Skip to main content

Advertisement

SpringerLink
Log in

Natural and semisynthetic diterpenoids with antiviral and immunomodulatory activities block the ERK signaling pathway

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

The pathogenesis of many viral infections lies on the damage caused by the immune response against the virus. Current antiviral drugs do not act on the inflammatory component of the disease. Thus, new compounds that inhibit both viral multiplication and the immunopathology elicited by the virus are an approach that should be considered. In the present study, we identified two jatropholones (2A and 5B) and one carnosic acid derivative (9C) that significantly inhibited multiplication of TK+ and TK− strains of HSV-1 in Vero cells. Compounds 2A, 5B and 9C also prevented HSV-1- and TLRs-induced inflammatory response in cultivated murine macrophages. In macrophages infected with HSV-1, the inhibitory effect of compounds 2A, 5B and 9C on TNF-α and IL-6 production could be associated with the block of ERK pathway, whereas NF-κB pathway was not hampered by any of the compounds. Besides, 2A, 5B and 9C also inhibited ERK pathway and reduced TNF-α production in macrophages stimulated with TLR2, TLR4 or TLR9 agonists and were able to hinder IL-6 secretion after activation with TLR2 or TLR4, but not with TLR9. The immunomodulatory effect of 2A, 5B and 9C in macrophages infected with HSV-1 may be a consequence of the inhibition of ERK pathway activated by TLRs. The availability of compounds with both antiviral and immunomodulatory properties which affect TLR signaling pathways might be a useful strategy to control the progress of virus-induced disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Field HJ, Vere Hodge RA (2013) Recent developments in anti-herpesvirus drugs. Br Med Bull 106:213–249

    Article  CAS  PubMed  Google Scholar 

  2. Knickelbein JE, Hendricks RL, Charukamnoetkanok P (2009) Management of herpes simplex virus stromal keratitis: an evidence-based review. Surv Ophthalmol 54:226–234

    Article  PubMed  Google Scholar 

  3. Antonelli G, Turriziani O (2012) Antiviral therapy: old and current issues. Int J Antimicrob Agents 40:95–102

    Article  CAS  PubMed  Google Scholar 

  4. Guess S, Stone DU, Chodosh J (2007) Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf 5:240–250

    Article  PubMed  Google Scholar 

  5. Mukhtar M, Arshad M, Ahmad M, Pomerantz RJ, Wigdahl B, Parveen Z (2008) Antiviral potentials of medicinal plants. Virus Res 131:111–120

    Article  CAS  PubMed  Google Scholar 

  6. Pifarré MP, Berra A, Coto CE, Alché LE (2002) Therapeutic action of meliacine, a plant-derived antiviral, on HSV-induced ocular disease in mice. Exp Eye Res 75:327–334

    Article  PubMed  Google Scholar 

  7. Alché LE, Ferek GA, Meo M, Coto CE, Maier MS (2003) An antiviral meliacarpin from leaves of Melia azedarach L. Z Naturforsch C 58:215–219

    Article  PubMed  Google Scholar 

  8. Bueno CA, Barquero AA, Di Cónsoli H, Maier MS, Alché LE (2009) A natural tetranortriterpenoid with immunomodulatory properties as a potential anti-HSV agent. Virus Res 141:47–54

    Article  CAS  PubMed  Google Scholar 

  9. Bueno CA, Alché LE, Barquero AA (2010) 1-Cinnamoyl-3,11-dihydroxymeliacarpin delays glycoprotein transport restraining virus multiplication without cytotoxicity. Biochem Biophys Res Commun 393:32–37

    Article  CAS  PubMed  Google Scholar 

  10. Bueno CA, Lombardi MG, Sales ME, Alché LE (2012) A natural antiviral and immunomodulatory compound with antiangiogenic properties. Microvasc Res 84:235–241

    Article  CAS  PubMed  Google Scholar 

  11. Aruoma OI, Spencer JP, Rossi R, Aeschbach R, Khan A, Mahmood N et al (1996) An evaluation of the antioxidant and antiviral action of extracts of rosemary and Provençal herbs. Food Chem Toxicol 34:449–456

