Skip to main content
SpringerLink
Log in

From the traditional Chinese medicine plant Schisandra chinensis new scaffolds effective on HIV-1 reverse transcriptase resistant to non-nucleoside inhibitors

  • Virology
  • Published:
Journal of Microbiology Aims and scope Submit manuscript

Abstract

HIV-1 reverse transcriptase (RT) is still an extremely attractive pharmaceutical target for the identification of new inhibitors possibly active on drug resistant strains. Medicinal plants are a rich source of chemical diversity and can be used to identify novel scaffolds to be further developed by chemical modifications. We investigated the ability of the main lignans from Schisandra chinensis (Turcz.) Baill. fruits, commonly used in Traditional Chinese Medicine, to affect HIV-1 RT functions. We purified 6 lignans from Schisandra chinensis fruits and assayed their effects on HIV-1 RT and viral replication. Among the S. chinensis fruit lignans, Schisandrin B and Deoxyschizandrin selectively inhibited the HIV-1 RT-associated DNA polymerase activity. Structure activity relationship revealed the importance of cyclooctadiene ring substituents for efficacy. In addition, Schisandrin B was also able to impair HIV-1 RT drug resistant mutants and the early phases of viral replication. We identified Schisandrin B and Deoxyschizandrin as new scaffold for the further development of novel HIV-1 RT inhibitors.

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

Similar content being viewed by others

References

  • Chang, R., Li, Y., Yang, X., Yue, Y., Dou, L., Wang, Y., Zhang, W., and Li, X. 2013. Protective role of deoxyschizandrin and schisantherin A against myocardial ischemia-reperfusion injury in rats. PLoS One 8, e61590.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen, M., Kilgore, N., Lee, K.H., and Chen, D.F. 2006. Rubrisandrins A and B, lignans and related anti-HIV compounds from Schisandra rubriflora. J. Nat. Prod. 69, 1697–1701.

    Article  CAS  PubMed  Google Scholar 

  • Chen, P., Pang, S., Yang, N., Meng, H., Liu, J., Zhou, N., Zhang, M., Xu, Z., Gao, W., Chen, B., et al. 2013. Beneficial effects of schisandrin B on the cardiac function in mice model of myocardial infarction. PLoS One 8, e79418.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Corona, A., Di Leva, F.S., Thierry, S., Pescatori, L., Cuzzucoli Crucitti, G., Subra, F., Delelis, O., Esposito, F., Rigogliuso, G., Costi, R., et al. 2014 Identification of highly conserved residues involved in the inhibition of the HIV-1 ribonuclease H function by diketoacid derivatives. Antimicrob. Agents Chemother. 58, 6101–1610.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Corona, A., Masaoka, T., Tocco, G., Tramontano, E., and Le Grice, S.F. 2013. Active site and allosteric inhibitors of the ribonuclease H activity of HIV reverse transcriptase. Future Med. Chem. 5, 2127–2139.

    Article  CAS  PubMed  Google Scholar 

  • Cos, P., Maes, L., Vlietinck, A., and Pieters, L. 2008. Plant-derived leading compounds for chemotherapy of human immunodeficiency virus (HIV) infection — an update (1998–2007). Planta Med. 74, 1323–1337.

    Article  CAS  PubMed  Google Scholar 

  • Distinto, S., Esposito, F., Kirchmair, J., Cardia, M.C., Gaspari, M., Maccioni, E., Alcaro, S., Markt, P., Wolber, G., Zinzula, L., et al. 2012. Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophorebased virtual screening approach. Eur. J. Med. Chem. 50, 216–229.

    Article  CAS  PubMed  Google Scholar 

  • Domaoal, R.A. and Demeter, L.M. 2004. Structural and biochemical effects of human immunodeficiency virus mutants resistant to non-nucleoside reverse transcriptase inhibitors. Int. J. Biochem. Cell. Biol. 36, 1735–1751.

    Article  CAS  PubMed  Google Scholar 

  • Esposito, F., Corona, A., and Tramontano, E. 2012. HIV-1 reverse transcriptase still remains a new drug target: structure, function, classical inhibitors, and new inhibitors with innovative mechanisms of actions. Mol. Biol. Int. doi: 10.1155/2012/586401.

    Google Scholar 

  • Esposito, F., Sanna, C., Del Vecchio, C., Cannas, V., Venditti, A., Corona, A., Bianco, A., Serrilli, A.M., Guarcini, L., Parolin, C., et al. 2013. Hypericum hircinum L. components as new singlemolecule inhibitors of both HIV-1 reverse transcriptase-associated DNA polymerase and ribonuclease H activities. Path. Dis. 68, 116–124.

    Article  CAS  Google Scholar 

  • Hancke, J.L., Burgos, R.A., and Ahumada, F. 1999. Schisandra chinensis (Turcz.) Baill. Fitoterapia 70, 451–471.

