Abstract
Poxviruses have been recognized for centuries as a threat for human health. The most dreadful representative of the family, Variola virus, responsible for smallpox, was eradicated last century, after a wide and intensive campaign of vaccination. Meanwhile, the importance of other poxviruses has been recognized in human pathology, as well as the possible use of microbial agents, including smallpox, by bioterrorists. Together with the development of safer vaccination approaches, the research on antivirals has already led to the discovery of several families of active therapeutic compounds. The increased understanding of the viral replication and pathogenicity, as well as improvements in pharmacokinetics has led to the development of new and promising classes of compounds. These new molecules are either prodrugs giving better bioavailability, or compounds interfering with new molecular targets, both viral and cellular. Over the last few years, these latter developments have opened new opportunities for the treatment of poxvirus infections, and are discussed in this chapter.
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References
Berche P (2001) The threat of smallpox and bioterrorism. Trends Microbiol 9: 15–18
Breman JG, Arita I (1980) The confirmation and maintenance of smallpox eradication. N Engl J Med 303: 1263–1273
Behbehani AM (1983) The smallpox story: life and death of an old disease. Microbiol Rev 47: 455–509
Di Giulio DB, Eckburg PB (2004) Human monkeypox: an emerging zoonosis. Lancet Infect Dis 4: 15–25
De Clercq E (2001) Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections. Clin Microbiol Rev 14: 382–397
Bauer DJ, St. Vincent L, Kempe CH, Downie AW (1963) Prophylactic treatment of smallpox contacts with N-methylisatin β-thiosemicarbazone. Lancet ii: 494–496
Hamre D, Brownlee KA, Donovick R (1951) Studies on the chemotheray of vaccinia virus. II. The activity of some thiosemicarbazones. J Immunol67: 305–312
De Clercq E (2003) Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev 16: 569–596
De Clercq E (2005) Recent highlights in the development of new antiviral drugs. Curr Opin Microbiol 8: 552–560
Roy A, Schneller SW, Keith KA, Hartline CB, Kern ER (2005) The 4’,4’-difluoro analog of 5’-noraristeromycin: a new structural prototype for possible antiviral drug development toward orthopoxvirus and cytomegalovirus. Bioorg Med Chem 13: 4443–4449
Smee DF, Sidwell RW (2003) A review of compounds exhibiting anti-orthopoxvirus activity in animal models. Antiviral Res 57: 41–52
Kim M, Yang H, Kim SK, Reche PA, Tirabassi RS, Hussey RE, Chishti Y, Rheinwald JG, Morehead TJ, Zech T et al (2004) Biochemical and functional analysis of smallpox growth factor (SPGF) and anti-SPGF monoclonal antibodies. J Biol Chem 279: 25838–25848
Tzahar E, Moyer JD, Waterman H, Barbacci EG, Bao J, Levkowitz G, Shelly M, Strano S, Pinkas-Kramarski R, Pierce JH et al (1998) Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network. EMBO J 17: 5948–5963
Buller RM, Chakrabarti S, Cooper JA, Twardzik DR, Moss B (1988) Deletion of the vaccinia virus growth factor gene reduces virus virulence. J Virol 62: 866–874
Opgenorth A, Nation N, Graham K, McFadden G (1993) Transforming growth factor alpha, Shope fibroma growth factor, and vaccinia growth factor can replace myxoma growth factor in the induction of myxomatosis in rabbits.Virology 192: 701–709
Fauci AS, Challberg MD (2005) Host-based antipoxvirus therapeutic strategies: turning the tables. J Clin Invest 115: 231–233
Yang H, Kim S-K, Kim M, Reche PA, Morehead TJ, Damon IK, Welsh RM, Reinherz EL (2005) Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction. J Clin Invest 115: 379–387
Smith GL, Law M (2004) The exit of vaccinia virus from infected cells. Virus Res 106: 189–197
Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D et al (2005) Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med 11: 731–739
McFadden G (2005) Gleevec casts a pox on poxviruses. Nat Med 11: 711–712
Wolffe EJ, Weisberg AS, Moss B (1998) Role for the vaccinia virus A36R outer envelope protein in the formation of virus-tipped actin-containing microvilli and cell-to-cell virus spread. Virology 244: 20–26
Parkinson JE, Smith GL (1994) Vaccinia virus gene A36R encodes a M(r) 43-50 K protein on the surface of extracellular enveloped virus. Virology 204: 376–390
