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Antiviral Drugs Against Alphaherpesvirus

  • Kimiyasu ShirakiEmail author
Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1045)

Abstract

The discovery of acyclovir and penciclovir has led to the development of a successful systemic therapy for treating herpes simplex virus infection and varicella-zoster virus infection, and the orally available prodrugs, valacyclovir and famciclovir, have improved antiviral treatment compliance. Acyclovir and penciclovir are phosphorylated by viral thymidine kinase and are incorporated into the DNA chain by viral DNA polymerase, resulting in chain termination. Helicase-primase plays an initial step in DNA synthesis to separate the double strand into two single strands (replication fork) and is a new target of antiviral therapy. The helicase-primase inhibitors (HPIs) pritelivir and amenamevir have novel mechanisms of action, drug resistance properties, pharmacokinetic characteristics, and clinical efficacy for treating genital herpes. The clinical study of amenamevir in herpes zoster has been completed, and amenamevir has been submitted for approval for treating herpes zoster in Japan. The clinical use of HPIs will be the beginning of a new era of anti-herpes therapy.

Keywords

Acyclovir Prodrug Valacyclovir Famciclovir Antivirals Helicase-primase Amenamevir Chain termination Resistance 
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References

  1. Beadle JR, Hartline C, Aldern KA et al (2002) Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrob Agents Chemother 46:2381–2386CrossRefPubMedPubMedCentralGoogle Scholar
  2. Biswas S, Sukla S, Field HJ (2014) Helicase-primase inhibitors for herpes simplex virus: looking to the future of non-nucleoside inhibitors for treating herpes virus infections. Future Med Chem 6:45–55CrossRefPubMedGoogle Scholar
  3. Bodsworth NJ, Boag F, Burdge D et al (1997) Evaluation of sorivudine (BV-araU) versus acyclovir in the treatment of acute localized herpes zoster in human immunodeficiency virus-infected adults. The Multinational Sorivudine Study Group. J Infect Dis 176:103–111CrossRefPubMedGoogle Scholar
  4. Boehmer PE, Lehman IR (1997) Herpes simplex virus DNA replication. Annu Rev Biochem 66:347–384CrossRefPubMedGoogle Scholar
  5. Chono K, Katsumata K, Kontani T et al (2010) ASP2151, a novel helicase-primase inhibitor, possesses antiviral activity against varicella-zoster virus and herpes simplex virus types 1 and 2. J Antimicrob Chemother 65:1733–1741CrossRefPubMedGoogle Scholar
  6. Chono K, Katsumata K, Kontani T et al (2012) Characterization of virus strains resistant to the herpes virus helicase-primase inhibitor ASP2151 (Amenamevir). Biochem Pharmacol 84:459–467CrossRefPubMedGoogle Scholar
  7. Chono K, Katsumata K, Suzuki H et al (2013) Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antivir Res 97:154–160CrossRefPubMedGoogle Scholar
  8. Coen DM, Schaffer PA, Furman PA et al (1982) Biochemical and genetic analysis of acyclovir-resistant mutants of herpes simplex virus type 1. Am J Med 73:351–360CrossRefPubMedGoogle Scholar
  9. Cohen JI, Seidel KE (1993) Generation of varicella-zoster virus (VZV) and viral mutants from cosmid DNAs: VZV thymidylate synthetase is not essential for replication in vitro. Proc Natl Acad Sci U S A 90:7376–7380CrossRefPubMedPubMedCentralGoogle Scholar
  10. Crute JJ, Grygon CA, Hargrave KD et al (2002) Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 8:386–391CrossRefPubMedGoogle Scholar
  11. Cundy KC (1999) Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin Pharmacokinet 36:127–143CrossRefPubMedGoogle Scholar
  12. Daikoku T, Tannai H, Honda M et al (2016) Subclinical generation of acyclovir-resistant herpes simplex virus with mutation of homopolymeric guanosine strings during acyclovir therapy. J Dermatol Sci 82:160–165CrossRefPubMedGoogle Scholar
  13. De Clercq E (2004) Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster. Biochem Pharmacol 68:2301–2315CrossRefPubMedGoogle Scholar
  14. De Clercq E (2005) (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU). Med Res Rev 25:1–20CrossRefPubMedGoogle Scholar
  15. De Clercq E, Descamps J, Ogata M et al (1982) In vitro susceptibility of varicella-zoster virus to E-5-(2-bromovinyl)-2′-deoxyuridine and related compounds. Antimicrob Agents Chemother 21:33–38CrossRefPubMedPubMedCentralGoogle Scholar
  16. Disease NIOaaI Herpes Drugs in Development (n.d.) In: Division of AIDS Anti-HIV/OI/TB Therapeutics DatabaseGoogle Scholar