    Article  CAS  Google Scholar 

  • Helseth, E., Kowalski, M., Gabuzda, D., Olshevsky, U., Haseltine, W., and Sodroski, J. 1990. Rapid complementation assays measuring replicative potential of human immunodeficiency virus type 1 envelope glycoprotein mutants. J. Virol. 64, 2416–2420.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hu, J., Mao, C., Gong, X., Lu, T., Chen, H., Huang, Z., and Cai, B. 2013. Simultaneous determination of eleven characteristic lignans in Schisandra chinensis by high-performance liquid chromatography. Pharmacogn. Mag. 9, 155–161.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lam, P.Y. and Ko, K.M. 2012. Schisandrin B as a hormetic agent for preventing age-related neurodegenerative diseases. Oxid. Med. Cell Longev. Article ID 250825.

    Google Scholar 

  • Li, T. and Peng, T. 2013. Traditional Chinese herbal medicine as a source of molecules with antiviral activity. Antiv. Res. 97, 1–9.

    Article  CAS  Google Scholar 

  • Li, J. and Vederas, J.C. 2009. Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161–165.

    Article  PubMed  Google Scholar 

  • Liu, G.T., Chang, H.M., Yeung, H.W., Tso, W.W., and Koo, A. 1985. Hepato-pharmacology of Fructus Schizandrae. Advances in Chinese medicinal materials research, pp. 257–268. Singapore, World Scientific.

    Google Scholar 

  • Liu, K.T. and Lesca, P. 1982. Pharmacological properties of dibenzo [a,c]cyclooctene derivatives isolated from Fructus Schizandrae chinensis III. Inhibitory effects on carbon tetrachloride-induced lipid peroxidation, metabolism and covalent binding of carbon tetrachloride to lipids. Chem-Biol. Interact. 41, 39–47.

    Article  CAS  PubMed  Google Scholar 

  • Maga, G., Amacker, M., Ruel, N., Hubscher, U., and Spadari, S. 1997. Resistance to nevirapine of HIV-1 reverse transcriptase mutants: loss of stabilizing inter-actions and thermodynamic or steric barriers are induced by different single amino acid substitutions. J. Mol. Biol. 274, 738–747.

    Article  CAS  PubMed  Google Scholar 

  • Mehellou, Y. and De Clercq, E. 2010. Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go? J. Med. Chem. 53, 521–538.

    Article  CAS  PubMed  Google Scholar 

  • Mellors, J.W., Dutschman, G.E., Im, G.J., Tramontano, E., Winkler, S.R., and Cheng, Y.C. 1992. In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase. Mol. Pharmacol. 41, 446–451.

    CAS  PubMed  Google Scholar 

  • Mellors, J., Im, G.J., Tramontano, E., Winkler, S.R., Medina, D.J., Dutschman, G.E., Bazmi, H.Z., Piras, G., Gonzales, C.J., and Cheng, Y.C. 1993. A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2butenyl)imidazo[4,5,1,jk][1,4] benzodiazepin-2(1H)- thione (TIBO R82150). Mol. Pharmacol. 43, 11–16.

    CAS  PubMed  Google Scholar 

  • Mossmann, T. 1983. Rapid colorimetric assay for cell growth and survival. Application to proliferation and cytotoxicity. J. Immunol. Methods 65, 55–63.

    Article  Google Scholar 

  • National Pharmacopoeia Committee. 2010. Pharmacopoeia of People Republic of China. Chemical Industry Press, Beijing, China.

    Google Scholar 

  • Nishida, H., Tatewaki, N., Nakajima, Y., Magara, T., Ko, K.M., Hamamori, Y., and Konishi, T. 2009. Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Res. 37, 5678–5689.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Opletal, L., Sovová, H., and Bártlová, M. 2004. Dibenzo[a,c]cyclooctadiene lignans of the genus Schisandra: importance, isolation and determination. J. Chromatog. 812, 357–371.

    CAS  Google Scholar 

  • Pan, M.H., Chiou, Y.S., Tsai, M.L., and Ho, C.T. 2011. Anti-inflammatory activity of traditional Chinese medicinal herbs. J Tradit. Complement. Med. 1, 8–24.

    PubMed Central  PubMed  Google Scholar 

  • Pan, S.Y., Zhou, S.F., Gao, S.H., Yu, Z.L., Zhang, S.F., Tang, M.K., Sun, J.N., Ma, D.L., Han, Y.F., Fong, W.F., et al. 2013. New perspectives on how to discover drugs from herbal medicines: CAM’s outstanding contribution to modern therapeutics. Evid. Based Complement Alternat. Med. Article ID 627375.

    Google Scholar 

  • Panossian, A. and Wikman, G. 2008. Pharmacology of Schisandra chinensis Bail.: an overview of Russian research and uses in medicine. J. Ethnopharmacol. 118, 183–212.

