Abstract
Riboviruses and retroviruses have been shown to spontaneously mutate at an extraordinarily high rate. While this genetic diversity allows viral subpopulations to escape conventional antivirals, it also has a cost. Indeed, this high mutation rate results in the synthesis of many defective virions. Stealth nucleosides are nucleoside analogues that are designed to increase the already high spontaneous mutation rate of viruses to the point where the virus cannot further replicate, a process known as ‘lethal mutagenesis’. Rather than causing chain termination and attempting to immediately halt viral replication, as with conventional nucleoside reverse transcriptase inhibitors (NRTI), stealth nucleosides are incorporated into the viral genome during replication and, by mispairing, cause mutations to the viral genome. These mutations affect all viral proteins and cumulatively, over a number of replication cycles, are lethal to the virus. There are two distinct stealth nucleoside platforms: DNA stealth nucleosides and RNA stealth nucleosides. DNA stealth nucleosides are currently being screened for activity against HIV and may have activity against hepatitis B virus and smallpox virus, with the clinical lead DNA stealth nucleoside demonstrating activity in the low nanomolar range. In addition, DNA stealth nucleosides have been shown to be able to effectively treat NRTI-resistant HIV strains in vitro, which is not surprising given that the two principal modes of resistance (low affinity of reverse transcriptase for a modified sugar or pyrophosphorolysis) should not be applicable to DNA stealth nucleosides. RNA stealth nucleosides are being developed for the treatment of ribovirus infections, and particularly hepatitis C virus infection. RNA stealth nucleosides are selected for their broad spectrum of antiviral activity, and current lead RNA stealth nucleosides have potency in the same range as ribavirin.
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References
Loeb LA, Essigmann JM, Kazazi F, et al. Lethal mutagenesis of HIV using nucleoside analogs. Proc Natl Acad Sci U S A 1999; 96: 1492–7
Loeb LA, Mullins JI. Lethal mutagenesis of HIV by mutagenic ribonucleoside analogs. AIDS Res Hum Retroviruses 2000; 16(1): 1–3
Drake JW, Holland JJ. Mutation rates among RNA viruses. Proc Natl Acad Sci U S A 1999; 96(24): 13910–3
Eigen M. Error catastrophe and antiviral strategy. Proc Natl Acad Sci U S A 2002; 99(21): 13374–6
Larder BA, Coates KE, Kemp SD. Zidovudine-resistant human immunodeficiency virus selected by passage in cell culture. J Virol 1991; 65(10): 5232–6
Kamath-Loeb AS, Hizi A, Tabone J, et al. Inefficient repair of RNA·DNA hybrids. Eur J Biochem 1997; 250(2): 492–501
Wood RD, Mitchell M, Sgouros J, et al. Human DNA repair genes. Science 2001; 291: 1284–9
Lim SE, Copeland WC. Differential incorporation and removal of anti-viral deoxynucleotides by human polymerase. J Biol Chem 2001; 276(26): 23616–23
Loveday C, Kaye S, Tenant-Flowers M, et al. HIV-1 RNA serum-load and resistant genotypes during early zidovudine therapy. Lancet 1995; 345: 820–4
Volberding P. The need for additional options in the treatment of human immunodeficiency virus infection. J Infect Dis 1995; 171(2 Suppl.): S150–4
Collier AC, Coombs RW, Schoenfeld DA, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. N Engl J Med 1996; 334(16): 1011–7
Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995; 374: 569–71
Shafer RW, Winters MA, Palmer S, et al. Multiple concurrent reverse transcriptase and protease mutations and multidrug resistance of HIV-1 isolates from heavily treated patients. Ann Intern Med 1998; 128(11): 906–11
Deeks SG. International perspectives on antiretroviral resistance. Nonnucleoside reverse transcriptase inhibitor resistance. J Acquir Immune Defic Syndr 2001; 26(1 Suppl.): S25–33
Stone VE. Strategies for optimizing adherence to highly active antiretroviral therapy: lessons from research and practice. Clin Infect Dis 2001; 33(6): 865–72
16. BHIVA Writing Committee. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2000; 1: 76–101
Smith KY. Selected metabolic and morphologic complications associated with highly active antiretroviral therapy. J Infect Dis 2002; 185(2 Suppl.): S123–7
Grant RM, Kahn J, Wamerdam M, et al. Transmission and transmissibility of drug resistant HIV-1 [abstract 368-M]. 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle (WA). Foundation for Retrovirology and Human Health [online]. Available from URL: http://www.retroconference.org [Accessed 2002]
Murata-Kamiya N, Kamiya H, Karino N, et al. Formation of 5-formyl-2′-deoxycytidine from 5-methyl-2′-deoxycytidine in duplex DNA by Fenton-type reactions and γ-irradiation. Nucleic Acids Res 1999; 27(22): 4385–90