Frischknecht F, Moreau V, Rottger S, Gonfloni S, Reckmann I, Superti-Furga G, Way M (1999) Actin-based motility of vaccinia virus mimics receptor tyrosine kinase signaling. Nature 401: 926–929
Hasobe M, McKee JG, Borcherding DR, Borchardt RT (1987) 9-(Trans-2’, trans-3’-dihydroxycyclopent-4’-enyl)-adenine and-3-deazaadenine: analogs of neplanocin A which retain potent antiviral activity but exhibit reduced cytotoxicity. Antimicrob Agents Chemother 31: 1849–1851
Neyts J, De Clercq E (2003) Therapy and short-term prophylaxis of poxvirus infections: historical background and perspectives. Antiviral Res 57: 25–33
Walton E, Jenkins SR, Nutt RF, Holly FW, Nemes M (1969) Branched-chain sugar nucleosides. V. Synthesis and antiviral properties of several branchedchain sugar nucleosides. J Med Chem 12: 306–309
Van Aerschot A, Mamos AP, Weyns NJ, Ikeda S, De Clercq E, Herdewijn P (1993) Antiviral activity of C-alkylated purine nucleosides obtained by crosscoupling with tetraalkyltin reagents. J Med Chem 36: 2938–2942
Neyts J, Andrei G, Snoeck R, Jähne G, Winkler I, Helsberg M, Balzarini J, De Clercq E (1994) The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication. Antimicrob Agents Chemother 38: 2710–2716
Neyts J, Balzarini J, Andrei G, Chaoyong Z, Snoeck R, Zimmerman A, Mertens T, Karlsson A, De Clercq E (1998) Intracellular metabolism of the N7-substituted acyclic nucleoside analog 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine, a potent inhibitor of herpesvirus replication. Mol Pharmacol 53: 157–165
Neyts J, Jähne G, Andrei G, Snoeck R, Winkler I, De Clercq E (1995) In vivo antiherpesvirus activity of N-7-substituted acyclic nucleoside analog 2-amino-7[(1,3-dihydroxy-2-propoxy)methyl]purine. Antimicrob Agents Chemother 39: 56–60
Neyts J, De Clercq E (2001) Efficacy of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine for the treatment of vaccinia (orthopox-) virus infections in mice. Antimicrob Agents Chemother 45: 84–87
Neyts J, De Clercq E (2002) Effect of 5-iodo-2’-deoxyuridine on vaccinia virus (orthopoxvirus) infections in mice. Antimicrob Agents Chemother 46: 2842–2847
De Clercq E, Holý A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC (1986) A novel selective broad-spectrum anti-DNA virus agents. Nature 323: 464–467
De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Holý A (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8: 261–272
De Clercq E, Neyts J (2004) Therapeutic potential of nucleoside/nucleotide analogues against poxvirus infections. Rev Med Virol 14: 289–300
Naesens L, Snoeck R, Andrei G, Balzarini J, Neyts J, De Clercq E (1997) HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: a review of their pharmacology and clinical potential in the treatment of viral infections. Antiviral Chem Chemother 8: 1–23
De Clercq E (2002) Cidofovir in the treatment of poxvirus infections. Antiviral Res 55: 1–13
Magee WC, Hostetler KY, Evans DH (2005) Mechanism of inhibition of vaccinia virus DNA polymerase by cidofovir diphosphate. Antimicrob Agents Chemother 49: 3153–3162
Snoeck R, Holý A, Dewolf-Peeters C, Van Den Oord J, De Clercq E, Andrei G (2002) Antivaccinia activities of acyclic nucleoside phosphonate derivatives in epithelial cells and organotypic cultures. Antimicrob Agents Chemother 46: 3356–3361
Dal Pozzo F, Andrei G, Holý A, Van Den Oord J, Scagliarini A, De Clercq E, Snoeck R (2005) Activities of acyclic nucleoside phosphonates against orf virus in human and ovine cell monolayers and organotypic ovine raft cultures. Antimicrob Agents Chemother 49: 4843–4852
Hocková D, Holý A, Masojidková M, Andrei G, Snoeck R, De Clercq E, Balzarini J (2004) Synthesis and antiviral activity of 2,4-diamino-5-cyano-6-[2-(phosphonomethoxy)ethoxy]pyrimidine and related compounds. Bioorg Med Chem 12: 3197–3202
Balzarini J, Pannecouque C, Naesens L, Snoeck R, De Clercq E, Hocková D, Holý A (2004) 6-[(Phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines, a new class of acyclic pyrimidine nucleoside phosphonates with antiviral activity. Nucleosides Nucleotides Nucleic Acids 23: 243–249
Lalezari JP, Stagg RJ, Kuppermann BD, Holland GN, Kramer F, Ives DV, Youle M, Robinson MR, Drew WL, Jaffe HS (1997) Intravenous cidofovir for periph eral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med 126: 257–263