  17. Drake JW (1993) Rates of spontaneous mutation among RNA viruses. Proc Natl Acad Sci U S A 90:4171–4175CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dunning J, Kennedy SB, Antierens A et al (2016) Experimental treatment of Ebola virus disease with Brincidofovir. PLoS One 11:e0162199CrossRefPubMedPubMedCentralGoogle Scholar
  19. Elion GB (1989) Nobel lecture in physiology or medicine—1988. The purine path to chemotherapy. In Vitro Cell Dev Biol 25:321–330CrossRefPubMedGoogle Scholar
  20. Elion GB, Furman PA, Fyfe JA et al (1977) Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci U S A 74:5716–5720CrossRefPubMedPubMedCentralGoogle Scholar
  21. Englund JA, Zimmerman ME, Swierkosz EM et al (1990) Herpes simplex virus resistant to acyclovir. A study in a tertiary care center. Ann Intern Med 112:416–422CrossRefPubMedGoogle Scholar
  22. Furuta Y, Takahashi K, Fukuda Y et al (2002) In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother 46:977–981CrossRefPubMedPubMedCentralGoogle Scholar
  23. Honda M, Okuda T, Hasegawa T et al (2001) Effect of long-term, low-dose acyclovir suppressive therapy on susceptibility to acyclovir and frequency of acyclovir resistance of herpes simplex virus type 2. Antivir Chem Chemother 12:233–239CrossRefPubMedGoogle Scholar
  24. Ida M, Kageyama S, Sato H et al (1999) Emergence of resistance to acyclovir and penciclovir in varicella-zoster virus and genetic analysis of acyclovir-resistant variants. Antivir Res 40:155–166CrossRefPubMedGoogle Scholar
  25. Jackson GG, Muldoon RL, Akers LW (1963) Serological evidence for prevention of influenzal infection in volunteers by an anti-influenzal drug adamantanamine hydrochloride. Antimicrob Agents Chemoter (Bethesda) 161:703–707Google Scholar
  26. James SH, Prichard MN (2014) Current and future therapies for herpes simplex virus infections: mechanism of action and drug resistance. Curr Opin Virol 8:54–61CrossRefPubMedGoogle Scholar
  27. James SH, Larson KB, Acosta EP et al (2015) Helicase-primase as a target of new therapies for herpes simplex virus infections. Clin Pharmacol Ther 97:66–78CrossRefPubMedGoogle Scholar
  28. Kamiyama T, Kurokawa M, Shiraki K (2001) Characterization of the DNA polymerase gene of varicella-zoster viruses resistant to acyclovir. J Gen Virol 82:2761–2765CrossRefPubMedGoogle Scholar
  29. Kawai H, Yoshida I, Suzutani T (1993) Antiviral activity of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil against thymidine kinase negative strains of varicella-zoster virus. Microbiol Immunol 37:877–882CrossRefPubMedGoogle Scholar
  30. Kern ER, Richards JT, Overall JC Jr et al (1981) A comparison of phosphonoacetic acid and phosphonoformic acid activity in genital herpes simplex virus type 1 and type 2 infections of mice. Antivir Res 1:225–235CrossRefPubMedGoogle Scholar
  31. Kleymann G, Fischer R, Betz UA et al (2002) New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat Med 8:392–398CrossRefPubMedGoogle Scholar
  32. Koszalka P, Tilmanis D, Hurt AC (2017) Influenza antivirals currently in late-phase clinical trial. Influenza Other Respir Viruses 1(3):240–246CrossRefGoogle Scholar
  33. Larder BA, Darby G (1986) Susceptibility to other antiherpes drugs of pathogenic variants of herpes simplex virus selected for resistance to acyclovir. Antimicrob Agents Chemother 29:894–898CrossRefPubMedPubMedCentralGoogle Scholar
  34. Littler E, Stuart AD, Chee MS (1992) Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. Nature 358:160–162CrossRefPubMedGoogle Scholar
  35. Machida H, Kuninaka A, Yoshino H (1982) Inhibitory effects of antiherpesviral thymidine analogs against varicella-zoster virus. Antimicrob Agents Chemother 21:358–361CrossRefPubMedPubMedCentralGoogle Scholar
  36. Miwa N, Kurosaki K, Yoshida Y et al (2005) Comparative efficacy of acyclovir and vidarabine on the replication of varicella-zoster virus. Antivir Res 65:49–55CrossRefPubMedGoogle Scholar
  37. Okuda T, Kurokawa M, Matsuo K et al (2004) Suppression of generation and replication of acyclovir-resistant herpes simplex virus by a sensitive virus. J Med Virol 72:112–120CrossRefPubMedGoogle Scholar
  38. Ostrander M, Cheng YC (1980) Properties of herpes simplex virus type 1 and type 2 DNA polymerase. Biochim Biophys Acta 609:232–245CrossRefPubMedGoogle Scholar
  39. Parris DS, Harrington JE (1982) Herpes simplex virus variants restraint to high concentrations of acyclovir exist in clinical isolates. Antimicrob Agents Chemother 22:71–77CrossRefPubMedPubMedCentralGoogle Scholar
