Inhibition of Herpes Simplex Virus Ribonucleotide Reductase by Synthetic Nonapeptides: A Potential Antiviral Therapy

  • Michel Liuzzi
  • Erika Scouten
  • Rolf Ingemarson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 312)


Herpes simplex virus (HSV) types 1 and 2 are pathogenic DNA viruses that cause diverse diseases in humansl, perhaps best exemplified by genital herpes which is primarily due to HSV-2 infection. It has been estimated that more than 20 million people are affected with genital herpes in the United States alone and that about 300,000 new cases are reported each year. Since herpesvirus infections are eventually attenuated by the host immune system in otherwise normal persons, newborns and immunocompromised patients are particularly vulnerable to more severe forms of infections. HSV belongs to the family of human herpesviruses which also includes varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpesviruses 6 and 7 (HHV-6 and HHV-7). While these different viruses are responsible for a variety of different pathologies associated with their specific life cycles in different human tissues, they do have several key features in common. After primary infection, herpesviruses have the capability to establish latency2, which is defined as a state in which the viral genome is present in certain cells but infectious virus is not produced. These viruses can be reactivated from the latent state by various stimuli such as ultraviolet light, stress and fever to produce new infectious virus. With respect to herpesvirus infections, development of vaccines has, thus far, met with little success. Therefore, it is important to develop alternative antiherpetic agents for use in the treatment of herpesvirus-induced diseases.


Herpes Simplex Virus Type Large Subunit Small Subunit Thymidine Kinase Genital Herpes 
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.


