Research on substances with activity against orthopoxviruses
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Biological Threats Identification and Countermeasure Center, Military Institute of Hygiene and Epidemiology, Puławy, Poland
Military Institute of Hygiene and Epidemiology, Warsaw, Poland
Department of Epidemiology, Medical University, Warsaw, Poland
Marcin Kołodziej   

Biological Threats Identification and Countermeasure Center, Military Institute of Hygiene and Epidemiology, Puławy, Poland
Ann Agric Environ Med. 2013;20(1):1–7
Although smallpox was eradicated over 30 years ago, the disease remains a major threat. High mortality, high infectivity and low resistance of the contemporary population make the smallpox virus very attractive to terrorists. The possible presence of illegal stocks of the virus or risk of deliberate genetic modifications cause serious concerns among experts. Hence, it is reasonable to seek effective drugs that could be used in case of smallpox outbreak. This paper reviews studies on compounds with proven in vitro or in vivo antipoxviruses potential, which show various mechanisms of action. Nucleoside analogues, such as cidofovir, can inhibit virus replication. Cidofovir derivatives are developed to improve the bioavailability of the drug. Among the nucleoside analogues under current investigation are: ANO (adenozine N1-oxide) and its derivatives, N-methanocarbothymidine [(N)-MCT], or derivatitives of aciklovir, peninclovir and brivudin. Recently, ST-246 – which effectively inhibits infection by limiting release of progeny virions – has become an object of attention. It has been also been demonstrated that compounds such as: nigericin, aptamers and peptides may have antiviral potential. An interesting strategy to fight infections was presented in experiments aimed at defining the role of individual genes (E3L, K3L or C6L) in the pathogenesis, and looking for their potential blockers. Additionally, among substances considered to be effective in the treatment of smallpox cases, there are factors that can block viral inhibitors of the human complement system, epidermal growth factor inhibitors or immunomodulators. Further studies on compounds with activity against poxviruses are necessary in order to broaden the pool of available means that could be used in the case of a new outbreak of smallpox.
Niemiałtowski M, Szulc L, Boratyńska A, Martyniszyn L, Struzik J, Karandys J. Ospa prawdziwa: patrząc wstecz od Edwarda Jennera, a nawet trochę dalej (Smallpox: looking back to Edward Jenner and even a little further). Post Mikrob. 2009; 48(4): 289-298 (in Polis).
Duraffour S, Meyer H, Andrei G, Snoeck R. Camelpox virus. Antivir Res. 2011; 92(2): 167-186.
Henderson DA, Inglesby TV, Bartlett JG, Ascher MS, Eitzen E, Jahrling PB, et al. Smallpox as a biological weapon. JAMA. 1999; 281: 2127-2137.
Johnson RF, Yellayi S, Cann JA, Johnson A, Smith AL, Paragas J, et al. Cowpox virus infection of cynomolgus macaques as a model of hemorrhagic smallpox. Virology. 2011; 418: 102-112.
Baker RO, Bray M, Huggins JW. Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections. Antivir Res. 2003; 57: 13-23.
Fan X, Zhang X, Zhou L, Keith KA, Kern ER, Torrence PF. A pyrimidine-pyrazolone nucleoside chimer with potent in vitro anti-orthopoxvirus activity. Bioorg Med Chem Lett. 2006; 16: 3224-3228.
Painter GR, Hostetler KY. Design and development of oral drugs for the prophylaxis and treatment of smallpox infection. Trends Biotechnol. 2004; 22(8): 423-427.
Fenner F, Henderson DA, Arita I, Ježek, Ladnyi ID. Smallpox in non-endemic countries. In: Fenner F, Henderson DA, Arita I, Ježek, Ladnyi ID. Smallpox and its eradication. WHO, Geneva 1988.p.1069-1101.
Myskiw C, Piper J, Huzarewich R, Booth TF, Cao J, He R. Nigericin is potent inhibitor of the early stage of vaccinia replication. Antivir Res. 2010; 88: 304-310.
Aquino LL, Wu JJ. Cutaneous manifestations of category A bioweapons. J Am Acad Dermatol. 2011; 65(6): 1213.e1-1213.e15.
Joniec J, Kołodziej M, Bartoszcze M, Kocik J, Knap J. Research on prevention and treatment of hemorrhagic fevers. Ann Agr Env Med. 2012; 19(2): 165-171.
Saccucci L, Crance J-M, Colas P, Bickle M, Garin D, Iseni F. Inhibition of vaccinia virus replication by peptide aptamers. Antivir Res. 2009; 82: 134-140.
Becker MN, Obraztsova M, Kern ER, Quenelle DC, Keith KA, Prichard MN, et al. Isolation and characterization of cidofovir resistant vaccinia viruses. Virol J. 2008; 5(58).
