TY - JOUR T1 - A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase. JF - Antiviral Res Y1 - 2009 A1 - Paeshuyse, Jan A1 - Letellier, Carine A1 - Froeyen, Matheus A1 - Dutartre, Hélène A1 - Vrancken, Robert A1 - Canard, Bruno A1 - De Clercq, Erik A1 - Gueiffier, Alain A1 - Teulade, Jean-Claude A1 - Herdewijn, Piet A1 - Puerstinger, Gerhard A1 - F. Koenen A1 - Pierre Kerkhofs A1 - Baraldi, Pier Giovanni A1 - Neyts, Johan KW - Amino Acid Substitution KW - Animals KW - Antiviral Agents KW - Benzodioxoles KW - Cattle KW - Cell Line KW - Diarrhea Virus 1, Bovine Viral KW - Diarrhea Virus 2, Bovine Viral KW - Drug Resistance, Viral KW - Hepacivirus KW - Inhibitory Concentration 50 KW - Models, Molecular KW - Mutation, Missense KW - RNA Replicase KW - triazoles KW - Viral Proteins KW - Virus Replication KW - Yellow fever virus AB -

[7-[3-(1,3-Benzodioxol-5-yl)propyl]-2-(2-furyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] (LZ37) was identified as a selective inhibitor of in vitro bovine viral diarrhea virus (BVDV) replication. The EC(50) values for inhibition of BVDV-induced cytopathic effect (CPE) formation, viral RNA synthesis and production of infectious virus were 4.3+/-0.7microM, 12.9+/-1microM and 5.8+/-0.6microM, respectively. LZ37 proved inactive against the hepatitis C virus and the flavivirus yellow fever. LZ37 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carried the F224Y mutation in the viral RNA-dependent RNA polymerase (RdRp). LZ37 showed cross-resistance with the imidazopyrrolopyridine AG110 [which selects for the E291G drug resistance mutation] as well as with the imidazopyridine BPIP [which selects for the F224S drug-resistant mutation]. LZ37 did not inhibit the in vitro activity of purified recombinant BVDV RdRp. Molecular modelling revealed that F224 is located near the tip of the finger domain of the RdRp. Docking of LZ37 in the crystal structure of the BVDV RdRp revealed several potential contacts including: (i) hydrophobic contacts of LZ37 with A221, A222, G223, F224 and A392; (ii) a stacking interaction between F224 side chain and the ring system of LZ37 and (iii) a hydrogen bond between the amino function of LZ37 and the O backbone atom of A392. It is concluded that LZ37 interacts with the same binding site as BPIP or VP32947 at the top of the finger domain of the polymerase that is a "hot spot" for inhibition of pestivirus replication.

VL - 82 CP - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19428605?dopt=Abstract M3 - 10.1016/j.antiviral.2009.02.192 ER -