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Open AccessArticle

Quinolinecarboxamides Inhibit the Replication of the Bovine Viral Diarrhea Virus by Targeting a Hot Spot for the Inhibition of Pestivirus Replication in the RNA-Dependent RNA Polymerase

1
KU Leuven University, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Herestraat 49, B-3000 Leuven, Belgium
2
Bio-Cheminformatics Research Group and Escuela de Ciencias Físicas y Matemáticas, Universidad de Las Americas, 170150 Quito, Ecuador
3
Institut für Pharmazie, Abteilung Pharmazeutische Chemie, Universität Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria
4
KU Leuven University, Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Herestraat 49, B-3000 Leuven, Belgium [email protected]
5
KU Leuven, Division Animal and Human Health Engineering, Laboratory for host pathogen interactions, Kasteelpark Arenberg 30, 3001 Leuven, Belgium
*
Author to whom correspondence should be addressed.
Academic Editor: Antonio Carta
Molecules 2020, 25(6), 1283; https://doi.org/10.3390/molecules25061283
Received: 31 January 2020 / Revised: 6 March 2020 / Accepted: 10 March 2020 / Published: 12 March 2020
(This article belongs to the Special Issue Antiviral Agents)
The bovine viral diarrhea virus (BVDV), a pestivirus from the family of Flaviviridae is ubiquitous and causes a range of clinical manifestations in livestock, mainly cattle. Two quinolinecarboxamide analogues were identified in a CPE-based screening effort, as selective inhibitors of the in vitro bovine viral diarrhea virus (BVDV) replication, i.e., TO505-6180/CSFCI (average EC50 = 0.07 µM, SD = 0.02 µM, CC50 > 100 µM) and TO502-2403/CSFCII (average EC50 = 0.2 µM, SD = 0.06 µM, CC50 > 100 µM). The initial antiviral activity observed for both hits against BVDV was corroborated by measuring the inhibitory effect on viral RNA synthesis and the production of infectious virus. Modification of the substituents on the quinolinecarboxamide scaffold resulted in analogues that proved about 7-fold more potent (average EC50 = 0.03 with a SD = 0.01 µM) and that were devoid of cellular toxicity, for the concentration range tested (SI = 3333). CSFCII resistant BVDV variants were selected and were found to carry the F224P mutation in the viral RNA-dependent RNA polymerase (RdRp), whereas CSFCI resistant BVDV carried two mutations in the same region of the RdRp, i.e., N264D and F224Y. Likewise, molecular modeling revealed that F224P/Y and N264D are located in a small cavity near the fingertip domain of the pestivirus polymerase. CSFC-resistant BVDV proved to be cross-resistant to earlier reported pestivirus inhibitors (BPIP, AG110, LZ37, and BBP) that are known to target the same region of the RdRp. CSFC analogues did not inhibit the in vitro activity of recombinant BVDV RdRp but inhibited the activity of BVDV replication complexes (RCs). CSFC analogues likely interact with the fingertip of the pestivirus RdRp at the same position as BPIP, AG110, LZ37, and BBP. This indicates that this region is a “hot spot” for the inhibition of pestivirus replication. View Full-Text
Keywords: bovine viral diarrhea virus; RNA-dependent RNA polymerase; substituted quinolinecarboxamide inhibitors bovine viral diarrhea virus; RNA-dependent RNA polymerase; substituted quinolinecarboxamide inhibitors
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Musiu, S.; Castillo, Y.P.; Muigg, A.; Pürstinger, G.; Leyssen, P.; Froeyen, M.; Neyts, J.; Paeshuyse, J. Quinolinecarboxamides Inhibit the Replication of the Bovine Viral Diarrhea Virus by Targeting a Hot Spot for the Inhibition of Pestivirus Replication in the RNA-Dependent RNA Polymerase. Molecules 2020, 25, 1283.

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