<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Musiu, Simone</style></author><author><style face="normal" font="default" size="100%">Pürstinger, Gerhard</style></author><author><style face="normal" font="default" size="100%">Stallinger, Sylvia</style></author><author><style face="normal" font="default" size="100%">Vrancken, Robert</style></author><author><style face="normal" font="default" size="100%">Andy Haegeman</style></author><author><style face="normal" font="default" size="100%">F. Koenen</style></author><author><style face="normal" font="default" size="100%">Leyssen, Pieter</style></author><author><style face="normal" font="default" size="100%">Froeyen, Mathy</style></author><author><style face="normal" font="default" size="100%">Neyts, Johan</style></author><author><style face="normal" font="default" size="100%">Paeshuyse, Jan</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Substituted 2,6-bis(benzimidazol-2-yl)pyridines: a novel chemical class of pestivirus inhibitors that targets a hot spot for inhibition of pestivirus replication in the RNA-dependent RNA polymerase.</style></title><secondary-title><style face="normal" font="default" size="100%">Antiviral Res</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Antiviral Res.</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">Antiviral Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">Benzimidazoles</style></keyword><keyword><style  face="normal" font="default" size="100%">Cattle</style></keyword><keyword><style  face="normal" font="default" size="100%">Cell Line</style></keyword><keyword><style  face="normal" font="default" size="100%">Classical swine fever virus</style></keyword><keyword><style  face="normal" font="default" size="100%">Diarrhea Virus 1, Bovine Viral</style></keyword><keyword><style  face="normal" font="default" size="100%">Drug Resistance, Viral</style></keyword><keyword><style  face="normal" font="default" size="100%">Enzyme Inhibitors</style></keyword><keyword><style  face="normal" font="default" size="100%">Hepacivirus</style></keyword><keyword><style  face="normal" font="default" size="100%">Models, Molecular</style></keyword><keyword><style  face="normal" font="default" size="100%">Mutation</style></keyword><keyword><style  face="normal" font="default" size="100%">Protein Conformation</style></keyword><keyword><style  face="normal" font="default" size="100%">Pyridines</style></keyword><keyword><style  face="normal" font="default" size="100%">RNA Replicase</style></keyword><keyword><style  face="normal" font="default" size="100%">Virus Replication</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2014</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2014 Jun</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">106</style></volume><pages><style face="normal" font="default" size="100%">71-9</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;2,6-Bis(benzimidazol-2-yl)pyridine (BBP/CSFA-0) was identified in a CPE-based screening as a selective inhibitor of the in vitro bovine viral diarrhea virus (BVDV) replication. The EC50-values for the inhibition of BVDV-induced cytopathic (CPE) effect, viral RNA synthesis and the production of infectious virus were 0.3±0.1μM, 0.05±0.01μM and 0.3±0.04μM, respectively. Furthermore, BBP/CSFA-0 inhibits the in vitro replication of the classical swine fever virus (CSFV) with an EC50 of 0.33±0.25μM. BBP/CSFA-0 proved in vitro inactive against the hepatitis C virus, that belongs like BVDV and CSFV to the family of Flaviviridae. Modification of the substituents on the two 1H-benzimidazole groups of BBP resulted in analogues equipotent in anti-BVDV activity (EC50=0.7±0.1μM), devoid of cytotoxicity (S.I.=142). BBP resistant BVDV was selected for and was found to carry the I261M mutation in the viral RNA-dependent RNA polymerase (RdRp). Likewise, BBP-resistant CSFV was selected for; this variant carries either an I261N or a P262A mutation in NS5B. Molecular modeling revealed that I261 and P262 are located in a small cavity near the fingertip domain of the pestivirus polymerase. BBP-resistant BVDV and CSFV proved to be cross-resistant to earlier reported pestivirus inhibitors (BPIP, AG110 and LZ37) that are known to target the same region of the RdRp. BBP did not inhibit the in vitro activity of recombinant BVDV RdRp but inhibited the activity of BVDV replication complexes (RCs). BBP interacts likely with the fingertip of the pestivirus RdRp at the same position as BPIP, AG110 and LZ37. This indicates that this region is a &quot;hot spot&quot; for inhibition of pestivirus replication.&lt;/p&gt;</style></abstract><custom1><style face="normal" font="default" size="100%">http://www.ncbi.nlm.nih.gov/pubmed/24680957?dopt=Abstract</style></custom1></record></records></xml>