Karino N, Ueno Y, Matsuda A. Synthesis and properties of oligonucleotides containing 5-formyl-2′-deoxycytidine: in vitro DNA polymerase reactions on DNA templates containing 5-formyl-2′-deoxycytidine. Nucleic Acids Res 2001; 29(12): 2456–63
Crotty S, Maag D, Arnold JJ, et al. The broad spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 2000; 8(12): 1375–9
Sierra S, Davila M, Lowenstein PR, et al. Response of foot-and-mouth disease virus to increased mutagenesis: influence of viral load and fitness and loss of infectivity. J Virol 2000; 74(18): 8316–23
Isel C, Ehresmann C, Walter P, et al. The emergence of different resistance mechanisms toward nucleoside inhibitors is explained by the properties of the wild type HIV-1 reverse transcriptase. J Biol Chem 2001; 276(52): 48725–32
Sluis-Cremer N, Arion D, Parniak MA. Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs). Cell Mol Life Sci 2000; 57: 1408–22
Naeger LK, Margot NA, Miller MD. Tenofovir (PMPA) is less susceptible to pyrophosphorolysis and nucleotide-dependent chain-terminator removal than zidovudine or stavudine. Nucleosides Nucleotides Nucleic Acids 2001; 20(4-7): 635–9
Huang H, Chopra R, Verdine GL, et al. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 1998; 282(5394): 1669–75
Hertogs K. The role of resistance testing technologies in drug development. Antiviral Drug Discovery and Development Summit. Princeton (NY): Strategic Research Institute, 2001
Boyer PL, Sarafianos SG, Arnold E, et al. The M184V mutation reduces the selective excision of zidovudine 5′-monophosphate (AZTMP) by the reverse transcriptase of human immunodeficiency virus type 1. J Virol 2002; 76(7): 3248–56
Schering Corporation. Physician’s Desk Reference, 56th ed. Montvale (NJ): Medical Economics Company, 2002: 3140–2
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958–65
Falk-Ytter Y, Kale H, Mullen DD, et al. Surprisingly small effect of antiviral treatment in patients with hepatitis C. Ann Intern Med 2002; 136(4): 288–92
Paillard F, Sterkers G, Vaquero C. Transcriptional and post-transcriptional regulation of TcR, CD4 and CD8 expression during activation of normal human T lymphocytes. EMBO J 1990; 250: 492–501
Patel P, Loeb LA. DNA polymerase active site is highly mutable: evolutionary consequences. Proc Natl Acad Sci U S A 2000; 97: 5095–100
Stubbe J, Ge J, Yee CS. The evolution of ribonucleotide reduction revisited. Trends Biochem Sci 2001; 26(2): 93–9
Markland W, McQuaid TJ, Jain J, et al. Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob Agents Chemother 2000; 44(4): 859–66
Fauci AS. Infectious diseases: considerations for the 21st century. Clin Infect Dis 2001; 32: 675–85
Li L, Faske SK, Daifuku R. Broad spectrum antiviral activity of a novel mutagenic ribonucleoside analog [abstract no F-1675]. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001; Chicago (IL). Washington (DC): American Society for Microbiology, 2001: 238
Bjelland S, Ånensen H, Knaevelsrud I, et al. Cellular effects of 5-formyluracil in DNA. Mutat Res 2001; 486: 147–54
Zhang Q-M, Miyabe I, Matsumoto Y, et al. Identification of repair enzymes for 5-formyluracil in DNA. J Biol Chem 2000; 275(45): 35471–7
Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci U S A 2001; 98(12): 6895–900
Cameron CE, Castro C. The mechanism of action of ribavirin: lethal mutagenesis of RNA virus genomes mediated by the viral RNA-dependent RNA polymerase. Curr Opin Infect Dis 2001; 14: 757–64
Storer R, Ashton CJ, Baxter AD, et al. The synthesis and antiviral activity of 4-fluoro-l-D-ribofuranosyl-lH-pyrazole-3-carboxamide. Nucleosides Nucleotides 1999; 18(2): 203–16
Maag D, Castro C, Hong Z, et al. Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J Biol Chem 2001; 276(49): 46094–8
Pariente N, Sierra S, Lowenstein PR, et al. Efficient virus extinction by combination of a mutagen and antiviral inhibitors. J Virol 2001; 75(20): 9723–30
Moriyama K, Otsuka C, Loakes D, et al. Highly efficient random mutagenesis in transcription-reverse-transcription cycles by a hydrogen bond ambivalent nucleoside 5′-triphosphate analogue: potential candidates for selective antiretroviral therapy. Nucleosides Nucleotides Nucleic Acids 2001; 20(8): 1473–83
Acknowledgements
I wish to acknowledge the work of the staff of Koronis Pharmaceuticals and, in particular, Drs A. Gall, K. Harris, L. Li and D. Sergueev, without whom this article would not have been possible. Koronis Pharmaceuticals has a worldwide exclusive licence from the University of Washington for patents related to Selective Viral Mutagenesis™ technologies.
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Daifuku, R. Stealth Nucleosides. BioDrugs 17, 169–177 (2003). https://doi.org/10.2165/00063030-200317030-00003
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DOI: https://doi.org/10.2165/00063030-200317030-00003