De Clercq E. Cidofovir in the therapy and short-term prophylaxis of poxvirus infections. Trends Pharmacol Sci. 2002; 23(10): 456-458.
Smee DF, Bailey KW, Wong M-H, Sidwell RW. Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antivir Res. 2001; 52: 55-62.
Smee DF, Wong M-H, Bailey KW, Beadle JR, Hostetler KY, Sidwell RW. Effects of four antiviral substances on lethal vaccinia virus (IHD strain) respiratory infections in mice. Int J Antimicrob Ag. 2004; 23: 430-437.
Keith KA, Hitchcock MJM, Lee WA, Holý A, Kern ER. Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication. Antimicrob Agents Ch. 2003; 47(7): 2193-2198.
Sauberei A, Meier C, Meerbach A, Schiel M, Helbig B, Wutzler P. In vitro activity od cycloSal-nucleoside monophosphates and polyhydroxy-carboxylates against othopoxvirus. Antivir Res. 2005; 67: 147-154.
Kane EM, Shuman S. Adenosine N 1 -Oxide Inhibits Vaccinia Virus Replication by blocking Translation of Viral Early mRNAs. J Virol. 1995; 69(10): 6352-6358.
Khandazhinskaya AL, Shirokova EA, Shipitsin AV, Karpenko IL, Belanov EF, Kukhanova MK et al. Adenosine N 1 -Oxide Analogues as Inhibitors of Orthopox Virus Replication Collect Czech Chem C. 2006; 71(7); 1107-1121.
Smee DF, Hurst BL, Wong M-H, Glazer RI, Rahman A, Sidewell RW. Efficacy of N-methanocarbathymidine in treating mice infected intranasally with the IHD and WR strains of vaccinia virus. Antivir Res. 2007; 76: 124-129.
Chu CK, Jin YH, Baker RO, Huggins J. Antiviral Activity od Cyclopentenyl Nucleosides Against Orthopox Viruses (Smallpox, Monkeypox and Cowpox). Bioorg Med Chem Lett. 2003; 13: 9-12.
Yang H, Pevear DC, Davies MH, Collett MS, Bailey T, Rippen S, et al. An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects from Lethal Orthopoxvirus Challenge. J Virol. 2005; 79(20): 13139-13149.
Quenelle DC, Buller RML, Parker S, Keith KA, Hruby DE, Jordan R, et al. Efficacy of Delayed Treatment with ST-246 Given Orally against Systemic Orthopoxvirus infections in Mice. Antimicrob Agents Ch. 2007; 51(2): 689-695.
Huggins J, Goff A, Eric M, Twenhafel N, Chapman J, Tate M, et al. Successful Treatment in the Monkeypox and Variola Primate Models of Smallpox by the Oral Drug ST-246. Antivir Res. 2007; 74: A1-A74(A35).
Silvermann JEY, Ciustea M, Shudofsky AMD, Bender F, Shoemaker RH, Ricciardi RP. Identification of polymerase and processivity inhibitors of vaccinia DNA synthesis using a stepwise screening approach. Antivir Res. 2008; 80: 114-123.
Dower K, Filone CM, Hodges EN, Bjornson ZB, Rubins KH, Brown LE, et al. Identification of pyridopyrimidinone inhibitor of orthopoxviruses from a diversity-oriented synthesis library. J Virol. 2012; 86(5): 2632-2640.
Bauer DJ, St Vincent L, Kempe CH, Downie AW. Prophylactic treatment of smallpox contacts with N-metylisatin β-thiosemicarbazone (compound 33t57, marboran). Lancet. 1963; 35: 494-496.
Borysiewicz J, Witaliński W. Effect of N,N’-bis(methylisatin-β-thio-semicarbazone)-2-methylpiperazine on vaccinia virus replication in vitro and in vivo. Brief report. Antimicrob Agents Ch. 1979; 62(1): 83-86.
Woodson B, Joklik WK. The inhibition of vaccinia virus multiplication by isatin-β-thiosemicarbazone. PNAS. 1965; 54(3): 946-953.
Neyts J, De Clercq E. Therapy and short-term prophylaxis of poxvirus infections: historical background and perspectives. Antivir Res. 2003; 57: 25-33.
Quenelle DC, Keith KA, Kern ER. In vitro and in vivo evaluation of isatin-β-thiosemicarbazone and marboran against vaccinia and cowpox virus infections. Antivir Res. 2006; 71: 24-30.
Prins C, Cresawn SG, Condit RC. An Isatin-β-thiosemicarbazone-resistant vaccinia virus containing a mutation in the second largest subunit of the viral RNA polymerase is defective in transcription elongaction. J Biol Chem. 2004; 279(43): 44858-44871.
Prichard MN, Kern ER. Orthopoxvirus Targets for the Development of Antiviral Therapies. Curr Drug Targets – Infections Disorders. 2005; 5: 17-28.