    Article  PubMed  Google Scholar 

  • Pao, T.T., Liu, K.T., Hsu, K.F., and Sung, C.Y. 1975. Studies on Fructus Schizandrae I: effects on increased SGPT levels in animals caused by hepatotoxic chemical agents. J. Chinese Med. 54, 275–277.

    Google Scholar 

  • Parolin, C., Gatto, B., Del Vecchio, C., Pecere, T., Tramontano, E., Cecchetti, V., Fravolini, A., Masiero, S., Palumbo, M., and Palù, G. 2003. New anti-human immunodeficiency virus type 1 6-aminoquinolones: mechanism of action. Antimicrob. Agents Chemother. 47, 889–896.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pu, H.J., Cao, Y.F., He, R.R., Zhao, Z.L., Song, J.H., Jiang, B., Huang, T., Tang, S.H., Lu, J.M., and Kurihara, H. 2012. Correlation between Antistress and hepatoprotective effects of Schisandra Lignans was related with its antioxidative actions in liver cells. Evid. Based Complement. Alternat. Med. 2012, 161062.

    PubMed Central  PubMed  Google Scholar 

  • Ren, J. and Stammers, D.K. 2008. Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Virus Res. 134, 157–170.

    Article  CAS  PubMed  Google Scholar 

  • Suchaud, V., Bailly, F., Lion, C., Tramontano, E., Esposito, F., Corona, A., Christ, F., Debyser, Z., and Cotelle, P. 2010. Development of a series of 3-hydroxyquinolin-2(1H)-ones as selective inhibitors of HIV-1 reverse transcriptase associated RNase H activity. Bioorg. Med. Chem. Lett. 22, 3988–3992.

    Article  Google Scholar 

  • Sun, H.D., Qiu, S.X., Lin, L.Z., Wang, Z.Y., Lin, Z.W., Pengsuparp, T., Pezzuto, J.M., Fong, H.H., Cordell, G.A., and Farnsworth, N.R. 1996. Nigranoic acid, a triterpenoid from Schisandra sphaerandra that inhibits HIV-1 reverse transcriptase. J. Nat. Prod. 59, 525–527.

    Article  CAS  PubMed  Google Scholar 

  • Tramontano, E. and Di Santo, R. 2010. HIV-1 RT-associated RNase H function inhibitors: Recent advances in drug development. Curr. Med. Chem. 17, 2837–2853.

    Article  CAS  PubMed  Google Scholar 

  • Tramontano, E., Esposito, F., Badas, R., Di Santo, R., Costi, R., and La Colla, P. 2005. 6-[1-(4-Fluorophenyl)methyl-1H-pyrrol-2-yl)]- 2,4-dioxo-5-hexenoic acid ethyl ester a novel diketo acid derivative which selectively inhibits the HIV-1 viral replication in cell culture and the ribonuclease H activity in vitro. Antiv. Res. 65, 117–124.

    Article  CAS  Google Scholar 

  • Xiao, W., Wang, R., Zhao, W., Tian, R., Shang, S., Yang, L., and Yang, J. 2010. Anti-HIV-1 activity of lignans from the fruits of Schisandra rubriflora. Arch. Pharm. Res. 33, 697–701.

    Article  CAS  PubMed  Google Scholar 

  • Xu, M., Wang, G., Xie, H., Wang, R., Wang, W., Li, X., Li, H., Zhu, D., and Yue, L. 2005. Determination of schizandrin in rat plasma by high-performance liquid chromatography-mass spectrometry and its application in rat pharmacokinetic studies. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 828, 55–61.

    Article  CAS  PubMed  Google Scholar 

  • Yu, D., Morris-Natschke, S.L., and Lee, K.H. 2007. New developments in natural products-based anti-AIDS research. Med. Res. Rev. 1, 108–132.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Medicinal Plant Development (IMPLAD), 151 Malianwa North Road Haidian District, 100193, Beijing, P. R. China

    Lijia Xu

  2. Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy

    Nicole Grandi, Daniela Mandas, Angela Corona, Dario Piano, Francesca Esposito & Enzo Tramontano

  3. Department of Molecular Medicine, University of Padova, via Gabelli 63, 35121, Padova, Italy

    Claudia Del Vecchio & Cristina Parolin

Authors
  1. Lijia Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicole Grandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia Del Vecchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniela Mandas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angela Corona
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dario Piano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francesca Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cristina Parolin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Enzo Tramontano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesca Esposito.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, L., Grandi, N., Del Vecchio, C. et al. From the traditional Chinese medicine plant Schisandra chinensis new scaffolds effective on HIV-1 reverse transcriptase resistant to non-nucleoside inhibitors. J Microbiol. 53, 288–293 (2015). https://doi.org/10.1007/s12275-015-4652-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12275-015-4652-0

Keywords

Search

Navigation