Advertisement

Antiviral Strategies

  • B. MüllerEmail author
  • Hans-Georg KräusslichEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 189)

Viruses are obligatory intracellular parasites, whose replication depends on pathways and functions of the host cell. Consequently, it is difficult to define virus-specific functions as suitable targets for anti-infective therapy. However, significant progress has been made in the past 50 years towards the development of effective and specific antivirals. In particular, human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, which cause chronic infections affecting millions of individuals world-wide, are a major focus of antiviral research. Initially, antivirals were mainly directed against virus-specific enzymes; more recently, drugs inhibiting the steps of virus entry or release have been developed. Rational approaches towards drug development, based on information about structure and function of viral proteins and molecular mechanisms of virus-host interactions, have become increasingly successful. Novel strategies currently explored in basic research or preclinical studies include approaches targeting host factors important for virus replication, the exploitation of the innate immune response system as well as the use of gene silencing strategies aimed at interfering with viral gene expression. Today, a number of effective virostatics targeting various viral replication steps are approved for treatment of important viral diseases. However, the use of these drugs is limited by the rapid development of antiviral resistance, which represents a central problem of current antiviral therapy.

Keywords

Antiviral Therapy Severe Acute Respiratory Syndrome Antiviral Drug Severe Acute Respiratory Syndrome Antiviral Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Allaway GP (2006) Development of Bevirimat (PA-457): first-in-class HIV maturation inhibitor. Retrovirology 3(Suppl 1):S8CrossRefGoogle Scholar
  2. Alymova IV, Taylor G, and Portner A (2005). Neuraminidase inhibitors as antiviral agents. Current drug targets 5:401–409PubMedCrossRefGoogle Scholar
  3. Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R (2003). Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science (New York, N.Y 300:1763– 1767PubMedGoogle Scholar
  4. Baltimore D (1971) Expression of animal virus genomes. Bacteriol Rev 35:235–241PubMedGoogle Scholar
  5. Baltimore D (1988) Gene therapy. Intracellular immunization. Nature 335:395–396PubMedCrossRefGoogle Scholar
  6. Bauer DJ (1985) A history of the discovery and clinical application of antiviral drugs. Br Med Bull 41:309–314PubMedGoogle Scholar
  7. Bauer DJ, Stvincent L, Kempe CH, Downie AW (1963) Prophylactic treatment of small pox contacts with N-methylisatin beta-thiosemicarbazone (Compound 33t57, Marboran). Lancet 35:494–496CrossRefGoogle Scholar
  8. Berkhout B (2004) RNA interference as an antiviral approach: targeting HIV-1. Curr Opin Mol Ther 6:141–145PubMedGoogle Scholar
  9. Bieniasz PD (2006) Late budding domains and host proteins in enveloped virus release. Virology 344:55–63PubMedCrossRefGoogle Scholar
  10. Bossart-Whitaker P, Carson M, Babu YS, Smith CD, Laver WG, Air GM (1993) Three-dimensional structure of influenza A N9 neuraminidase and its complex with the inhibitor 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid. J Mol Biol 232:1069–1083PubMedCrossRefGoogle Scholar
  11. Bourne CR, Finn MG, Zlotnick A (2006) Global structural changes in hepatitis B virus capsids induced by the assembly effector HAP1. J Virol 80:11055–11061PubMedCrossRefGoogle Scholar
  12. Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ (2008) Identification of host proteins required for HIV infection through a functional genomic screen. Science 319:921–926PubMedCrossRefGoogle Scholar
  13. Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI (2006) Adamantane resistance among influenza A viruses isolated early during the 2005–2006 influenza season in the United States. JAMA 295:891–894PubMedCrossRefGoogle Scholar