Lacy SA, Hitchcock MJM, Lee WA, Tellier P, Cundy KC (1998) Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol Sci 44: 97–106
Smee DF, Sidwell RW, Kefauver D, Bray M, Huggins JW (2002) Characterization of wild-type and cidofovir-resistant strains of camelpox, cowpox, monkeypox, and vaccinia viruses. Antimicrob Agents Chemother 46: 1329–1335
Smee DF, Wandersee MK, Bailey KW, Hostetler KY, Holý A, Sidwell RW (2005) Characterization and treatment of cidofovir-resistant vaccinia (WR strain) virus infections in cell culture and mice. Antiviral Chem Chemother 16: 203–211
Painter GR, Hostetler KY (2004) Design and development of oral drugs for the prophylaxis and treatment of smallpox infection. Trends Biotechnol 22: 423–427
Ciesla SL, Trahan J, Wan WB, Beadle JR, Aldern KA, Painter GR, Hostetler KY (2003) Esterification of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney. Antiviral Res 59: 163–171
Aldern KA, Ciesla SL, Winegarden KL, Hostetler KY (2003) Increased antiviral activity of 1-0-hexadecyloxopropyl-[2-14C] cidofovir in MRC-5 human lung fibroblasts is explained by unique cellular uptake and metabolism. Mol Pharmacol 63: 678–681
Keith KA, Wan WB, Ciesla SL, Beadle JR, Hostetler KY, Kern ER (2004) Inhibitory activity of alkoxyalkyl and alkyl esters of cidofovir and cyclic cidofovir against orthopoxvirus replication in vitro. Antimicrob Agents Chemother 48: 1869–1871
Kern ER, Hartline C, Harden E, Keith K, Rodriguez N, Beadle JR, Hostetler KY (2002) Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir. Antimicrob Agents Chemother 46: 991–995
Hartline CB, Gustin KM, Wan WB, Ciesla SL, Beadle JR, Hostetler KY, Kern ER (2005) Ether lipid-ester prodrugs of acyclic nucleoside phosphonates: activity against adenovirus replication in vitro. J Infect Dis 191: 396–399
Wan WB, Beadle JR, Hartline C, Kern ER, Ciesla SL, Valiaeva N, Hostetler KY (2005) Comparison of the antiviral activities of alkoxyalkyl and alkyl esters of cidofovir against human and murine cytomegalovirus replication in vitro. Antimicrob Agents Chemother 49: 656–662
Neyts J, De Clercq E (1993) Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethox ypropyl)cytosine for the treatment of lethal vaccinia virus infections in severe combined immune deficiency (SCID) mice. J Med Virol 41: 242–246
Smee DF, Bailey KW, Sidwell RW (2001) Treatment of lethal vaccinia virus respiratory infections in mice with cidofovir. Antiviral Chem Chemother 12: 71–76
Smee DF, Bailey KW, Wong MH, Sidwell RW (2001) Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antiviral Res 52: 55–62
Bray M, Martinez M, Smee DF, Kefauver D, Thompson E, Huggins JW (2000) Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J Infect Dis 181: 10–19
Smee DF, Bailey KW, Wong M, Sidwell RW (2000) Intranasal treatment of cowpox virus respiratory infections in mice with cidofovir. Antiviral Res 47: 171–177
Bray M, Martinez M, Kefauver D, West M, Roy C (2002) Treatment of aerosolized cowpox virus infection in mice with aerosolized cidofovir. Antiviral Res 54: 129–142
Robbins SJ, Jackson RJ, Fenner F, Beaton S, Medveczky J, Ramshaw IA, Ramsay AJ (2005) The efficacy of cidofovir treatment of mice infected with ectromelia (mousepox) virus encoding interleukin-4. Antiviral Res 66: 1–7
De Clercq E, Andrei G, Balzarini J, Leyssen P, Naesens L, Neyts J, Pannecouque C, Snoeck R, Ying C, Hocková D, Holý A (2005) Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethox y)alkoxy]-2,4-diaminopyrimidines. Nucleosides Nucleotides Nucleic Acids 24: 331–341
Smee DF, Wong M-H, Bailey KW, Beadle JR, Hostetler KY, Sidwell RW (2004) Effects of four antiviral substances on lethal vaccinia virus (IHD strain) respiratory infections in mice. Int J Antimicrob Agents 23: 430–437
Buller RM, Owens G, Schriewer J, Melman L, Beadle JR, Hostetler KY (2004) Efficacy of oral active ether lipid analogs of cidofovir in a lethal mousepox model. Virology 318: 474–481
Quenelle DC, Collins DJ, Wan WB, Beadle JR, Hostetler KY, Kern ER (2004) Oral treatment of cowpox and vaccinia virus infections in mice with ether lipid esters of cidofovir. Antimicrob Agents Chemother 48: 404–412
Lu S, Cheng L, Hostetler KY, Koh HJ, Beadle JR, Davidson MC, Freeman WR (2005) Intraocular properties of hexadecyloxypropyl-cyclic-cidofovir in Guinea pigs. J Ocul Pharmacol Ther 21: 205–209