    Article  CAS  PubMed  Google Scholar 

  12. Poeckel D, Greiner C, Verhoff M, Rau O, Tausch L, Hörnig C et al (2008) Carnosic acid and carnosol potently inhibit human 5-lipoxygenase and suppress pro-inflammatory responses of stimulated human polymorphonuclear leukocytes. Biochem Pharmacol 76:91–97

    Article  CAS  PubMed  Google Scholar 

  13. Krawczyk E, Luczak M, Kniotek M, Nowaczyk M (2005) 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 57:791–797

    Article  CAS  PubMed  Google Scholar 

  14. Zhang Y, Ma X (2010) Triptolide inhibits IL-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alpha. J Immunol 184:3866–3877

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Sabandar CW, Ahmat N, Jaafar FM, Sahidin I (2013) Medicinal property, phytochemistry and pharmacology of several Jatropha species (Euphorbiaceae): a review. Phytochemistry 85:7–29

    Article  CAS  PubMed  Google Scholar 

  16. Pertino M, Schmeda-Hirschmann G, Rodríguez JA, Theoduloz C (2007) Gastroprotective effect and cytotoxicity of semisynthetic jatropholone derivatives. Planta Med 73:1095–1100

    Article  CAS  PubMed  Google Scholar 

  17. Pertino M, Schmeda-hirschmann G, Rodr JA, Theoduloz C (2007) Gastroprotective effect and cytotoxicity of terpenes from the Paraguayan crude drug “yagua rova” (Jatropha isabelli). J Ethnopharmacol 111:553–559

    Article  CAS  PubMed  Google Scholar 

  18. Theoduloz C, Rodríguez JA, Pertino M, Schmeda-Hirschmann G (2007) Antiproliferative activity of the diterpenes jatrophone and jatropholone and their derivatives. Planta Med 73:1520–1522

    Google Scholar 

  19. Pertino MW, Theoduloz C, Rodríguez JA, Yáñez T, Lazo V, Schmeda-Hirschmann G (2010) Gastroprotective effect of carnosic acid γ-lactone derivatives. J Nat Prod 73:639–643

    Article  CAS  PubMed  Google Scholar 

  20. Theoduloz C, Pertino MW, Rodríguez JA, Schmeda-Hirschmann G (2011) Gastroprotective effect and cytotoxicity of carnosic acid derivatives. Planta Med 77:882–887

    Article  CAS  PubMed  Google Scholar 

  21. Kodukula P, Liu T, Van Rooijen N, Jager MJ, Hendricks RL (1999) Macrophage control of herpes simplex virus type 1 replication in the peripheral nervous system. J Immunol 162:2895–2905

    CAS  PubMed  Google Scholar 

  22. Mott K, Brick DJ, van Rooijen N, Ghiasi H (2007) Macrophages are important determinants of acute ocular HSV-1 infection in immunized mice. Invest Ophthalmol Vis Sci 48:5605–5615

    Article  PubMed  Google Scholar 

  23. Melchjorsen J, Sirén J, Julkunen I, Paludan SR, Matikainen S (2006) Induction of cytokine expression by herpes simplex virus in human monocyte-derived macrophages and dendritic cells is dependent on virus replication and is counteracted by ICP27 targeting NF-κB and IRF-3. J Gen Virol 87:1099–1108

    Article  CAS  PubMed  Google Scholar 

  24. Cai M, Li M, Wang K, Wang S, Lu Q, Yan J et al (2013) The herpes simplex virus 1-encoded envelope glycoprotein B activates NF-κB through the Toll-like receptor 2 and MyD88/TRAF6-dependent signaling pathway. PloS One 8:e54586

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Boivin N, Menasria R, Piret J, Boivin G (2012) Modulation of TLR9 response in a mouse model of herpes simplex virus encephalitis. Antiviral Res 96:414–421

    Article  CAS  PubMed  Google Scholar 

  26. Sarangi PP, Kim B, Kurt-Jones E, Rouse BT (2007) Innate recognition network driving herpes simplex virus-induced corneal immunopathology: role of the toll pathway in early inflammatory events in stromal keratitis. J Virol 81:11128–11138

