A novel, highly selective inhibitor of pestivirus replication that targets the viral RNA-dependent RNA polymerase

Jan Paeshuyse, Pieter Leyssen, Eric Mabery, Nina Boddeker, Robert Vrancken, Matheus Froeyen, Israrul H. Ansari, Hélène Dutartre, Jef Rozenski, Laura H V G Gil, Carine Letellier, Robert Lanford, Bruno Canard, Frank Koenen, Pierre Kerkhofs, Ruben O. Donis, Piet Herdewijn, Julia Watson, Erik De Clercq, Gerhard PuerstingerJohan Neyts

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

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 pfaenotype 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 BVBV 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.

Original languageEnglish (US)
Pages (from-to)149-160
Number of pages12
JournalJournal of Virology
Volume80
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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    Paeshuyse, J., Leyssen, P., Mabery, E., Boddeker, N., Vrancken, R., Froeyen, M., Ansari, I. H., Dutartre, H., Rozenski, J., Gil, L. H. V. G., Letellier, C., Lanford, R., Canard, B., Koenen, F., Kerkhofs, P., Donis, R. O., Herdewijn, P., Watson, J., De Clercq, E., ... Neyts, J. (2006). A novel, highly selective inhibitor of pestivirus replication that targets the viral RNA-dependent RNA polymerase. Journal of Virology, 80(1), 149-160. https://doi.org/10.1128/JVI.80.1.149-160.2006