Meadows KP, Tyring SK, Pavia AT, Rallis TM (1997) Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. Arch Dermatol 133: 987–990
Ibarra V, Blanco JR, Oteo JA, Rosel L (2000) Efficacy of cidofovir in the treatment of recalcitrant molluscum contagiosum in an AIDS patient. Acta Derm Venereol 80: 315–316
Geerinck K, Lukito G, Snoeck R, De Vos R, De Clercq E, Vanrenterghem Y, Degreef H, Maes B (2001) A case of human orf in an immunocompromised patient treated successfully with cidofovir cream. J Med Virol 64: 543–549
Kile JC, Fleischauer AT, Beard B, Kuehnert MJ, Kanwal RS, Pontones P, Messersmith HJ, Teclaw R, Karem KL, Braden ZH, Damon I, Khan AS, Fisher M (2005) Transmission of monkeypox among persons exposed to infected prairie dogs in Indiana in 2003. Arch Pediatr Adolesc Med 159: 1022–1025
Anderson MG, Frenkel LD, Homann S, Guffey J (2003) A case of severe monkeypox virus disease in an American child: emerging infections and changing professional values. Pediatr Infect Dis J 22: 1093–1096
Abu-Daya A, Brown PM, Fox KR (1995) DNA sequence specificity of several AT-selective minor groove binding ligands. Nucleic Acids Res 23: 3385–3392
Broyles SS, Kremer M, Knutson BA (2004) Antiviral activity of distamycin A against vaccinia virus is the result of inhibition of postreplicative mRNA synthesis. J Virol 78: 2137–2141
Byrd CM, Bolken TC, Mjalli AM, Arimilli MN, Andrews RC, Rothlein R, Andrei T, Rao M, Owens KL, Hruby DE (2004) New class of orthopoxvirus antiviral drugs that block viral maturation. J Virol 78: 12147–12156
Byrd CM, Bolken T, Hruby DE (2002) The vaccinia virus I7L gene product is the core protein proteinase. J Virol 76: 8973–8976
Byrd CM, Bolken TC, Hruby DE (2003) Molecular dissection of the vaccinia virus I7L core protein proteinase. J Virol 77: 11279–11283
Yang G, Pevear DC, Davies MH, Collett MS, Bailey T, Rippen S, Barone L, Burns C, Rhodes G, Tohan S et al (2005) An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge. J Virol 79: 13139–13149
Husain M, Weisberg A, Moss B (2003) Topology of epitope-tagged F13L protein, a major membrane component of extracellular vaccinia virions. Virology 308: 233–242
Blasco R, Moss B (1991) Extracellular vaccinia virus formation and cell-to-cell virus transmission are prevented by deletion of the gene encoding the 37,000-dalton outer envelope protein. J Virol 65: 5910–5920
Seet BT, Johnston JB, Brunetti CR, Barrett JW, Everett H, Cameron C, Sypula J, Nazarian SH, Lucas A, McFadden G (2003) Poxviruses and immune evasion. Annu Rev Immunol 21: 377–423
van den Broek MF, Muller U, Huang S, Zinkernagel RM, Aguet M (1995) Immune defense in mice lacking type I and/or type II interferon receptors. Immunol Rev 148: 5–18
Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M (1993) Immune response in mice that lack the interferon-gamma receptor. Science 259: 1742–1745
Weimar W, Stitz I, Billiau A, Cantell K, Schellekens H (1980) Prevention of vaccinia lesions in Rhesus monkeys by human leucocyte and fibroblast interferon. J Gen Virol 48: 25–30
Liu G, Zhai Q, Schaffner DJ, Wu A, Yohannes A, Robinson TM, Maland M, Wells J, Voss TG, Bailey C, Alibek K (2004) Prevention of lethal respiratory vaccinia infections in mice with interferon-α and interferon-γ. FEMS Immunol Med Microbiol 40: 201–206
Moss B, Shisler JL (2001) Immunology 101 at poxvirus U: immune evasion genes. Semin Immunol 13: 59–66
Katze MG, He Y, Gale M Jr (2002) Viruses and interferon: a fight for supremacy. Nat Rev Immunol 2: 676–687
Symons JA, Tscharke DC, Price N, Smith GL (2002) A study of the vaccinia virus interferon gamma receptor and its contribution to virus virulence. J Gen Virol 83: 1953–1964
Ahmed CMI, Burkhart MA, Subramaniam PS, Mujtaba MG, Johnson HM (2005) Peptide mimetics of gamma interferon possess antiviral properties against vaccinia virus and other viruses in the presence of poxvirus B8R protein. J Virol 79: 5632–5639
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Snoeck, R., Andrei, G., De Clercq, E. (2007). Therapy of poxvirus infections. In: Mercer, A.A., Schmidt, A., Weber, O. (eds) Poxviruses. Birkhäuser Advances in Infectious Diseases. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-7557-7_18
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