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  1. 1.
    B. N. Fields, “Virology”, Raven Press, New York (1990).Google Scholar
  2. 2.
    J.G. Stevens, Human herpesviruses: a consideration of the latent state, Microbiol. Rev. 53: 18 (1989).Google Scholar
  3. 3.
    G.J. Galasso, R.J. Whitley, and T.C. Merigan, “Antiviral Agents and Viral Diseases of Man”, Raven Press, New York (1990).Google Scholar
  4. 4.
    D.J. McGeoch, M.A. Dalrymple, A.J. Davison, A. Dolan, M.C. Frame, D. McNab, L.J. Perry, J.E. Scott, and P. Taylor, The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1, J. Gen. Virol. 69:1531 (1988).PubMedCrossRefGoogle Scholar
  5. 5.
    R.W. Honess, and B. Roizman, Regulation of herpesviruses macromolecular synthesis: I. Cascade regulation of the synthesis of three groups of viral proteins, J. Virol. 14:8 (1974).PubMedGoogle Scholar
  6. 6.
    W.M. Shannon, Mechanisms of action and pharmacology: chemical agents, in: “Antiviral Agents: Viral Diseases of Man”, G.J. Galasso, R.J. Whitley, and T.C. Merigan, eds., Raven Press, New York (1984).Google Scholar
  7. 7.
    S.A. Plotkin, S.E. Starr, and C.K. Bryan, In vivo and in vitro responses of cytomegalovirus to acyclovir, Am. J. Med. 73:257 (1982).PubMedCrossRefGoogle Scholar
  8. 8.
    E. DeClercq, J. Descamps, P. DeSomer, P.J. Barr, A.S. Jones, and R.T. Walker, (E)-5-(2-Bromovinyl)-2’-deoxyuridine: a potent and selective antiherpes agent, Proc. Natl. Acad. Sci. U.S.A. 76:2947 (1979).CrossRefGoogle Scholar
  9. 9.
    H.J. Field, The development of antiviral drug resistance, in: “Antiviral Agents: The Development and Assessment of Antiviral Chemotherapy”, H.J. Field, ed., CRC Press, Boca Raton, Florida (1988).Google Scholar
  10. 10.
    P. Reichard, Interactions between deoxyribonucleotide and DNA synthesis, Annu. Rev. Biochem. 57:349 (1988).PubMedCrossRefGoogle Scholar
  11. 11.
    R. Ingemarson, and H. Lankinen, The herpes simplex virus type 1 ribonucleotide reductase is a tight complex of the type composed of 40 K and 140 K proteins, of which the latter shows multiple forms due to proteolysis, J. Virol. 156:417 (1987).CrossRefGoogle Scholar
  12. 12.
    M. Lammers, and H. Follman, The ribonucleotide reductases: a unique group of metalloenzymes essential for cell proliferation, Struct. Bonding 54: 27(1983).Google Scholar
  13. 13.
    D. Huszar, and S. Bachetti, Partial purification and characterization of the ribonucleotide reductase induced by herpes simplex virus infection of mammalian cells, J. Virol. 37:580 (1981).PubMedGoogle Scholar
  14. 14.
    Y. Langelier, M. Deschamps, and G. Buttier, Analysis of dCMP deaminase and CDP reductase levels in hamster cells infected with herpes simplex virus, J. Virol. 26:547 (1978).PubMedGoogle Scholar
  15. 15.
    L.M. Nutter, S.P. Grill, and Y.-C. Cheng, Can ribonucleotide reductase be considered as an effective target for developing antiherpes simplex virus type II (HSV-2) compounds? Biochem. Pharmac. 34:777 (1985).CrossRefGoogle Scholar
  16. 16.
    T. Spector, D.R. Averett, D.J. Nelson, C.U. Lambe, R.W. Morrison, M.H. StClair, and P.A. Furman, Potentiation of antiherpetic activity of acyclovir by ribonucleotide reductase inhibition, Proc. Natl. Acad. Sci. USA 82:4254 (1985).PubMedCrossRefGoogle Scholar
  17. 17.
    S.R. Turk, C. Shipman, and J.C. Drach, Selective inhibition of herpes virus ribonucleotide diphosphate reductase by derivatives of 2-acetylpyridine thiosemicarbazone, Biochem. Pharmac. 35:1539 (1986).CrossRefGoogle Scholar
  18. 18.
    V.G. Preston, J.W. Palfreyman, and B.M. Dutia, Identification of a herpes simplex virus type 1 polypeptide which is a component of the virus-induced ribonucleotide reductase, J. Gen. Virol. 65:1457 (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    D.J. Goldstein, and S.K. Weller, Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis: isolation and characterization of an ICP6 lac Z insertion mutant, J. Virol. 62:196 (1988).PubMedGoogle Scholar
  20. 20.
    J.M. Cameron, I. McDougall, H.S. Marsden, V.G. Preston, M.D. Ryan, and J.H. Subak-Sharpe, Ribonucleotide reductase encoded by herpes simplex virus is a determinant of the pathogenicity of the virus in mice and a valid antiviral target, J. Gen. Virol. 69:2607 (1988).PubMedCrossRefGoogle Scholar
  21. 21.
    J.G. Jacobson, D.A. Leib, D.J. Goldstein, C.L. Bogard, P.A. Schaffer, S.K. Weller, and D.M. Coen, A herpes simplex virus ribonucleotide reductase deletion mutant is defective for productive acute and reactivatable latent infections of mice and for replication in mouse cells, Virology 173:276 (1989).PubMedCrossRefGoogle Scholar
  22. 22.
