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Antimicrobial Agents and Chemotherapy, May 2009, p. 1850-1857, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.00934-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mutations in the Nonstructural Protein 3A Confer Resistance to the Novel Enterovirus Replication Inhibitor TTP-8307{triangledown}

Armando M. De Palma,1 Hendrik Jan Thibaut,1,{dagger} Lonneke van der Linden,2,{dagger} Kjerstin Lanke,2 Ward Heggermont,1 Stephen Ireland,3 Robert Andrews,3 Murty Arimilli,3 Taleb H. Al-Tel,3 Erik De Clercq,1 Frank van Kuppeveld,2 and Johan Neyts1*

Rega Institute for Medical Research, University of Leuven, B-3000 Leuven, Belgium,1 Department of Medical Microbiology, Radboud University Nijmegen, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands,2 Transtech Pharma, Inc., 4170 Mendenhall Oaks Parkway, High Point, North Carolina 272653

Received 15 July 2008/ Returned for modification 19 September 2008/ Accepted 19 January 2009

A novel compound, TTP-8307, was identified as a potent inhibitor of the replication of several rhino- and enteroviruses. TTP-8307 inhibits viral RNA synthesis in a dose-dependent manner, without affecting polyprotein synthesis and/or processing. Drug-resistant variants of coxsackievirus B3 were all shown to carry at least one amino acid mutation in the nonstructural protein 3A. In particular, three mutations located in a nonstructured region preceding the hydrophobic domain (V45A, I54F, and H57Y) appeared to contribute to the drug-resistant phenotype. This region has previously been identified as a hot sport for mutations that resulted in resistance to enviroxime, the sole 3A-targeting enterovirus inhibitor reported thus far. This was corroborated by the fact that TTP-8307 and enviroxime proved cross-resistant. It is hypothesized that TTP-8307 and enviroxime disrupt proper interactions of 3A(B) with other viral or cellular proteins that are required for efficient replication.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32(0)16-33-73-53. Fax: 32(0)16-33-73-40. E-mail: johan.neyts{at}rega.kuleuven.be

{triangledown} Published ahead of print on 23 February 2009.

{dagger} These two authors made equal contributions.

Antimicrobial Agents and Chemotherapy, May 2009, p. 1850-1857, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.00934-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Arita, M., Wakita, T., Shimizu, H. (2009). Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime. J. Gen. Virol. 90: 1869-1879 [Abstract] [Full Text]  


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