real-time PCR. Antiviral Res. 2006;69:152–157. doi: 10.1016/j.antiviral.2005.11.004. PubMed DOI

McClain D.S., Fuller A.O. Cell-specific kinetics and efficiency of herpes simplex virus type 1 entry are determined by two distinct phases of attachment. Virology. 1994;198:690–702. doi: 10.1006/viro.1994.1081. PubMed DOI

Silva I.T., Costa G.M., Stoco P.H., Schenkel E.P., Reginatto F.H., Simões C.M.O. In vitro antiherpes effects of a c-glycosylflavonoid enriched fraction of Cecropia glaziovii Sneth. Lett. Appl. Microbiol. 2010;51:143–148. doi: 10.1111/j.1472-765X.2010.02870.x. PubMed DOI

Klysik K., Pietraszek A., Karewicz A., Nowakowska M. Acyclovir in the Treatment of Herpes Viruses—A Review. Curr. Med. Chem. 2018 doi: 10.2174/0929867325666180309105519. PubMed DOI

Ouyang J., Sun F., Feng W., Xie Y., Ren L., Chen Y. Antimicrobial Activity of Galangin and Its Effects on Murein Hydrolases of Vancomycin-Intermediate Staphylococcus aureus (VISA) Strain Mu50. Chemother. 2018;63:20. doi: 10.1159/000481658. PubMed DOI

Céliz G., Daz M., Audisio M.C. Antibacterial activity of naringin derivatives against pathogenic strains. J. Appl. Microb. 2011;111:731. doi: 10.1111/j.1365-2672.2011.05070.x. PubMed DOI

Pujol C.A., Carlucci M.J., Matulewicz M.C., Damonte E.B. Natural sulfated polysaccharides for the prevention and control of viral infections. Top. Heterocycl. Chem. 2007;11:259–281.

Choi J.H., Jang A.Y., Lin S., Lim S., Kim D., Park K., Han S.M., Yeo J.H., Seo H.S. Melittin, a honeybee venom‑derived antimicrobial peptide, may target methicillin‑resistant Staphylococcus aureus. Mol. Med. Rep. 2015;12:6483. doi: 10.3892/mmr.2015.4275. PubMed DOI PMC

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