Lethal mutagenesis of picornaviruses with N-6-modified purine nucleoside analogues

Antimicrobial Agents and Chemotherapy
Jason D GraciCraig E Cameron

Abstract

RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analog...Continue Reading

References

Oct 1, 1989·Journal of Virology·R F Baltera, D R Tershak
Nov 1, 1982·Analytical Biochemistry·A L Pogolotti, D V Santi
Nov 9, 1994·Molecular and Cellular Biochemistry·T W Traut
Feb 17, 1999·Proceedings of the National Academy of Sciences of the United States of America·L A LoebJ I Mullins
Jul 20, 2002·Virology·Jason D Graci, Craig E Cameron
May 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Julie K Pfeiffer, Karla Kirkegaard
Apr 13, 2004·Antiviral Chemistry & Chemotherapy·Jason D Graci, Craig E Cameron
May 10, 2005·The Journal of Biological Chemistry·Jamie J ArnoldCraig E Cameron
May 14, 2005·Antiviral Research·Kevin S HarrisRichard Daifuku
Jun 8, 2006·Annual Review of Biochemistry·Pär Nordlund, Peter Reichard
Jun 9, 2006·The Journal of General Virology·Ratree TakhampunyaRadhakrishnan Padmanabhan
Jan 5, 2007·Journal of Virology·J J BullC O Wilke
Mar 3, 2007·Bioorganic & Medicinal Chemistry Letters·Esmir GunicJean-Luc Girardet
Jun 6, 2007·Bioorganic & Medicinal Chemistry·Kathleen TooDavid Loakes
Aug 10, 2007·Journal of Virology·Jason D GraciCraig E Cameron

❮ Previous
Next ❯

Citations

Aug 7, 2013·Journal of Medicinal Chemistry·Laurent F BonnacSteven E Patterson
Oct 22, 2008·The Journal of Antimicrobial Chemotherapy·Tzu-Chun ChenShin-Ru Shih
May 6, 2009·Antimicrobial Agents and Chemotherapy·Tzu-Chun ChenShin-Ru Shih
Sep 4, 2009·Journal of Virology·Michael J DappLouis M Mansky
Dec 23, 2011·Journal of Virology·Jason D GraciCraig E Cameron
Jun 13, 2012·Microbiology and Molecular Biology Reviews : MMBR·Esteban DomingoCelia Perales
Jan 24, 2013·Virology Journal·Rei-Lin Kuo, Shin-Ru Shih
Jun 16, 2010·PLoS Computational Biology·Eamon B O'DeaClaus O Wilke
Aug 10, 2012·PLoS Computational Biology·C Scott Wylie, Eugene I Shakhnovich
Nov 17, 2009·PLoS Pathogens·Celia PeralesEsteban Domingo
Sep 11, 2008·Genetics·James J Bull, Claus O Wilke
Jul 22, 2009·Genetics·Peiqiu Chen, Eugene I Shakhnovich
Sep 4, 2009·Future Virology·Jason D Graci, Craig E Cameron
Feb 14, 2014·Journal of Biomedical Science·Chee Wah TanYoke Fun Chan
Jan 18, 2011·Antiviral Research·Heléne NorderRolf Hilgenfeld
Oct 12, 2010·Seminars in Cancer Biology·Edward J Fox, Lawrence A Loeb
May 29, 2012·Natural Resource Modeling·L J S AllenP van den Driessche
Sep 10, 2016·Scientific Reports·Fengwen XuFei Guo
Aug 8, 2014·Journal of Virology·Cheng-Lin DengBo Zhang
Nov 2, 2019·Science Translational Medicine·Saravanan GunaseelanJustin Jang Hann Chu
Jun 24, 2017·Annual Review of Virology·Kimi AzadJohn E Johnson

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.