  14. Bunka DH, Stockley PG (2006) Aptamers come of age — at last. Nat Rev 4:588–596CrossRefGoogle Scholar
  15. Damm EM, Pelkmans L (2006) Systems biology of virus entry in mammalian cells. Cell Microbiol 8:1219–1227PubMedCrossRefGoogle Scholar
  16. De Clercq E, Descamps J, De Somer P, Holy A (1978) (S)-9-(2,3-Dihydroxypropyl)adenine: an aliphatic nucleoside analog with broad-spectrum antiviral activity. Science 5:563–565CrossRefGoogle Scholar
  17. De Clercq E, Holy, A (2005) Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nature reviews 4:928–940PubMedCrossRefGoogle Scholar
  18. Deres K, Schroder CH, Paessens A, Goldmann S, Hacker HJ, Weber O, Kramer T, Niewohner U, Pleiss U, Stoltefuss J et al. (2003) Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids. Science 299:893–896PubMedCrossRefGoogle Scholar
  19. Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ (1977) Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci USA 74:5716–5720PubMedCrossRefGoogle Scholar
  20. Eshleman SH, Mracna M, Guay LA, Deseyve M, Cunningham S, Mirochnick M, Musoke P, Fleming T, Glenn Fowler M, Mofenson LM et al. (2001) Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). Aids 15:1951–1957PubMedCrossRefGoogle Scholar
  21. Eshleman SH, Hoover DR, Chen S, Hudelson SE, Guay LA, Mwatha A, Fiscus SA, Mmiro F, Musoke P, Jackson JB et al. (2005a) Nevirapine (NVP) resistance in women with HIV-1 subtype C, compared with subtypes A and D, after the administration of single-dose NVP. J Infect Dis 192:30–36CrossRefGoogle Scholar
  22. Eshleman SH, Hoover DR, Chen S, Hudelson SE, Guay LA, Mwatha A, Fiscus SA, Mmiro F, Musoke P, Jackson JB et al. (2005b) Resistance after single-dose nevirapine prophylaxis emerges in a high proportion of Malawian newborns. Aids 19:2167–2169CrossRefGoogle Scholar
  23. Flys TS, Chen S, Jones DC, Hoover DR, Church JD, Fiscus SA, Mwatha A, Guay LA, Mmiro F, Musoke P et al. (2006) Quantitative analysis of HIV-1 variants with the K103N resistance mutation after single-dose nevirapine in women with HIV-1 subtypes A, C, and D. J Acquir Immune Defic Syndr 42:610–613PubMedCrossRefGoogle Scholar
  24. Foy LiK, Sumpter R, Loo YM, Johnson CL, Wang C, Fish PM, Yoneyama M, Fujita T, Lemon SM, Gale M Jr (2005) Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. PNAS 102:2986–2991PubMedCrossRefGoogle Scholar
  25. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D et al. (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Engl J Med 347:975–982PubMedCrossRefGoogle Scholar
  26. Galiana-Arnoux D, Dostert C, Schneemann A, Hoffmann JA, and Imler JL (2006). Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. Nature immunology 7:590–597PubMedCrossRefGoogle Scholar
  27. Gottwein E, Mukherjee N, Sachse C, Frenzel C, Majoros WH, Chi JT, Braich R, Manoharan M, Soutschek J, Ohler U, Cullen BR (2007) A viral microRNA functions as an orthologue of cellular miR-155.Nature 450:1096–1099PubMedCrossRefGoogle Scholar
  28. Gripon P, Rumin S, Urban S, Le Seyec J, Glaise D, Cannie I, Guyomard C, Lucas J, Trepo C, Guguen-Guillouzo C (2002) Infection of a human hepatoma cell line by hepatitis B virus. Proceedings of the National Academy of Sciences of the United States of America 99:15655– 15660PubMedCrossRefGoogle Scholar
  29. Gripon P, Cannie I, Urban S (2005). Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol 79:1613–1622PubMedCrossRefGoogle Scholar
  30. Harris RS, Liddament MT (2004) Retroviral restriction by APOBEC proteins. Nat Rev Immunol 4:868–877PubMedCrossRefGoogle Scholar
  31. Haasnoot J, Berkhout B (2006) RNA interference: its use as antiviral therapy. Handb Exp Pharmacol 173:117–150PubMedCrossRefGoogle Scholar
  32. Hamre D, Brownlee KA, Donovick R (1951) Studies on the chemotherapy of vaccinia virus. II. The activity of some thiosemicarbazones. J Immunol 67:305–312PubMedGoogle Scholar
