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Journal of Virology, January 2006, p. 149-160, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.149-160.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Novel, Highly Selective Inhibitor of Pestivirus Replication That Targets the Viral RNA-Dependent RNA Polymerase

Jan Paeshuyse,1 Pieter Leyssen,1 Eric Mabery,2 Nina Boddeker,2 Robert Vrancken,3 Matheus Froeyen,1 Israrul H. Ansari,4 Hélène Dutartre,5 Jef Rozenski,1 Laura H. V. G. Gil,4 Carine Letellier,3 Robert Lanford,6 Bruno Canard,5 Frank Koenen,3 Pierre Kerkhofs,3 Ruben O. Donis,4 Piet Herdewijn,1 Julia Watson,2 Erik De Clercq,1 Gerhard Puerstinger,7 and Johan Neyts1*

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium,1 Gilead Sciences, Foster City, California,2 Veterinary and Agrochemical Research Centre, Ukkel, Belgium,3 Department of Veterinary and Biomedical Sciences, University of Nebraska—Lincoln, Lincoln, Nebraska,4 Laboratory AFMB-UMR 6098, Marseille, France,5 Department of Virology and Immunology, Southwest National Primate Research Center, and Southwest Foundation for Biomedical Research, San Antonio, Texas,6 Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Austria7

Received 27 June 2005/ Accepted 8 October 2005

We report on the highly potent and selective antipestivirus activity of 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP). The 50% effective concentration (EC50) for inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect formation was 0.04 ± 0.01 µM. Comparable reduction of viral RNA synthesis (EC50 = 0.12 ± 0.02 µM) and production of infectious virus (EC50 = 0.074 ± 0.003 µM) were observed. The selectivity index (ratio of 50% cytostatic concentration/EC50) of BPIP was ~2,000. BPIP was inactive against the hepatitis C virus subgenomic replicon and yellow fever virus but demonstrated weak activity against GB virus. Drug-resistant mutants were at least 300-fold less susceptible to BPIP than wild-type virus; showed cross-resistance to N-propyl-N-[2-(2H-1,2,4-triazino[5,6-b]indol-3-ylthio)ethyl]-1-propanamine (VP32947), and carried the F224S mutation in the viral RNA-dependent RNA polymerase (RdRp). When the F224S mutation was introduced into an infectious clone, the drug-resistant phenotype was obtained. BPIP did not inhibit the in vitro activity of recombinant BVDV RdRp, but did inhibit the activity of replication complexes (RCs). Computational docking revealed that F224 is located at the top of the finger domain of the polymerase. Docking of BPIP in the crystal structure of the BVDV RdRp revealed aromatic ring stacking, some hydrophobic contacts, and a hydrogen bond. Since two structurally unrelated compounds, i.e., BPIP and VP32947, target the same region of the BVDV RdRp, this position may be expected to be critical in the functioning of the polymerase or assembly of the RC. The potential of BPIP for the treatment of pestivirus and hepacivirus infections is discussed.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32-16-337341. Fax: 32-16-337340. E-mail: johan.neyts{at}rega.kuleuven.ac.be.

Journal of Virology, January 2006, p. 149-160, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.149-160.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Vrancken, R., Haegeman, A., Paeshuyse, J., Puerstinger, G., Rozenski, J., Wright, M., Tignon, M., Le Potier, M.-F., Neyts, J., Koenen, F. (2009). Proof of concept for the reduction of classical swine fever infection in pigs by a novel viral polymerase inhibitor. J. Gen. Virol. 90: 1335-1342 [Abstract] [Full Text]  
  • Paeshuyse, J., Chezal, J.-M., Froeyen, M., Leyssen, P., Dutartre, H., Vrancken, R., Canard, B., Letellier, C., Li, T., Mittendorfer, H., Koenen, F., Kerkhofs, P., De Clercq, E., Herdewijn, P., Puerstinger, G., Gueiffier, A., Chavignon, O., Teulade, J.-C., Neyts, J. (2007). The Imidazopyrrolopyridine Analogue AG110 Is a Novel, Highly Selective Inhibitor of Pestiviruses That Targets the Viral RNA-Dependent RNA Polymerase at a Hot Spot for Inhibition of Viral Replication. J. Virol. 81: 11046-11053 [Abstract] [Full Text]  


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