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Bereczky-Veress B, Abdelmagid N, Piehl F, Bergström T, Olsson T, Sköldenberg B et al (2010) Influence of perineurial cells and Toll-like receptors 2 and 9 on Herpes simplex type 1 entry to the central nervous system in rat encephalitis. PloS One 5:e12350

    Article  PubMed Central  PubMed  Google Scholar 

  28. Takeda S, Miyazaki D, Sasaki S, Yamamoto Y, Terasaka Y, Yakura K et al (2011) Roles played by toll-like receptor-9 in corneal endothelial cells after herpes simplex virus type 1 infection. Invest Ophthalmol Vis Sci 52:6729–6736

    Article  CAS  PubMed  Google Scholar 

  29. Johnson AC, Heinzel FP, Diaconu E, Sun Y, Hise AG, Golenbock D et al (2005) Activation of toll-like receptor (TLR)2, TLR4, and TLR9 in the mammalian cornea induces MyD88-dependent corneal inflammation. Invest Ophthalmol Vis Sci 46:589–595

    Article  PubMed  Google Scholar 

  30. Skelly MJ, Burger AA, Adekola O (2012) Herpes simplex virus encephalitis a review of current disease management with three case reports. Antimicrob Agents Chemother 23:13–18

    CAS  Google Scholar 

  31. Kamei S, Sekizawa T, Shiota H, Mizutani T, Itoyama Y, Takasu T et al (2005) Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry 76:1544–1549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Faith SA, Sweet TJ, Bailey E, Booth T, Docherty JJ (2006) Resveratrol suppresses nuclear factor-kB in herpes simplex virus infected cells. Antiviral Res 72:242–251

    Article  CAS  PubMed  Google Scholar 

  33. Torres NI, Castilla V, Bruttomesso AC, Eiras J, Galagovsky LR, Wachsman MB (2012) In vitro antiviral activity of dehydroepiandrosterone, 17 synthetic analogs and ERK modulators against herpes simplex virus type 1. Antiviral Res 95:37–48

    Article  CAS  PubMed  Google Scholar 

  34. Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM et al (2013) The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 497:498–502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Pan H-Y, Yano M, Kido H (2011) Effects of inhibitors of Toll-like receptors, protease-activated receptor-2 signalings and trypsin on influenza A virus replication and upregulation of cellular factors in cardiomyocytes. J Med Invest 58(1–2):19–28

    Article  PubMed  Google Scholar 

  36. Zhou S, Cerny AM, Bowen G, Chan M, Knipe DM, Kurt-Jones EA et al (2010) Discovery of a novel TLR2 signaling inhibitor with anti-viral activity. Antiviral Res 87:295–306

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Isabel Paz and Guillermo Assad Ferek for their technical assistance. This work was supported by Grants from the National Research Council of Argentina (CONICET) (PIP 1007) and Universidad de Buenos Aires (UBA) (X002). Dr. L.E. Alché, Dr. F.M. Michelini and Dr. C.A. Bueno are Research Members of CONICET.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Laboratorio de Virología, Departamento de Química Biológica-IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón II, Piso 4º, Ciudad Universitaria, C-1428GBA, Buenos Aires, Argentina

    Carlos Alberto Bueno, Flavia Mariana Michelini, Catalina Arredondo Gómez & Laura Edith Alché

  2. Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile

    Mariano Walter Pertino & Guillermo Schmeda-Hirschmann

Authors
  1. Carlos Alberto Bueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Flavia Mariana Michelini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mariano Walter Pertino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Catalina Arredondo Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guillermo Schmeda-Hirschmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laura Edith Alché
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura Edith Alché.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bueno, C.A., Michelini, F.M., Pertino, M.W. et al. Natural and semisynthetic diterpenoids with antiviral and immunomodulatory activities block the ERK signaling pathway. Med Microbiol Immunol 204, 575–584 (2015). https://doi.org/10.1007/s00430-014-0383-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-014-0383-9

Keywords

Search

Navigation