  33. Hengel H, Koszinowski UH, Conzelmann KK (2005) Viruses know it all: new insights into IFN networks. Trends Immunol 26:396–401PubMedCrossRefGoogle Scholar
  34. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123–126PubMedCrossRefGoogle Scholar
  35. Hoofnagle JH, Seeff LB (2006) Peginterferon and ribavirin for chronic hepatitis C. New Engl J Med 355:2444–2451PubMedCrossRefGoogle Scholar
  36. Jackson JB, Becker-Pergola G, Guay LA, Musoke P, Mracna M, Fowler MG, Mofenson LM, Mirochnick M, Mmiro F, Eshleman SH (2000). Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission. Aids 14:F111–F115PubMedCrossRefGoogle Scholar
  37. Johnson CL, Gale M Jr (2006) CARD games between virus and host get a new player. Trends Immunol 27:1–4PubMedCrossRefGoogle Scholar
  38. Kielian M, Rey FA (2006) Virus membrane-fusion proteins: more than one way to make a hairpin. Nat Rev Microbiol 4:67–76PubMedCrossRefGoogle Scholar
  39. Lai L, Han X, Chen H, Wei P, Huang C, Liu S, Fan K, Zhou L, Liu Z, Pei J et al. (2006) Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase. Curr Pharm Des 12:4555–4564PubMedCrossRefGoogle Scholar
  40. Lee EJ, Kantor R, Zijenah L, Sheldon W, Emel L, Mateta P, Johnston E, Wells J, Shetty AK, Coovadia H et al. (2005) Breast-milk shedding of drug-resistant HIV-1 subtype C in women exposed to single-dose nevirapine. J Infect Dis 192:1260–1264PubMedCrossRefGoogle Scholar
  41. Li F, Goila-Gaur R, Salzwedel K, Kilgore NR, Reddick M, Matallana C, Castillo A, Zoumplis D, Martin DE, Orenstein JM et al. (2003) PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc Natl Acad Sci USA 100:13555–13560PubMedCrossRefGoogle Scholar
  42. Li F, Wild C (2005) HIV-1 assembly and budding as targets for drug discovery. Curr Opin Investig Drugs 6:148–154PubMedGoogle Scholar
  43. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ (2005) Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci USA 102:17717–17722PubMedCrossRefGoogle Scholar
  44. Lilly F (1967) Susceptibility to two strains of Friend leukemia virus in mice. Science 155:461–462PubMedCrossRefGoogle Scholar
  45. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL, Heathcote EJ, Little NR, Griffiths DA et al. (2003) Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 125:1714–1722PubMedCrossRefGoogle Scholar
  46. Luban J (2007) Cyclophilin A, TRIM5, and resistance to human immunodeficiency virus type 1 infection. J Virol 81:1054–1061PubMedCrossRefGoogle Scholar
  47. Ludwig S (2007) Influenza viruses and MAP kinase cascades – novel targets for antiviral intervention. Signal Transduction 7:81–88CrossRefGoogle Scholar
  48. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK (2001) Peginterferon alfa-2b plus ribavirin compared with in-terferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958–965PubMedCrossRefGoogle Scholar
  49. Mansky LM, Temin HM (1995) Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 69:5087–5094PubMedGoogle Scholar
  50. Matzen K, Elzaouk L, Matskevich AA, Nitzsche A, Heinrich J, Moelling K (2007) RNase H-mediated retrovirus destruction in vivo triggered by oligodeoxynucleotides.Nat Biotechnol 25:669–674PubMedCrossRefGoogle Scholar
  51. Medawar PB, Medawar JS (1983) Viruses. In: Medawar PB, Medawar JS (eds) Aristotle to zoos: a philosophical dictionary of biology. Harvard University Press, Cambridge, MA p. 275Google Scholar
  52. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–1172PubMedCrossRefGoogle Scholar
  53. Müller B, Kräusslich HG (2008) Antiviral drugs. In: Offermanns u. Rosenthal (ed) Encyclopedic reference of molecular pharmacology, 2nd ed. Springer Verlag, HeidelbergGoogle Scholar
  54. Münch J, Standker L, Adermann K, Schulz A, Schindler M, Chinnadurai R, Pöhlmann S, Chaipan C, Biet T, Peters T et al. (2007) Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 129:263–275PubMedCrossRefGoogle Scholar
  55. Nisole S, Stoye JP, Saib A (2005). TRIM family proteins: retroviral restriction and antiviral defence. Nat Rev Microbiol 3:799–808PubMedCrossRefGoogle Scholar