    R.T. Kintner, C.R. Brandt, R.J. Visally, A.M. Pumfery, and D.R. Grau, The herpes simplex virus ribonucleotide reductase is required for ocular virulence, Invest. Ophtalmol. Visual Sci. 32:852 (1991).Google Scholar
  23. 23.
    S.R. Turk, N.A. Kik, G.M. Birch, D. Chiego, Jr., and C. Shipman, Jr., Herpes simplex virus type 1 ribonucleotide reductase null mutants induce lesions in guinea pigs, Virology 173:733 (1989).PubMedCrossRefGoogle Scholar
  24. 24.
    T. Spector, Ribonucleotide reductase encoded by herpesviruses: inhibitors and chemotherapeutic considerations, in: “International Encyclopedia of Pharmacology and Therapeutics”, J.G. Cory, and A.H. Cory, eds., Pergamon Press, Elmsford, New York (1989).Google Scholar
  25. 25.
    B.M. Dutia, M.C. Frame, J.H. Subak-Sharpe, W.N. Clark, and H.S. Marsden, Specific inhibition of herpes ribonucleotide reductase by synthetic peptides, Nature (London) 321:439 (1986).CrossRefGoogle Scholar
  26. 26.
    E.A. Cohen, P. Gaudreau, P. Brazeau, and Y. Langelier, Specific inhibition of herpesvirus ribonucleotide reductase by a nonapeptide derived from the carboxy terminus of subunit 2, Nature (London) 321:441 (1986).CrossRefGoogle Scholar
  27. 27.
    A.J. Davison and J.E. Scott, The complete DNA sequence of varicella-zoster virus, J. Gen. Virol. 67:1759 (1986).PubMedCrossRefGoogle Scholar
  28. 28.
    R. Baer, A.T. Bankier, M.D. Biggin, P.L. Deininger, P.J. Farewell, T.J. Gibson, G. Hatfull, G.S. Hudson, S.C. Satchwell, C. Seguin, P.S. Tuffnell, and B.G. Barrell, DNA sequence and expression of the B95–8 Epstein-Barr virus genome, Nature 310:207 (1984).PubMedCrossRefGoogle Scholar
  29. 29.
    E. Telford, H. Lankinen, and H.S. Marsden, Inhibition of equine herpesvirus type 1 subtype 1-induced ribonucleotide reductase by the nonapeptide YAGAVVNDL, J. Gen. Virol. 71:1373 (1990).PubMedCrossRefGoogle Scholar
  30. 30.
    E.A. Cohen, H. Paradis, P. Gaudreau, P. Brazeau, and Y. Langelier, Identification of viral polypeptides involved in pseudorabies virus ribonucleotide reductase activity, J. Virol. 61:2046 (1987).PubMedGoogle Scholar
  31. 31.
    G. Cosentino, P. LavaHee, S. Rakhit, R. Plante, Y. Gaudette, C. Lawetz, P. Whitehead, J.-S. Duceppe, C. Lepine-Frenette, N. Dansereau, C. Guilbeault, Y. Langelier, P. Gaudreau, L. Thelander, and Y. Guindon, Specific inhibition of ribonucleotide reductases by peptides corresponding to the C-terminal of their second subunit, Biochem. Cell Biol. 67:79 (1991).CrossRefGoogle Scholar
  32. 32.
    F.-D. Yang, R.A. Spanevello, I. Celiker, R. Hirschmann, H. Rubin, and B.S. Cooperman, The carboxyl terminus heptapeptide of the R2 subunit of mammalian ribonucleotide reductase inhibits enzyme activity and can be used to purify the R1 subunit, FEBS Lett. 272:61 (1990).PubMedCrossRefGoogle Scholar
  33. 33.
    E.A. Cohen, J. Charron, J. Perret and Y. Langelier, Herpes simplex virus ribonucleotide reductase induced in infected BHK-21/C13 cells: biochemical evidence for the existence of two non-identical subunits, H1 and H2, J. Gen. Virol. 66:733 (1985).PubMedCrossRefGoogle Scholar
  34. 34.
    M. Dixon and E.C. Webb, “Enzymes”, Academic Press, New York (1979).Google Scholar
  35. 35.
    Y.-C. Cheng, and W.H. Prusoff, Relationship between inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (ISO) of an enzymatic reaction, Biochem. Parmac. 22:3099 (1973).CrossRefGoogle Scholar
  36. 36.
    P.J.F. Henderson, A linear equation that describes the steady-state kinetics of enzymes and subcellular particles interacting with tightly bound inhibitors, Biochem. J. 127:321 (1972).PubMedGoogle Scholar
  37. 37.
    H. Paradis, P. Gaudreau, P. Brazeau, and Y. Langelier, Mechanism of inhibition of herpes simplex virus (HSV) ribonucleotide reductase by a nonapeptide corresponding to the carboxyl terminus of its subunit 2. Specific binding of a photoaffinity analog, [4’-azido-Phe6] HSV2-(6–15), to subunit 1, J. Biol. Chem. 263:16045 (1988).PubMedGoogle Scholar
  38. 38.
    H. Paradis, Y. Langelier, J. Michaud, P. Brazeau, and P. Gaudreau, Studies on in vitro proteolytic sensitivity of peptides inhibiting herpes simplex virus ribonucleotide reductases lead to discovery of a stable and potent inhibitor, Int. J. Peptide Protein Res. 37:72 (1991).CrossRefGoogle Scholar
  39. 39.
    E. Telford, A. Owsianka, and H.S. Marsden, Stability of the herpesvirus ribonucleotide reductase-inhibiting nonapeptide YAGAVVNDL in extracts of HSV1-infected cells, Antiviral Chem. Chemother. 1:223 (1990).Google Scholar
  40. 40.
    Our unpublished results.Google Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Michel Liuzzi
    • 1
  • Erika Scouten
  • Rolf Ingemarson
  1. 1.Department of BiochemistryBio-Mega Inc.LavalCanada

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