Black EP, Condit RC. Phenotypic Characteriszation of mutans in Vaccinia Virus Gene G2R, a Putative Transcription Elongation Factor. J Virol. 1996; 70(1): 47-54.
Kołodziej M, Joniec J, Bartoszcze M, Mirski T, Gryko R. Peptydy – nowe możliwości zwalczania zakażeń wirusowych. Przegl Epidemiol. 2011; 65: 477-482.
Meyer C, Hahn U, Rentmeister A. Cell-Specific Aptamers as Emerging Therapeutics. J Nucleic Acids. 2011; doi:10.4061/2011/904750.
Altmann SE, Jones JC, Schultz-Cherry S, Brandt CR. Inhibition of Vaccinia virus entry by a broad spectrum antiviral peptide. Virology. 2009; 388: 248-259.
Tarbet EB, Larson D, Anderson BJ, Bailey KW, Wong M-H, Smee DF. Evaluation of imiquimod for topical treatment of vaccinia virus cutaneous infections in immunosuppressed hairless mice. Antivir Res. 2011; 90: 126-133.
Perino J, Crouzier D, Spehner D, Debouzy J-C, Garin D, Crance J-M, et al. Lung surfactant DPPG phospholipid inhibits vaccinia virus infection. Antivir Res. 2011; 89: 89-97.
Deptała A, Soborczyk A, Krajewska K. Leczenie interferujące z funkcją receptora dla naskórkowego czynnika wzrostu (EGFR) u chorych na raka gruczołu krokowego (The treatment interfering with EGFR in prostate cancer patients). Onkol Prak Klin. 2011; 7(4): 208-214 (in Polish).
Wcisło G, Szczylik C. Szlak sygnałowy receptora naskórkowego czynnika wzrostu (EGFR) i potencjalne zastosowanie kliniczne jego blokowania w raku nerki (Inhibition of molecular signaling of epidermal growth factor receptor (EGFR) and its clinical potential for treating renal cell cancer). Onkol Prak Klin. 2011; 7(4): 197-207.
Langhammer S, Koban R, Yue C, Ellerbrok H. Inhibition of poxvirus spreading by the anti-tumor drug Gefitinib (Iressa). Antivir Res. 2011; 89: 64-70.
Brandt TA, Jacobs BL. Both Carboxy- and Amino-Terminal Domains of the Vaccinia Virus Interferon Resistance Gene, E3L, Are Required for Pathogenesis in a Mouse Model. J Virol. 2001; 75(2): 850-856.
Kwon J-A, Rich A. Biological function of the vaccinia virus Z-DNA-binding protein E3L: Gene transactivation and antiapoptotic activity in HeLa cells. PNAS. 2005; 102(36): 12759-12764.
Rice AD, Turner PC, Embury JE, Moldawer LL, Baker HV, Moyer RW. Roles of Vaccinia Virus Gene E3L and K3L and Host Genes PKR and RNase L during Intratracheal Infection of C57BL/6 Mice. J Virol. 2011; 85(1): 550-567.
Dave RS, McGettigan JP, Quereshi T, Schnell MJ, Nunnari G, Pomerantz RJ. siRNA targeting Vaccinia virus double-stranded RNA binding protein [E3L] exerts potent antiviral effects. Virology. 2006; 348: 489-497.
Li W-X, Li H, Lu R, Li F, Dus M, Atkinson P, et al. Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. PNAS. 2004; 101(5): 1350-1355.
Lantermann M, Schwantes A, Sliva K, Sutter G, Schnierle BS. Vaccinia virus double-stranded RNA-binding protein E3 does not interfere with siRNA-mediated gene silencing in mammalian cells. Virus Res. 2007; 126: 1-8.
Unterholzner L, Sumner RP, Baran M, Ren H, Mansur DS, Bourke NM, et al. Vaccinia Virus Protein C6 Is a Virulence Factor that Binds TBK-1 Adaptor Proteins and Inhibits Activation of IRF3 and IRF7. PLoS Pathog. 2011; 7(9): e1002247. doi:10.1371/journal.ppat.1002247.
Rosengard AM, Liu Y, Nie Z, Jimenez R. Variola virus immune evasion design: Expression of a highly efficient inhibitor of human complement. PNAS. 2002; 99(13): 8808-8813.
Liszewski MK, Leung MK, Hauhart R, Mark R, Buller L, Bertram P, et al. Structure and Regulatory Profile of the Monkeypox Inhibitor of Complement: Comparison to Homologs in Vaccinia and Variola and Evidence for Dimer Formation. J Immunol. 2006; 176(6): 3725-3734.
Liszewski MK, Leung MK, Hauhart R, Fang CJ, Bertram P, Atkinson JP. Smallpox Inhibitor of Complement Enzymes (SPICE): Dissecting Functional Sites and Abrogating Activity. J Immunol. 2009; 183(5): 3150-3159.