Abstract
Harringtonine (HT) and homoharringtonine (HHT), alkaloid esters isolated from the genus Cephalotaxus, exhibit antitumor activity. A semisynthetic HHT has been approved for treatment of chronic myelogenous leukemia. In addition to antileukemic activity, HT and HHT are reported to possess potent antiviral activity. In this study, we investigated the effects of HT and HHT on replication of varicella-zoster virus (VZV) in vitro. HT and HHT, but not their biologically inactive parental alkaloid cephalotaxine (CET), significantly inhibited replication of recombinant VZV-pOka luciferase. Furthermore, HT and HHT, but not CET, strongly induced down-regulation of VZV lytic genes and exerted potent antiviral effects against a VZV clinical isolate. The collective data support the utility of HT and HHT as effective antiviral candidates for treatment of VZV-associated diseases.
Keywords: varicella zoster virus, antiviral, harringtonine, homoharringtonine
References
- Arvin A.M. Varicella-zoster virus. Clin. Microbiol. Rev. 1996;9:361–381. doi: 10.1128/CMR.9.3.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arvin A.M. Antiviral therapy for varicella and herpes zoster. Semin. Pediatr. Infect. Dis. 2002;13:12–21. doi: 10.1053/spid.2002.29753. [DOI] [PubMed] [Google Scholar]
- Arvin A., Gilden D. In Knipe, D.M. and Howley, P.M. (eds.), Fields virology, Philadelphia (Pennsylvania): Lippincott Williams & Wilkins. 2013. Varicella-zoster virus, pp. pp. 2015–2057. [Google Scholar]
- Bae S., Kim S.Y., Do M.H., Lee C.H., Song Y.J. 1,2,3,4,6-penta-O-galloyl-ß-D-glucose, a bioactive compound in Elaeocarpus sylvestris extract, inhibits varicella-zoster virus replication. Antiviral Res. 2017;144:266–272. doi: 10.1016/j.antiviral.2017.06.018. [DOI] [PubMed] [Google Scholar]
- Bae S., Song Y.J. Inhibition of varicellazoster virus replication by an ethanol extract of Lysimachia mauritiana. Mol. Med. Rep. 2017;15:3847–3851. doi: 10.3892/mmr.2017.6444. [DOI] [PubMed] [Google Scholar]
- Cao J., Forrest J.C., Zhang X. A screen of the NIH clinical collection small molecule library identifies potential anticoronavirus drugs. Antiviral Res. 2015;114:1–10. doi: 10.1016/j.antiviral.2014.11.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen R., Guo L., Chen Y., Jiang Y., Wierda W.G., Plunkett W. Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. Blood. 2011;117:156–164. doi: 10.1182/blood-2010-01-262808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen J.I., Brunell P.A., Straus S.E., Krause P.R. Recent advances in varicella-zoster virus infection. Ann. Intern. Med. 1999;130:922–932. doi: 10.7326/0003-4819-130-11-199906010-00017. [DOI] [PubMed] [Google Scholar]
- Fresno M., Jimenez A., Vazquez D. Inhibition of translation in eukaryotic systems by harringtonine. Eur. J. Biochem. 1977;72:323–330. doi: 10.1111/j.1432-1033.1977.tb11256.x. [DOI] [PubMed] [Google Scholar]
- Gnann J.W., Jr . Antiviral therapy of varicella-zoster virus infections. 2007. [PubMed] [Google Scholar]
- Huang M.T. Harringtonine, an inhibitor of initiation of protein biosynthesis. Mol. Pharmacol. 1975;11:511–519. [PubMed] [Google Scholar]
- Ida M., Kageyama S., Sato H., Kamiyama T., Yamamura J., Kurokawa M., Morohashi M., Shiraki K. Emergence of resistance to acyclovir and penciclovir in varicella-zoster virus and genetic analysis of acyclovir-resistant variants. Antiviral Res. 1999;40:155–166. doi: 10.1016/S0166-3542(98)00057-6. [DOI] [PubMed] [Google Scholar]