  40. Patrone M, Percivalle E, Secchi M et al (2003) The human cytomegalovirus UL45 gene product is a late, virion-associated protein and influences virus growth at low multiplicities of infection. J Gen Virol 84:3359–3370CrossRefPubMedGoogle Scholar
  41. Reyes M, Shaik NS, Graber JM et al (2003) Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics. Arch Intern Med 163:76–80CrossRefPubMedGoogle Scholar
  42. Safrin S, Cherrington J, Jaffe HS (1997) Clinical uses of cidofovir. Rev Med Virol 7:145–156CrossRefPubMedGoogle Scholar
  43. Sasadeusz JJ, Tufaro F, Safrin S et al (1997) Homopolymer mutational hot spots mediate herpes simplex virus resistance to acyclovir. J Virol 71:3872–3878PubMedPubMedCentralGoogle Scholar
  44. Schwartz PM, Novack J, Shipman C Jr et al (1984) Metabolism of arabinosyladenine in herpes simplex virus-infected and uninfected cells. Correlation with inhibition of DNA synthesis and role in antiviral selectivity. Biochem Pharmacol 33:2431–2438CrossRefPubMedGoogle Scholar
  45. Shipman C Jr, Smith SH, Carlson RH et al (1976) Antiviral activity of arabinosyladenine and arabinosylhypoxanthine in herpes simplex virus-infected KB cells: selective inhibition of viral deoxyribonucleic acid synthesis in synchronized suspension cultures. Antimicrob Agents Chemother 9:120–127CrossRefPubMedPubMedCentralGoogle Scholar
  46. Shiraki K (2017) Helicase-primase inhibitor amenamevir for herpesvirus infection: towards practical application for treating herpes zoster. Drugs Today 53(11):573CrossRefPubMedGoogle Scholar
  47. Shiraki K, Namazue J, Okuno T, Yamanishi K, Takahashi M (1990) Novel sensitivity of acyclovir-resistant varicella-zoster virus to anti-herpetic drugs. Antivir Chem Chemother 1:373–375CrossRefGoogle Scholar
  48. Shiraki K, Ochiai H, Namazue J et al (1992) Comparison of antiviral assay methods using cell-free and cell-associated varicella-zoster virus. Antivir Res 18:209–214CrossRefPubMedGoogle Scholar
  49. Spector FC, Liang L, Giordano H et al (1998) Inhibition of herpes simplex virus replication by a 2-amino thiazole via interactions with the helicase component of the UL5-UL8-UL52 complex. J Virol 72:6979–6987PubMedPubMedCentralGoogle Scholar
  50. Stranska R, Schuurman R, Nienhuis E et al (2005) Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization. J Clin Virol 32:7–18CrossRefPubMedGoogle Scholar
  51. Sullivan V, Talarico CL, Stanat SC et al (1992) A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells. Nature 358:162–164CrossRefPubMedGoogle Scholar
  52. Suzuki M, Okuda T, Shiraki K (2006) Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antivir Res 72:157–161CrossRefPubMedGoogle Scholar
  53. Tyring S, Wald A, Zadeikis N et al (2012) ASP2151 for the treatment of genital herpes: a randomized, double-blind, placebo- and valacyclovir-controlled, dose-finding study. J Infect Dis 205:1100–1110CrossRefPubMedGoogle Scholar
  54. Vere Hodge RA, Cheng Y-C (1993) The mode of action of penciclovir. Antivir Chem Chemother 4:13–24CrossRefGoogle Scholar
  55. Von Itzstein M, Wu WY, Kok GB et al (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363:418–423CrossRefGoogle Scholar
  56. Wald A, Corey L, Timmler B et al (2014) Helicase-primase inhibitor pritelivir for HSV-2 infection. N Engl J Med 370:201–210CrossRefPubMedGoogle Scholar
  57. Wald A, Timmler B, Magaret A et al (2016) Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences: a randomized clinical trial. JAMA 316:2495–2503CrossRefPubMedGoogle Scholar
  58. Wassilew SW, Wutzler P, Brivddin Herpes Zoster Study G (2003) Oral brivudin in comparison with acyclovir for herpes zoster: a survey study on postherpetic neuralgia. Antivir Res 59:57–60CrossRefGoogle Scholar
  59. Whitley RJ, Alford CA, Hirsch MS et al (1986) Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 314:144–149CrossRefPubMedGoogle Scholar
  60. Yajima M, Yamada H, Takemoto M et al (2017) Profile of anti-herpetic action of ASP2151 (amenamevir) as a helicase-primase inhibitor. Antivir Res 139:95–101CrossRefPubMedGoogle Scholar
  61. Yokota T, Konno K, Mori S et al (1989) Mechanism of selective inhibition of varicella zoster virus replication by 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil. Mol Pharmacol 36:312–316PubMedGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of VirologyUniversity of ToyamaToyamaJapan

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