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Antimicrobial Agents and Chemotherapy, March 2008, p. 971-979, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01056-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues{triangledown} ,{dagger}

Jason D. Graci,1,{ddagger} Kathleen Too,3 Eric D. Smidansky,1 Jocelyn P. Edathil,2 Eric W. Barr,1 Daniel A. Harki,2,§ Jessica E. Galarraga,1 J. Martin Bollinger Jr.,1 Blake R. Peterson,2 David Loakes,3 Daniel M. Brown,3 and Craig E. Cameron1*

Department of Biochemistry and Molecular Biology,1 Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802,2 Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom3

Received 10 August 2007/ Returned for modification 1 October 2007/ Accepted 31 December 2007

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 analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis.

* Corresponding author. Mailing address: 201 Althouse Laboratory, University Park, PA 16802. Phone: (814) 863-8705. Fax: (814) 863-7024. E-mail: cec9{at}psu.edu

{triangledown} Published ahead of print on 7 January 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

{ddagger} Present address: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080.

§ Present address: California Institute of Technology, Division of Chemistry and Chemical Engineering, Pasadena, CA 91125.

Antimicrobial Agents and Chemotherapy, March 2008, p. 971-979, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01056-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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