- Jeon J.S., Won Y.H., Kim I.K., Ahn J.H., Shin O.S., Kim J.H., Lee C.H. Analysis of single nucleotide polymorphism among varicella-zoster virus and identification of vaccine-specific sites. Virology. 2016;496:277–286. doi: 10.1016/j.virol.2016.06.017. [DOI] [PubMed] [Google Scholar]
- Jia K., Yuan Y., Liu W., Liu L., Qin Q., Yi M. Identification of inhibitory compounds against Singapore grouper iridovirus infection by cell viability-based screening assay and droplet digital PCR. Mar. Biotechnol. (NY) 2018;20:35–44. doi: 10.1007/s10126-017-9785-1. [DOI] [PubMed] [Google Scholar]
- Kaur P., Thiruchelvan M., Lee R.C., Chen H., Chen K.C., Ng M.L., Chu J.J. Inhibition of chikungunya virus replication by harringtonine, a novel antiviral that suppresses viral protein expression. Antimicrob. Agents Chemother. 2013;57:155–167. doi: 10.1128/AAC.01467-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim J.E., Kim S.Y., Lim S.Y., Kieff E., Song Y.J. Role of Ca2+/calmodulin-dependent kinase II-IRAK1 interaction in LMP1-induced NF-kappaB activation. Mol. Cell. Biol. 2014;34:325–334. doi: 10.1128/MCB.00912-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lu S., Wang J. Homoharringtonine and omacetaxine for myeloid hematological malignancies. J. Hematol. Oncol. 2014;7:2. doi: 10.1186/1756-8722-7-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morfin F., Thouvenot D., De Turenne-Tessier M., Lina B., Aymard M., Ooka T. Phenotypic and genetic characterization of thymidine kinase from clinical strains of varicellazoster virus resistant to acyclovir. Antimicrob. Agents Chemother. 1999;43:2412–2416. doi: 10.1128/AAC.43.10.2412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Powell R.G., Weisleder D., Smith J. C.R. Antitumor alkaloids for Cephalataxus harringtonia: Structure and activity. J. Pharm. Sci. 1972;61:1227–1230. doi: 10.1002/jps.2600610812. [DOI] [PubMed] [Google Scholar]
- Quintas-Cardama A., Kantarjian H., Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa2009. Cancer. 2009;115:5382–5393. doi: 10.1002/cncr.24601. [DOI] [PubMed] [Google Scholar]
- Romero M.R., Serrano M.A., Efferth T., Alvarez M., Marin J.J. Effect of cantharidin, cephalotaxine and homoharringtonine on “in vitro” models of hepatitis B virus (HBV) and bovine viral diarrhoea virus (BVDV) replication. Planta Med. 2007;73:552–558. doi: 10.1055/s-2007-967184. [DOI] [PubMed] [Google Scholar]
- Tujebajeva R.M., Graifer D.M., Matasova N.B., Fedorova O.S., Odintsov V.B., Ajtkhozhina N.A., Karpova G.G. Selective inhibition of the polypeptide chain elongation in eukaryotic cells. Biochim. Biophys. Acta. 1992;1129:177–182. doi: 10.1016/0167-4781(92)90484-H. [DOI] [PubMed] [Google Scholar]
- Zhang Z., Rowe J., Wang W., Sommer M., Arvin A., Moffat J., Zhu H. Genetic analysis of varicella-zoster virus ORF0 to ORF4 by use of a novel luciferase bacterial artificial chromosome system. J. Virol. 2007;81:9024–9033. doi: 10.1128/JVI.02666-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhou D.C., Zittoun R., Marie J.P. Homoharringtonine: An effective new natural product in cancer chemotherapy. Bull. Cancer. 1995;82:987–995. [PubMed] [Google Scholar]