  56. Pelkmans L, Fava E, Grabner H, Hannus M, Habermann B, Krausz E, Zerial M (2005) Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis. Nature 436:78–86PubMedCrossRefGoogle Scholar
  57. Petersen J, Dandri M, Mier W, Lütgehetmann M, Volz T, von Weizsäcker F, Haberkorn U, Fischer L, Pollok JM, Erbes B, Seitz S, Urban S (2008) Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 26:335–341PubMedCrossRefGoogle Scholar
  58. Pornillos O, Garrus JE, Sundquist WI (2002) Mechanisms of enveloped RNA virus budding. Trends Cell Biol 12:569–579PubMedCrossRefGoogle Scholar
  59. Ray N, Doms RW (2006). HIV-1 coreceptors and their inhibitors. Current topics in microbiology and immunology 303:97–120PubMedCrossRefGoogle Scholar
  60. Seth RB, Sun L, Chen ZJ (2006) Antiviral innate immunity pathways. Cell research 16:141–147PubMedCrossRefGoogle Scholar
  61. Shapiro RL, Thior I, Gilbert PB, Lockman S, Wester C, Smeaton LM, Stevens L, Heymann SJ, Ndung'u T, Gaseitsiwe S et al. (2006) Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana. Aids 20:1281–1288PubMedCrossRefGoogle Scholar
  62. Sieczkarski SB, Whittaker GR (2005) Viral entry. Curr Top Microbiol Immunol 285:1–23PubMedCrossRefGoogle Scholar
  63. Snell NJ (2001). Ribavirin—current status of a broad spectrum antiviral agent. Expert opinion on pharmacotherapy 2:1317–1324PubMedCrossRefGoogle Scholar
  64. Steeves R, Lilly F (1977) Interactions between host and viral genomes in mouse leukemia. Ann Rev Genetics 11:277–296CrossRefGoogle Scholar
  65. Sticht J, Humbert M, Findlow S, Bodem J, Muller B, Dietrich U, Werner J, Krausslich HG (2005) A peptide inhibitor of HIV-1 assembly in vitro. Nat Struct Mol Biol 12:671–677PubMedCrossRefGoogle Scholar
  66. Stockman LJ, Bellamy R, Garner P (2006) SARS: systematic review of treatment effects. PLoS Med 3:e343PubMedCrossRefGoogle Scholar
  67. Taylor JM, Quilty D, Banadyga L, Barry M (2006) The vaccinia virus protein F1L interacts with Bim and inhibits activation of the pro-apoptotic protein Bax. The Journal of biological chemistry 281:39728–39739PubMedCrossRefGoogle Scholar
  68. ter Brake O, Konstantinova P, Ceylan M, Berkhout B (2006) Silencing of HIV-1 with RNA interference: a multiple shRNA approach. Mol Ther 14:883–892PubMedCrossRefGoogle Scholar
  69. von Laer D, Hasselmann S, Hasselmann K (2006) Gene therapy for HIV infection: what does it need to make it work? J Gene Med 8:658–667CrossRefGoogle Scholar
  70. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, A. Habermann A, Kräusslich HG, Mizokami M, Bartenschlager R, Liang TJ (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature medicine 11:791–796PubMedCrossRefGoogle Scholar
  71. Wang XH, Aliyari R, Li WX, Li HW, Kim K, Carthew R, Atkinson P, Ding SW (2006) RNA interference directs innate immunity against viruses in adult Drosophila. Science 312:452–454PubMedCrossRefGoogle Scholar
  72. Waterhouse PM, Wang MB, Lough T. (2001). Gene silencing as an adaptive defence against viruses. Nature 411:834–842PubMedCrossRefGoogle Scholar
  73. Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH et al. (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373:117–122PubMedCrossRefGoogle Scholar
  74. Wensing AM, van de Vijver DA, Angarano G, Asjo B, Balotta C, Boeri E, Camacho R, Chaix ML, Costagliola D, De Luca A et al. (2005) Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 192:958–966PubMedCrossRefGoogle Scholar
  75. Wilkins C, Dishongh R, Moore SC, Whitt MA, Chow M, Machaca K (2005) RNA interference is an antiviral defence mechanism in Caenorhabditis elegans. Nature 436:1044–1047PubMedCrossRefGoogle Scholar
  76. Zhang H, Zhao Q, Bhattacharya S, Waheed AA, Tong X, Hong A, Heck S, Curreli F, Goger M, Cowburn D, Freed EO, Debnath AK (2008) A cell-penetrating helical peptide as a potential HIV-1 inhibitor. J Mol Biol 378:565–580PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Department of VirologyUniversity of HeidelbergHeidelbergGermany

Personalised recommendations